Dear All What are the Antigen-Presenting Cells (APC) and how do they work? What is the percentage of B cells in the peripheral blood?
Professor Ahmed Halawa
Admin
3 years ago
Dear All
Of course B cells are important in the immune response to transplantation. It acts as antigen presenting cell and secrete antibodies. B cell interact with T cells also.
The question here What are the types of HLA presented by B cells and T cells? What is meant by B cell and T cell crossmatch?
B cells express both MHC I AND MHC II while T cells express only MHC I.
The crossmatch is essential step for determination of DSA. when using complement dependent technique, lymphocytes from the donor are added to recipipient’s serum which may contain antibodies against the host cells. but yo identify against which MHC (HLA) the antibodies are direct, there is initially separation of donor’s lymphocytes into CD 19+ <–>B and CD 3= <–>T cells. after mixing the recipients serum with the separated lymphocytes, complement is added with viability dye. so if there are DSA against MHC I , B and T lymphocytes will undergo lysis, If only against MHC II, only B cells will undergo lysis, if absent -no DSAs are present.
HLA class I are expressed on the surface of both B cells and T cells; On the other hand, HLA class II expression is restricted to B cells. A positive B cell cross match demonstrates the presence of HLA class I and/or HLA class II antibodies, but a positive T cell crossmatch determines the presence of HLA class I antibodies. So, if the B cell cross match is positive and the T cell cross match is negative, we can conclude there are HLA class II antibodies. On the other hand, since B cells express a higher amount of class I HLA antigens, a positive B cell cross match concomitant with a negative T cell cross match may indicate low levels of class I antibodies.
T cell has class I HLA which is expressed in all nucleated cells
B cell has class I and II HLA….class II is expressed in APCs (antigen presenting cells).
T cell crossmatch positive means antibodies antibodies against class I
B cell crossmatch positive means antibodies against class I or II
B cell crossmatch has much false positive results because it may be related to B cell viability , also antibodies against class II HLA are less likely to induce hyperacute rejection than class I antibodies
so T cell crossmatch is more linked to hyperacute rejection ; if positive , should take it seriously and will go for desensitization protocol.
WILLIAM R MULLEY, JOHN KANELLIS. Understanding crossmatch testing in organ transplantation: A case-based guide for the general nephrologist. Nephrology16(2011)125–133.
What are the types of HLA presented by B cells and T cells?
HLA Class I are present on all nucleated cells, hence present on both B cell and T cell.
HLA Class II is present on antigen presenting cells (e.g. B cells).
So, B cells present both class I and class II, while T cells present class I.
What is meant by B cell and T cell crossmatch?
Crossmatch includes T cell crossmatch and B cell crossmatch.
T cell crossmatch: If positive, Implies presence of HLA class I antibodies
B cell crossmatch: If positive, implies presence of HLA class I or Class II antibodies.
If B cell cross match is positive, with T cell Crossmatch positive: Either class I alone or class I and II antibodies present.
If B cell cross match is positive, with T cell Crossmatch negative: Class II antibodies or low level of class I antibodies (as B cells express higher levels of class I antigens) (1,2)
Reference: 1)Pellegrino MA, Belvedere M, Pellegrino AG, et al. B peripheral lymphocytes express more HLA antigens than T peripheral lymphocytes, Transplantation 1978;25:93-95. 2) Mulley WR, Kanellis J. Understanding crossmatch testing in organ transplantation: a case based guide for the general nephrologist. Nephrology 2011;16:125-133.
B cells express both class I & II HLA
T cells express class I HLA
Positive B cell crossmatch indicate the presence of class II HLA ab & to lesser extent class I HLA ab
Positive T cell crossmatch indicate the presence of class I HLA ab
T cell and B cell +XM
T lymphocytes express HLA class I and B lymphocytes HLA class I and II.
DSA directed against HLA class I give rise to a +T and +B cell XM.
Since HLA class I is expressed by all nucleated cells (e.g. graft EC and RTEC), there has been broad agreement that a +T cell XM prohibits transplantation.
• Only B cells express HLA class II. Therefore a B+/T– XM may indicate the presence of HLA class II DSA • B cells may express HLA class I at higher levels than T cells
. Thus a B+/T– XM may reflect low levels of HLA class I DSA
• B cells express cell surface Ig and Fc receptors. For this reason circulating immune complexes and autoantibodies may give rise to a false positive B cell XM, particularly by flow cytometry (FC). In these circumstances no DSA would be detectable by solid phase assay.
False + B-cell XM (no detectable DSA – >50% of +B-cell XM in some reports) do not ↑risk of poor outcomes.
HLA-class I antigens are expressed on T cells and B cells, and some but not all studies
suggest that the cell surface expression of HLA-class I antigens is higher on B than T cells.
HLA-class II antigens are expressed on B cells but not on resting T cells
Thus, a T+B+ FCXM, rather than a T+B-, is the expected result in the presence of HLA-
class I antibodies.
A T-B+ FCXM is the anticipated result in the presence of HLA-class II antibodies only
since HLA-class II antigens are expressed on B cells but not on resting T cells
Antigen-presenting cells:
Antigen-presenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells.
Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.
percentage of B cells in the peripheral blood 5-10%.
the primary antigen presenting cells are macrophages , dendritic cells and B lymphocytes , they have four primary functions
1-monitor the intracellular and extracellular environment
2-processing antigens by specific pathway
3-transporting the antigens from tissues to the peripheral lymphoid organs for interaction with T-cells.
4-provide activating signals to stimulate CD8 + cytotoxic T cell resulting in killing the intercellular pathogens like viruses also APCs activate c4+helper cells leading to specific AB production and humoral immune response this type of immune response important in defense against extracellular bacteria , parasites and allergic disease
5- T-cell priming and cross priming which reflect the cooperation between T-cells and B cells , as antigen presentation by B cells plays critical role in the development of acute humoral response through the MHC class 2 restricted pathway
the understanding of the critical role of the APC for normal immune response as well as their response to pathogenesis with in infection , autoimmune , allergic response , organ and tissue rejection this help in the developing of APC cell – based cancer immunotherapy , vaccination ,biological agents like abatacept that block costimulation by APCS , rituximab , B lymphocyte CD20 depleting agent.
sorry my previous contribuation to the below Questions and the second part regarding the % of lymphocytes in the peripheral blood its in the range of 8-33% of WBC count in adult .
What are the Antigen-Presenting Cells (APC) and how do they work? What is the percentage of B cells in the peripheral blood?
*HLA Class I are presented on all nucleated cells, so it present on both B cell and T cell.
HLA Class II is present on antigen presenting cells APCs like B cells.
So that B cells present in both class I and class II, but T cells present class I.
What is meant by B cell and T cell crossmatch?
Crossmatch includes T cell crossmatch and B cell crossmatch.
Positive T cell crossmatch reflects presence of HLA class I antibodies.
Positive B cell crossmatch reflects presence of HLA class I or Class II antibodies.
When B cell cross match is positive, with T cell Crossmatch positive this meant that it will be class I alone or class I and II antibodies present.
When B cell cross match is positive, with T cell Crossmatch negative this meant that it will be Class II antibodies or low level of class I antibodies (as B cells express higher levels of class I antigens despite Tcells )
What is the percentage of B cells in the peripheral blood?
5-10%
What are the Antigen-Presenting Cells (APC) and how do they work?
Classical antigen presenting cells (APCs) are dendritic cells (DCs) and B cells . To mount an immune response, APCs must first recognize and bind their target. To do so, APCs express antigen-specific surface receptors including pattern recognition receptors (PRRs).
PRRs detect pathogen-associated molecular patterns (PAMPs), which are produced by microbes, and damage-associated molecular patterns (DAMPs), which are produced by damaged or mutated host cells (1).
One major family of PRR is the Toll-like receptors (TLRs). TLRs are typically expressed on the cell surface or within endosomes and are type I transmembrane proteins whose extracellular domains express leucine-rich repeats that are used to recognize and bind to specific PAMPs (14–16). Once the extracellular domain binds its target, the TLR activates a cytosolic signaling cascade which is initiated by an adaptor protein that interacts with the intracellular domain of the TLR. Depending on the TLR, the two adaptor sets that can be activated are TIRAP-MyD88 and TRAM-TRIF .
Another group of PRR is the nucleotide binding oligomerization domain (NOD)-like receptors (NLRs). NLRs are present in the cytoplasm and, like TLRs, initiate signaling cascades upon binding to microbial PAMPs .
After binding to their appropriate PAMP or DAMP, APCs internalize their target by initiating phagocytosis, pinocytosis, or clathrin-mediated endocytosis. The pathway by which molecules are endocytosed determines how they will be degraded and then displayed by major histocompatibility complex (MHC) for T cell recognition 2.
1 ten Broeke T, Wubbolts R, Stoorvogel W. MHC class II antigen presentation by dendritic cells regulated through endosomal sorting. Cold Spring Harb Perspect Biol. (2013) 5:a016873.
2 Fukata M, Vamadevan AS, Abreu MT. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Semin Immunol. (2009) 21:242–53.
What are the types of HLA presented by B cells and T cells?
What is meant by B cell and T cell crossmatch?
HLA class I are expressed on all nucleated cells including B cells and T cells but B cells shows a high number of class I HLA antigens than T cells .
HLA class II is expressen only ob APCS including B cells surface .
positive T cell crossmatch means presence of HLA class I antibodies only .
positive B cell cross match means the presence of both of HLA classes or one of them but
if the B cell cross match is positive and the T cell cross match is negative, it means there are HLA class II antibodiesonly or with low levels of class I antibodies.
Last edited 3 years ago by Shereen Yousef
Abdulrahman Ishag
3 years ago
B-cells participate in the cellular immunity through the following;
-act as Ag presenting cells, they present the Ag to the T-cells, lead to their activation with subsequent graft damage(CMR).
-they secret cytokines (IL2 &TNFa),that activate T-cells.
B-cells play a major role in humeral immunity through ;
-they differentiate into plasma cells, secret antibodies leading to (AMR)
B-cells ( regulator ) have a role in immunological tolerance ,as they can suppress others B-cells .
B-cells can differentiate into memory B cells, can induce memory response once reactivated.
Reference: 1- Pouliquen E, Koenig A, Chen CC, et al. Recent advances in renal transplantation: antibody-mediated rejection takes center stage. F1000Prime Rep 2015; 7: 51. 2- William Hoffman, Fadi G. Lakkis, and Geetha Chalasani B Cells, Antibodies, and More Clin J Am Soc Nephrol 11: 137–154, 2016. doi: 10.2215/CJN.09430915
Ahmed Ziada
3 years ago
B cell responsible for Anti-body production and plasma cell proliferation which lead to antibody mediated projection and sensitization
Ahmed Omran
3 years ago
HLA class I Ags are expressed on the surface of both B &T cells; but HLA class II Ags are expressed on B cells .A positive B cell cross XM denotes presence of HLA class I and/or HLA class II antibodies, but a positive T cell XM denotes presence of HLA class I antibodies. So, if the B cell XM is positive and the T cell XM is negative, that denotes that there are HLA class II antibodies. As B cells express a higher amount of class I HLA antigens, a positive B cell cross match with a negative T cell cross match may denote low levels of class I antibodies.
B cells are related to plasma cell production &antibody formation essentially responsible for humoral immunity; leading to ABMR and sensitization.
REFERENCES
Danovitch, GM; Handbook of kidney transplantation, Sixth edition,2018
Hamdy Hegazy
3 years ago
What is the role of B cells in transplantation? Functions of B-cells include: 1- Antibodies production. 2- Thymocytes maturation into T-cells. 3- Lymphoid organogenesis. 4- T-Cell tolerance. 5- Regulatory B cells immunosuppressive effect via IL10, IL35, TGF-B. 6- B-cells express HLA-I and HLA-II, however T-cells express only HLA-I. B- lymphocytes play an important role in kidney transplant rejection. So, B-cell positive cross match means presence of antibodies against either HLA-I or HLA-II. What is the percentage of B cells in the peripheral blood? 2-10 % of peripheral blood cells. What are the Antigen-Presenting Cells (APC) and how do they work?
An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material; they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, thus functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs.
After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome. Within the phagolysosome, the components are broken down into fragments; the fragments are then loaded onto MHC class I or MHC class II molecules and are transported to the cell surface for antigen presentation. Note that T lymphocytes cannot properly respond to the antigen unless it is processed and embedded in an MHC II molecule. APCs express MHC on their surfaces, and when combined with a foreign antigen, these complexes signal a “non-self” invader. Once the fragment of antigen is embedded in the MHC II molecule, the immune cell can respond. Helper T- cells are one of the main lymphocytes that respond to antigen-presenting cells. Recall that all other nucleated cells of the body expressed MHC I molecules, which signal “healthy” or “normal.” Reference: · Biology 2e. Provided by: OpenStax. Located at: http://cnx.org/contents/185cbf87-c72e-48f5-b51e-f14f21b5eabd@10.8. License: CC BY: Attribution. License Terms: Access for free at https://openstax.org/books/biology-2e/pages/1-introduction
Mahmoud Hamada
3 years ago
What are the Antigen-Presenting Cells (APC) and how do they work?
APC are mainy three categories:
Macrophages
Dentritic cells
B- lymphocytes.
What is the percentage of B cells in the peripheral blood? 15-20%
Wael Hassan
3 years ago
B cell responsible for plasma cell production and AB formation .
Mainly responsible fo humoral immunity
So it’s role in transplantation that it make AB lead to AMR and sensitization
Abdullah Raoof
3 years ago
b cell are responsible for antibody production therefor is responsible for AMR .
CREFULL CROSMATCH ( fo patient serum with donor Ag ) was resposible of elimination of this complication.
anti ABO Ab and anti HLA Ab ( especially DSA ) are important in this field .
B cell activation needs Ag presentation by T cells . the Ag attach to b cell recepter then internalized and degraded to peptide . this peptide is expressed in ( ag- MHC) complex in the cell wall which activate t cell. the resultant of this activation is plasma cell ( Ab factory ) in the bone marrow and the memeory cell ( cd 27 positive ) in secondary lymphoid tissue . the IgM ab HAS LOW ( MINIMUM ) ROLE IN KIDNEY TRANSPLANTATION ( LOW AFFINITY AB WHLE the IG g ab ( high affinity ) has important role in transplantation .
Targeting B Lymphocytes and Plasma Cells in Transplantation
Since all human B lymphocytes express the surface marker CD20, monoclonal antibodies against CD20 (Rituximab)
are quite effective at depleting B lymphocytes in the circulation and to a lesser extent in lymphoid organs.
Plasma cells, however, do not express CD20, THEREFORE IT IS NOT EFFECTIVE in treatment of AMR .
proteasome inhibitors, IS USED IN THE TREATMENT OF AMR AND SENSITIZED PATIENT .
Finally, B-lymphocyte depletion at the time of transplantation can increase the incidence of
acute rejection because of nonselective depletion of both pathogenic and regulatory B lymphocytes.
Abdulrahman Ishag
3 years ago
Functions of B cell in transplantation
B-cells participate in the cellular immunity through the following;
-act as Ag presenting cells, they present the Ag to the T-cells, lead to their activation with subsequent graft damage(CMR).
-they secret cytokines (IL2 &TNFa),that activate T-cells.
B-cells play a major role in humeral immunity through ;
-they differentiate into plasma cells, secret antibodies leading to (AMR)
B-cells ( regulator ) have a role in immunological tolerance ,as they can suppress others B-cells .
B-cells can differentiate into memory B cells, can induce memory response once reactivated. Reference: 1- Pouliquen E, Koenig A, Chen CC, et al. Recent advances in renal transplantation: antibody-mediated rejection takes center stage. F1000Prime Rep 2015; 7: 51. 2- William Hoffman, Fadi G. Lakkis, and Geetha Chalasani B Cells, Antibodies, and More Clin J Am Soc Nephrol 11: 137–154, 2016. doi: 10.2215/CJN.09430915
Ben Lomatayo
3 years ago
B cells expresses HLA I & HLA II
B cells involved in crossmatch test
B cells mediates hyper-acute rejection & Chronic AMR
B cell is important component of immunologic memory
B cell is therapeutic target e.g. use of RTX , proteasome inhibitors, IVIG
Many other roles
Ahmed mehlis
3 years ago
●What are the types of HLA presented by B cells and T cells?
HLA presented b cells class 1/11
HLA presented by T cells class 1 only
●What is meant by B cell and T cell crossmatch?
If positive crossmatch for both B and T cells this means that HlA type 1 and type present .
But if possible B positive cross match and negative T crossmatch,
This means HLA type 2 only present.
●Antigen-presenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells. Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.
●
What is the percentage of B cells in the peripheral blood?
Up to 10 % in prepheral blood
Shereen Yousef
3 years ago
B cells and their downstream effector plasma cells (PCs) play a major role in acute and chronic ABMR [1].
Memory B cells rapidly differentiate to PCs following a secondary anamnestic response [2].
Post-transplant donor-specific antibody (DSA) and de novo DSA (dnDSA) are major risk factors and barriers to long-term stable graft survival .
Once DSA develops, almost 40% of affected patients lose their graft in contrast to patients with no dnDSA [3].
patients with preformed DSA, who comprise 40% of transplant waitlists, showed higher risk of rejection, either acute or chronic antibody-mediated rejection (ABMR) [4]. Alloantibody is also a major barrier to transplant tolerance.
Accommodation
Recent studies have shown that 30% of nonsensitized patients develop de novo DSA post-transplantation without demonstrating clinical signs of rejection [5]. This condition is referred to as accommodation [78,79]. Accommodation describes a biologic state in which grafts function despite noxious stimuli, like alloantibodies, against them.
B cells as antigen-presenting cells
Although chronic rejection is commonly considered an antibody-mediated process, Zeng et al. [6] have provided evidence that B cells are capable of promoting chronic rejection independently of antibody production.
Noorchasm and colleagues reported that indirect alloantigen presentation by recipient B cells plays a critical role in the activation of alloreactive CD4+ T cells [7]
cells may contribute to allograft rejection independently of antibody production by shaping the T-cell response through a combination of antigen presentation, cytokine production, and costimulation [8].
Additionally, one important role of B cells may include supporting the basic architecture of lymphoid tissue to allow optimal interaction between T cells, dendritic cells, and other components of the immune response [9].
B cells may play a pivotal role in the induction and maintenance of transplant tolerance [10].
Regulatory B cells (Bregs) have proven their importance in controlling immunity
Bregs function through IL-10 and through secretion of other cytokines (TGF-β, IL-35) to suppress CD4+ T-cell proliferation, suppress CD8+ effector T-cell function, induce T-cell apoptosis through binding the FAS and PD-1 receptors, induce Tregs, suppress antigen-presenting and cytokine secretion by dendritic cells and M1 macrophages, and suppress natural killer (NK) cells and neutrophils [11].
Reference
1 Clatworthy MR, Targeting B. Cells and antibody in transplantation. Am J Transplant 2011; 11: 1359.
2 Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol 2015; 15: 149.
3 Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant 2015; 15: 2921.
4 Lefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol 2010; 21: 1398.
5 Gill JS, Landsberg D, Johnston O, et al. Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection. Transplantation 2010; 89: 178.
6 Zeng Q, Ng YH, Singh T, et al. B cells mediate chronic allograft rejection independently of antibody production. J Clin Invest 2014; 124: 1052.
7 Noorchashm H, Reed AJ, Rostami SY, et al. B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J Immunol 2006; 177: 7715.
8 Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol 2010; 10: 236.
9 Nolte MA, Arens R, Kraus M, et al. B cells are crucial for both development and maintenance of the splenic marginal zone. J Immunol 2004; 172: 3620.
10. Chong AS, Sciammas R.Matchmaking the B-cell signature of tolerance to regulatory B cells. Am J Transplant 2011; 11: 2555.
11 Peng B, Ming Y, Yang C. Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation. Cell Death Dis 2018; 9: 109
Theepa Nesam
3 years ago
What are the Antigen-Presenting Cells (APC) and how do they work?
Antigen presenting cells (APC)
CD4 activation requires presentation of antigen of MHC-2 and the role carried out by APC
Examples of APC – B cells, Dendritic Cells (DC) , macrophages, activated human endothelial cells but DC is the most potent APC
DC present in all organs that are transplanted and in secondary lymphoid organs
Expression of CD11c and MHC-2 are useful markers to recognise classical DC in human tissues
After transplantation, DC cells migrate out of the organ( transplanted) into blood stream and will recognise recipient lymphoid system in which they interact and stimulate immune response
Mechanisms of antigen presentation by Dc in Alloimmunity
Donor tissue-resident DCs and shed antigens from transplanted allograft together activate recipient T cells for alloimmunity
Direct antigen presentation – migrating donor derived DCs within local lymphoid tissue
Semi direct antigen presentation -shed allo- MHC /peptide exosomes being acquired by recipient Dcs for presentation to recipient T cells
What is the percentage of B cells in the peripheral blood
Lymphocytes in human circulating blood are approximately 80 to 90 percent T cells and 10 to 20 percent B cells
References
Knechtle, S., n.d. Kidney Transplantation: Principles and Practice.
Theepa Nesam
3 years ago
B cell functions and its role in transplantation
Role of B cell
B cells is always called as antibody secreting cells but they are multifunctional leukocyte population.
B cells can act as Antigen presenting cells because they express and co stimulators molecules such as CD40.
As APC, B cells engage T cells via TCR and vocal stimulatory molecules which in turn creates a cel cluster that enables cytokines secreted by T cell to influence B cell activation, differentiation and antibody production.
B cell express complement receptors, so can interact with complement coated damaged cells, facilitating antigen presentation and induces regulation of adaptive immunity
B cells mostly T cell dependant for activation and antibody production and encounter antigen in secondary lymphoid tissue
B cell and its role in Antibody mediated rejection (AMR)
B cells may be contributing to rejection process as B cells, B cell clusters and B cell, those have been described as being present in immunosuppression free transplantation recipient that showed operational tolerance to donor alloantigens
B cell may have the ability to regulate the alloimmunity response depending on the specific circumstances in transplantation recipient
Mechanism
When B cell encounter an antigen, it bind their surface BCR – may either develop into short lived germ line encoded antibody or becoming center B cell
Then, B cell divide and mutate region genes ( somatic hyper stimulation) to produce antibody with a higher affinity for antigen
B cell also undergo class switching the heavy chain present in antibody changes from mu to other isotypes
When multiple division and hyper stimulation happens, B cells with high affinity BCR are positively selected and differentiation into either B cell or plasma cells
Tfh after engaged by germinal centre which presented antigen to them , stimulating progress of GC reaction and development of memory B cell(CD27) and plasma cells
Small proportion of plasma cells arising from GC become long lived plasma cells in bone marrow
References
Knechtle, S., n.d. Kidney Transplantation: Principles and Practice.
AMAL Anan
3 years ago
~An antigen-presenting cell or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.
~Almost all cell types can present antigens in some way. They are found in a variety of tissue types. Professional antigen-presenting cells, including macrophages, B cells and dendritic cells, present foreign antigens to helper T cells, while virus-infected cells (or cancer cells) can present antigens originating inside the cell to cytotoxic T cells. In addition to the MHC family of proteins, antigen presentation relies on other specialized signaling molecules on the surfaces of both APCs and T cells.
Antigen-presenting cells are vital for effective adaptive immune response, as the functioning of both cytotoxic and helper T cells is dependent on APCs. Antigen presentation allows for specificity of adaptive immunity and can contribute to immune responses against both intracellular and extracellular pathogens. It is also involved in defense against tumors. Some cancer therapies involve the creation of artificial APCs to prime the adaptive immune system to target malignant cells.
~ Antigen-presenting cells fall into two categories: professional and non-professional. Those that express MHC class II molecules along with co-stimulatory molecules and pattern recognition receptors are often called professional antigen-presenting cells.The non-professional APCs express MHC class I molecules.
Professional APCs specialize in presenting antigens to T cells. They are very efficient at internalizing antigens, either by phagocytosis (e.g. macrophages), or by receptor-mediated endocytosis (B cells), processing the antigen into peptide fragments and then displaying those peptides (bound to a class II MHC molecule) on their membrane. The T cell recognizes and interacts with the antigen-class II MHC molecule complex on the membrane of the antigen-presenting cell.
The main types of professional antigen-presenting cells are dendritic cells, macrophages and B cells.
~Non-professional antigen presenting cells include all nucleated cell types in the body. They use an MHC class I molecule coupled to beta-2 microglobulin to display endogenous peptides on the cell membrane. These peptides originate within the cell itself, in contrast to the exogenous antigen displayed by professional APCs using MHC class II molecules.
References:
***Kambayashi T, Laufer TM (November 2014). “Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell?”. Nature Reviews. Immunology. 14 (11): 719–30. doi:10.1038/nri3754. PMID 25324123. S2CID 22184839.
***den Haan JM, Arens R, van Zelm MC (December 2014). “The activation of the adaptive immune system: cross-talk between antigen-presenting cells, T cells and B cells”. Immunology Letters. 162 (2 Pt B): 103–12. doi:10.1016/j.imlet.2014.10.011. PMID 25455596.
***Hivroz C, Chemin K, Tourret M, Bohineust A (2012). “Crosstalk between T lymphocytes and dendritic cells”. Critical Reviews in Immunology. 32 (2): 139–55.
Mahmoud Rabie
3 years ago
Previously, it was thought that T cells are the corner stone of graft rejections, but nowadays the interest in the role of B cells increased markedly.
In the indirect way to recognize the allograft, the B cells act as APCs and represent the donor antigens to the recipient T cells triggering the rejection process.
B cells activity in renal transplantation can be detected by markers such as C4d deposition in peritubular capillaries and the presence of DSAs in the patient circulation.
CDC cross matching is done by mixing the patient serum with the donor lymphocytes.
If CDC T cells crossmatch is positive , it means that the recipient have antibodies against HLA class l antigen, while if CDC B cells is positive, it means that he has antibodies against both class I and class II antigens.
What is the role of B cells in transplantation
B cell are subtype of adaptive immunity
B cell recognize antigen by b cell receptors (antibody itself) presented to it by follicular tcell in the 2ry lymphoid organs differentiate to plasma cell (effector b cell) which secrets the antibodies which results in ABMR (acute and chronic) which identified in the pathology by microvascular inflammation (PTC and G) plus C4d stain in PTC and TMA
And identified in the serum by circulating DSA
Role of B cell is not restricted on antibodies formation it also act as APC as it has MHC class 2 and present antigens to Tcell so play role in Tcell mediated rejection
B cell is divided into subtypes(Naïve,effector which is plasma cell, memory, regulatory)
Breg secrets IL10 which plays important role in tolerance and identification of transcriptional signature had been seen in tolerant patients which showed upregulation of b cell related genes
Target therapeutics targeting b cell
1)ATG depleting induction which produces both tcell and b cell lysis but it has been shown that it affect Breg and inhibit tolerance
2) rutiximab which anti CD20 on Naïve bcell not on effector (plasma cell)…so it shouldn’t be used alone as its functions limited only also its efficacy is limited due to anti rutiximab antibodies so CD19level it’s better to be measured
3) obnitozomab(gazyva) which is also CD20 but more potent than rutiximab and studies giving promising results but still on small size and lack of randomization
4)bortezomib which is antiplasma cell which theoretical was thought to be effective but results were disappointing
5)IVIG which is widely used and block BCR and antibodies and its very effective drug in both desensitization and treatment of ABMR
What are the Antigen-Presenting Cells (APC) and how do they work?
b cell , macrophages and denderitic cells
What is the percentage of B cells in the peripheral blood
Its around 5-10%0of total peripheral blood
References:
1- Schmitz R, Fitch ZW, Schroder PM, Choi AY, Jackson AM, Knechtle SJ, et al. B cells in transplant tolerance and rejection: friends or foes? Transpl Int. 2020;33(1):30–40.
2- Clatworthy MR. B-cell regulation and its application to transplantation. Transpl Int. 2014;27(2):117–28.
3- Karahan GE, Claas FHJ, Heidt S. B cell immunity in solid organ transplantation. Front Immunol.
Nasrin Esfandiar
3 years ago
Nowadays the role of Bcells are more prominent in kidney transplantation. Bcells can cause allograft rejection by producing alloantibodies, induction of Tcells trigger macrophages, Natural Killer cells and activating complement. The preformed antibody includes anti-ABO and also anti-HLA antibodies play a significant role in hyperacute rejection. After the transplantation, donor specific antibodies that were against HLA and sometimes even non-HLA antigens of donor, play a major part in chronic and acute ABMRs. Bcells became mature in secondary lymphoid organs, with the help of TFH. Ag is detected by Bcell Receptor and is internalized and transformed into peptides and is bounded to MHC class 2 at the surface of B lymphocytes and is detected by CD4+ T lymphocytes. T lymphocytes help this process by cytokines and costimulatory ligands. In germinal center, B cells are proliferated and transformed to plasma cells and memory Bcells. Memory Bcells react vigorously and fast in response to antigens that previously produced antibodies. Antibodies attached to donor antigens can induce antibody mediated rejection by complement activation and stimulation of NK cells and macrophages attaching FC reseptors. B cells can play role of antigen presenting cells and secret inflammatory cytokines like TNF-α. Immunomodulatory function of B regulatory cells (B regs) and secretion of IL-10 may play role in chronic rejection or reversely tolerance. Referances:
1. Dijke, E. I., Platt, J. L., Blair, P., Clatworthy, M. R., Patel, J. K., Kfoury, A. G., & Cascalho, M. (2016). B cells in transplantation. In Journal of Heart and Lung Transplantation (Vol. 35, Issue 6).
2. Schmitz, R., Fitch, Z. W., Schroder, P. M., Choi, A. Y., Jackson, A. M., Knechtle, S. J., & Kwun, J. (2020). B cells in transplant tolerance and rejection: friends or foes? In Transplant International (Vol. 33, Issue 1).
Alyaa Ali
3 years ago
Beside producing antibodies , B cells can regulate cellular immunity and can contribute to the genesis of tolerance , B cell response is one of obstacles for transplantation .
B cells triggers humoral immunity ( antibody mediated rejection ) through formation of donor specific antibodies against HLA antigens . response of B cells to antigens:
if the antigen is foreign polysaccharides such as blood group , the response will be T cell independent , but if the antigen is foreign proteins such as HLA antigen that need T cell help. B-cell responses to proteins manifest both memory of and progressive increase in affinity of the B-cell receptor to the antigen and this occur due to mutations in the variable regions of immunoglobulin genes followed by selection and survival of the mutated B cells that compete more effectively for antigen and T-cell help( affinity maturation) these form memory B cells then they can be differentiated to plasma cells. they lead to acute and chronic antibody mediated rejection , transplant tolerance Dijke, Esme I et al. “B cells in transplantation.” The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation vol. 35,6 (2016): 704-10. .
Assafi Mohammed
3 years ago
The role of B cells in transplantation:
B cells, besides producing antibodies ,it can also regulate cellular immunity, contribute to the genesis of tolerance and induce accommodation.
Humoral immunity has been considered the preeminent immune barrier to transplantation for many decades.
Allotransplantation evokes production of donor-specific antibodies (DSAs) which play a major role beside a genetic locus ,the major histocompatibility complex [MHC].This genetic locus(MHC) was shown to govern acceptance and rejection of transplants.
The complicated relationship between antibodies and graft outcome became still more complex by the observations of Mitchison* who showed that administration of cytotoxic antibodies even in large quantities failed to cause rejection, whereas transfer of cells led to rejection. Finally, around the time of Gorer’s death, Szenberg and Warner** reported that rejection of grafts was sometimes caused by cells associated with the thymus, later called T cells, and that antibodies arise from cells arising from a distinct origin, ultimately called B cells. {*:Passive transfer of transplantation immunity.MITCHISON NA Nature.1953 Feb 7;171(4345):267-8.}{**: Szenberg A, Warner NL. Dissociation of immunological responsiveness in fowls with a hormonally arrested development of lymphoid tissues. Nature. 1962;194:146–147.}
Besides producing antibodies, B cells enable lymphoid organogenesis.
B cells promote the development of dendritic cells, which serve as antigen-presenting cells, in secondary lymphoid tissues.
T cells have long been known to provide help for B cells, but only more recently has it been apparent that B cells reciprocate—they enable thymocytes to diversify and to mature into T cells.
B cells provide survival signals for maintaining T cells in the periphery and regulate T-cell functions in ways that are not yet fully understood.
B cells present antigen and facilitate activation of T cells and contribute to T-cell tolerance and to accommodation that protects target tissues when tolerance fails.
Given the manifold and complex interactions between B cells and T cells, there is uncertainty about how best to weigh the impact of B-cell responses on an organ graft at a given point in time and what short-term and especially long-term impact can be expected as new B cell–directed therapies emerge.
Although all transplants might cause DSAs to be produced (unless inhibited by immunosuppression), only organ grafts (and not cellular grafts) are susceptible to antibody-mediated damage. Antibodies and complement mainly attack endothelial cells of organ transplants because antibodies and complement are found predominantly inside blood vessels. Although antibodies and complement can penetrate blood vessel walls, they do so only slowly, and parenchymal cells and cellular transplants are relatively unaffected by DSAs.
Today, humoral immunity, detected by assay of DSAs in blood, predicts increased risk of acute and chronic rejection, although few transplant physicians would treat a recipient with DSAs but no change in graft function or biopsy. However, the assays for DSAs in common use, based on binding to antigen on beads, do not represent all potential antigens or polymorphisms in a given recipient and do not model steric factors that might limit binding to the antigens that are displayed.
The immune response of transplant recipients is usually assayed by testing the blood for the presence and concentration of DSAs and by evaluating graft function. DSAs are generally understood to refer to antibodies specific for HLA of the donor; however, DSAs might also refer to antibodies against donor blood groups. Graft recipients are often found to produce antibodies specific for HLA not present in the donor, but some of these anti-HLA antibodies cross-react with donor HLA. Furthermore, some methods (solid phase assays in particular) commonly used for detecting DSAs and anti-HLA antibodies might suggest that antibodies recognize donor antigens when in fact they do not (because standard antigens rather than donor-derived antigens are used, as reviewed by Tait et al ;Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation.Transplantation. 2013 Jan 15; 95(1):19-47.).
saja Mohammed
3 years ago
HLA class I genes are expressed by all nucleated cells and control the activation, function of cytotoxic T cells so express both T cells and B cells . HLA class II molecule expression is restricted to antigen presenting cells (dendritic cells, macrophages, monocytes), and B cells. so during acute graft rejection both class I and II HLA can be expressed by vascular endothelial cell. B cells activation and differentiation to antibody-secreting plasma cells play major role in acute and chronic ABMR . B cells shape the T-cell response through a combination of APC, cytokine production, and costimulation , complement activation .
in acute ischemic hypo perfusion injury B cells activation have direct effects on the allograft and induce acute humeral rejection.
interesting growing evidence from recent studies demonstrates that B cells may play a pivotal role in the induction and maintenance of transplant tolerance through accommodation effect of the regulatory B cells.
References
1-handbook of transplantation ,Fifth Edition. Gabriel M.Danovitch.
2-Understanding crossmatch testing in organ transplantation: A case-based guide for the general nephrologistnep_1414 125..133 WILLIAM R MULLEY1,2 and JOHN KANELLIS1,
3-B cells in transplant tolerance and rejection: friends or foes? Robin Schmitz, Zachary W. Fitch, Paul M. Schroder, Ashley Y. Choi, Annette M. Jackson, Stuart J. Knechtle & Jean Kwun.
Mohammed Sobair
3 years ago
B cells in transplant rejection:
1–Differntiate to antibody secreting plasma cells.
2-Bcell shape t-cell response through a combination of antigen presenting cell, cytokine
production and co stimulation.
3- Direct B-cell effect by initiate ischemic injury.
B cells as antigen-presenting cells:
B cells are capable of promoting chronic rejection independently of antibody production,
by shaping the T-cell response through a combination of antigen presentation, cytokine
production, and costimulation. (1)
B-cell response to tissue injury:
Kidney injury in ischemia/reperfusion injury and transplantation are both mediated by a
B-cell response to dysfunctional tissue repair.
Role of B cells in promoting tolerance:
Growing evidence demonstrates that B cells may play a pivotal role in the induction and
maintenance of transplant tolerance. Upregulation of B-cell-related genes and their
molecular pathways were associated with tolerance. References:
1- Bo Peng, Yangzi et al .Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation. Cell Death & Disease volume 9, Article number: 109 (2018)
Ahmed Fouad Omar
3 years ago
What are the types of HLA presented by B cells and T cells? What is meant by B cell and T cell crossmatch?
B cells express both class I & II HLA (class I is expressed in all nucleated+ it is one of APCs so additionally it has class II HLA)
T cells express class I HLA( class I is expressed in all nucleated cells)
Positive B cell crossmatch indicate the presence of class II HLA AB & to lesser extent class I HLA AB
Positive T cell crossmatch indicate the presence of class I HLA AB
Ahmed Fouad Omar
3 years ago
What are the Antigen-Presenting Cells (APC) and how do they work?
Antigen presenting cells (APCs) are critical for the initiation of adaptive immune responses and for maintenance of peripheral tolerance.
APCs are cells that can process a protein antigen, break it into peptides, and present it in conjunction with class II MHC molecules on the cell surface where it may interact with appropriate T cellreceptors(CD4+ TH cells.. However APCs including DCs can also present exogenous antigens to the MHC I receptor to activate CD8+ T cells during a process called cross-presentation).
Professional APCs include dendritic cells, macrophages, and B cells, whereas nonprofessional APCs that function in antigen presentation for only brief periods include thymic epithelial cells and vascular endothelial cells
Dendritic cells, macrophages, and B cells are the principal APCs for T cells, whereas follicular dendritic cells are the main antigen presenting cells for B cells.
What is the percentage of B cells in the peripheral blood?
Lymphocytes in human circulating blood are approximately 80 to 90% T cells and 10 to 20 % B cells. They represent 10-15% of the peripheral blood mononuclear cells and carry the marker CD19
Cross-Talk Between Antigen Presenting Cells and T Cells Impacts Intestinal Homeostasis, Bacterial Infections, and Tumorigenesis
Stephen J. Guadino and Pawan KumarFront. Immunol., 06 March 2019
Last edited 3 years ago by Ahmed Fouad Omar
Ahmed Fouad Omar
3 years ago
B lymphocytes (BL) play an essential role in the biological processes mediating renal graft rejection and tolerance through various effector mechanisms
B cells can perpetuate alloimmune responses in multiple ways:
§ Differentiation into antibody-producing plasma cells that can secrete antibodies that can cause hyper acute rejection in sensitized patients
§ sustaining long-term humoral immune memory(memory B cells)
§ serving as antigen-presenting cells to CD4 TH cells
§ organizing the formation of tertiary lymphoid organs with lymphotoxin expression
§ secreting pro- as well as anti-inflammatory cytokines to trigger polarization of naïve T lymphocytes into Th1 or Th2 cells
§ Maintenance of the fine equilibrium required for tolerance(Breg cells)
The cross-talk between B cells and T cells in the course of immune responses forms the basis of these diverse functions
B cell subsets: Naïve, transitional, plasma cells, memory B cells and B regular cells
Targeting B cells should take into consideration their different functions and the consequences as simple depletion of all B cells can interfere with beneficial effects of certain B cell subpopulations.
Why are B Cells Important in renal Transplantation?
Currently available immunosuppressive regimens are centered on T cells to reduce acute rejection rates and hence improved short-term graft survival but they are not effective in controlling humoral immune responses since antibody-mediated rejection (ABMR)
Depletion of B cells at the time of kidney transplantation seemed to enhance acute T cell-mediated rejection as they may eliminate a population of B cells with regulatory properties (B regulatory cells (Breg)), thus enhancing the T cell allo-response
Moving forward rational strategies to target B cells need to maximize the tolerogenic capacity of B cells while minimizing their immunostimulatory effects.
Essential role for B cells in transplantation tolerance.
B cells in renal transplantation: pathological aspects and therapeutic interventions
Nicholas Barnett, Anthony Dorling, Nizam Mamode.Nephrology Dialysis Transplantation, Volume 26, Issue 3, March 2011, Pages 767–774
Monitoring of B Cell in Kidney Transplantation: Development of a Novel Clusters Analysis and Role of Transitional B Cells in Transplant Outcome.
Rafael Alfaro et al, Diagnostics 2021, 11, 641.
Mohamad Habli
3 years ago
What are the Antigen-Presenting Cells (APC) and how do they work? What is the percentage of B cells in the peripheral blood?
Antigen-presenting cell is cell that displays antigen bound by MHC proteins on its surface. Antigen-presenting cells include macrophages, dendritic cells and B cells. APCs present foreign antigens to helper T cells. Antigen-presenting cells are vital for effective adaptive immune response, as the functioning of both cytotoxic and helper T cells is dependent on APCs.
Among all peripheral blood lymphocytes, B cells account for 2–10% of all lymphocytes.
Ban Mezher
3 years ago
Professional APC include dendritic cells, macrophage & B cells , & non professional APC ( function temporary as APC) include thyme epithelial cells & vascular endothelial cells.
It can process the protein antigen & break it to peptide & present it with class II MHC on cell surface to interact with T cells receptor.
B cells compromised 5-10% of peripheral blood mononuclear cells.
Tahani Hadi
3 years ago
B cells are part of immune system cells that are proliferate and differentiate in the bone marrow ,they are characterized by expression of antibody through antigen surface receptors BCR ,after many levels of division and differentiation B cells will be divided into either memory B cells or plasma cells .
B cells are responsible in the immune system to activate and produce antibodies (humoral)response leading to hyperacute rejection ,acute ABMR and chronic ABMR .
Also they play a role in initiating cellular response or immunity by presenting antigens to CD 4+ T cells and regulate other immune cells to produce cytokines .
ABMR caused from pathway of alloantibody effector function by direct activation of endothelial cells to MHC leading to complement activation (classical pathway) or immune cells activation that express complement receptors like macrophages,neutrophils,money and natural killer cells .
ABMR treatment usually difficult and it’s diagnosed by alot of methods mainly by detection alloantibodies and complement activation in graft biopsy through C4d staining although in chronic ABMR C4d may be negative ,also ABMR can be detected by graft function detorioration and DSA detection .
Regarding HLA types question :
Class I is present in all nuclaeted cells also T and B cells
Class II is restricted in bone marrow derived cells ,B cells and present mainly in antigen presenting cells APC which are ;macrophages, mesengial cells and dendritic cells these will make antigens present peptides to CD4+ T cells leading to their activation and by this it will activate CD8+ cell.
Amer Hussein
3 years ago
An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytosethe pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material; they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, thus functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs percentage of B cellin prripheralbloof about 5–10/
//B cells play a role in graft rejection via several mechanisms. Specifically, B cells produce high-affinity antibodies to alloantigens including allogeneic major histocompatibility complex (MHC) with the help of follicular helper T cells. B cells also function as antigen-presenting cells for alloreactive T cells, resulting in the activation of alloreactive T cells. Conversely, the frequency of regulatory B cells increases under inflammatory conditions and suppresses the rejection process. Here, the differential roles of the major B cell subpopulations (B-1, follicular B, marginal zone B, and regulatory B cells) involved in transplantation rejection
Jamila Elamouri
3 years ago
Role of the B-cell in transplantation:
B-cells express surface antibody (Ig) as BCR, and variable surface markers during their development, to adapt and facilitate their function.
Ex: CD20, CD19, CD27, CD32B (FcyRIIB).
The function of B-Cell:
1- Act as a precursor to Antibody producing plasma cells, these antibodies react with proteins and peptide Ag (T-dependent Ag), also, interact with carbohydrate/polysaccharide antigens (T-independent Ag).
2- Act as immune effector
3- Negatively regulate or modulate the immune response.
4- T-cell activation via Ag presentation leads to immune response.
5- Formation of an ectopic germinal center.
(As they can clonally expand, they can form a nucleus of lymphoid tissue in the inflamed tissue and allograft.) (Arrangement (orchestration) of the microarchitecture of the secondary lymphoid tissues).
6- Enhancing innate immune response. B-Cell subsets: B1-cell:
· Produce natural antibodies (that have a low affinity, poly-reactive) to T-cell independent Ag, as the first line of defence, as well, these antibodies are protective in atherosclerosis which may be of relevant role in vasculopathy in transplantation.
· Have a phagocytic and microbiocidal activity. B2-cell:
Formed in the bone marrow released as immature B-cells and circulate through 2RY lymphoid organs (spleen and lymph nodes) as naïve B cells which express IgM and IgD. These cells are either:
· Follicular B cell (T-dependent response)
· Marginal Zone B cell (T-independent response), express CD21(CR2), and memory marker CD27.
Plasma cell Memory B Cell Regulatory B cell (Bregs) has regulatory immune inhibitory function via the production of IL-10 (also called B10 cell), it expresses CD24, CD38, CD5, and CD27.
B-cell also expresses CD19 which is a co-receptor that can lower the threshold for B-cell activation.
B-cell activation can also be facilitated by complement components (C3b, C3d) that bind to CD21.
B-cell expresses- TLR (Toll-like receptor 12, 6,7,9,10)
B-cell may also receive pro-activation and survival signals via cytokines (BAFF= TNF tumor necrosis factor family), overexpression of it can cause hypergammglobulinemia. B-cells express either Co-activating receptors or inhibitory receptors (FcyRIIB)
The inhibitory receptors, in their cytoplasmic domain, have tyrosine protein, ligation of it with BCR, negatively regulates B-cell activation. This protein is called immunoreceptor tyrosine inhibitory motifs (ITIM receptor). The inhibitory receptors are important in terminating germinal center (GC) responses once sufficient antigen-specific IgG has been generated. (Overexpression of them results in reduced autoimmunity.
CD22, is a glycoprotein of Ig superfamily, co-ligation of CD22 to BCR reduces B-cell activation while sequestratingCD22 away from the BCR, resulting in B-cell hyperactivity.
· B-cells with high affinity for antigen are differentiated to either memory or plasma cells.
· within the B-cell follicles there is CD4T-cell (expresses Bcl-6) which is known as follicular helper cell (Tfh). The Tfh cells are essential for the development of the germinal centre B-cell response. Inhibition of these cells may represent a possible strategy in future attempts to inhibit humoral alloimmunity.
· Small proportion of plasma cells arising from the germinal centre become established as long-lived plasma cells in the bone marrow and act as long-term antibody factories, producing IgG. They do not proliferate, and they reside within a number of limited niches, like the inflamed tissue in autoimmunity and within the allografts.
· B-cell can produce lymphotoxin-B and VEGF-A that play a role in orchestrating the development of these structures within the allografts.
From that, we can conclude that the B –cell has multiple roles in transplant immunology
In summary, the B-cell have roles in: 1- Acute T-cell mediated rejection. 2- Acute and chronic antibody-mediated rejection. 3- Immunomodulatory role via interleukin production (IL10). 4- Transplant tolerance.
Transplanted graft tolerance might allow patients to wean off immunosuppression and maintain normal graft function.
Regulatory B-cell (Brgs) has an important role in promoting and maintaining tolerance.
Identification of transcriptional signature intolerant patients shows upregulation of B cell-related gene.
The majority of biomarkers associated with tolerance were found to be B-cell related.
the body underwent several mechanisms to adapt for tolerance, like changing the harmful type of IgG to IgG2 that is not harmful to the graft, if true to say that.
# So, B-cell has harmful (rejection) and beneficial (tolerance)effects in transplantation, by cell depletion, the benefit of B-cell can be lost.
· De novo donor-specific antibodies (DSA) production is frequently associated with acute antibody-mediated rejection (AMR) which has a deleterious effect on the transplantation outcome. · DSA and non-HLA Abs may contribute to the long-term allograft exhaustion in chronic AMR.
References:
1- Schmitz R, Fitch ZW, Schroder PM, Choi AY, Jackson AM, Knechtle SJ, et al. B cells in transplant tolerance and rejection: friends or foes? Transpl Int. 2020;33(1):30–40.
2- Clatworthy MR. B-cell regulation and its application to transplantation. Transpl Int. 2014;27(2):117–28.
3- Karahan GE, Claas FHJ, Heidt S. B cell immunity in solid organ transplantation. Front Immunol.
Wessam Moustafa
3 years ago
What are the Antigen-Presenting Cells (APC) and how do they work?
What is the percentage of B cells in the peripheral blood?
APCs are immune cells , that present antigens to T lymphocytes, they process antigens and present it on its surface in conjugation with Class II MHC .
Types of APCs include , dendritic cells , B cells and macrophages
Percentage of B cells in peripheral blood as a total 2.5% in other articles up to 10%
( peripheral B cells are subclassified into naive , memory , plasmablast and immature B cells )
Perez-Andres M, Paiva B, Nieto WG, Caraux A, Schmitz A, Almeida J, Vogt RF, Marti GE, Rawstron AC, Van Zelm MC, Van Dongen JJM, Johnsen HE, Klein B, Orfao A. Human peripheral blood B-cell compartments: A crossroad in B-cell traffic. Cytometry Part B 2010; 78B (Suppl. 1): S47–S60.
Wessam Moustafa
3 years ago
B cells have multifactorial role in initiating and regulating allograft injury
B cells and their progeny of plasma cells , were thought initially to have the main function of DSAs production and so mediating ABMR (1)
Now B cells are recognized to present donor antigens to T cells ,thus mediating T cell mediated allograft injury ( 2)
Moreover, some animal studies ,showed that B cells may have immunoregulatory functions , through secretion of IL 10 , they can suppress Effector T cells , and upregulate Treg ( regulatory T cells ) and hence their role in transplantation tolerance , and so the idea of complete B cell depletion that may be harmful as it depletes regulatory B cells .
Studies also proved that tolerant recepient ,exhibit B cell derived gene products not found in recipients receiving immunosuppression
Generally B cells may cause allograft rejection independently of antibody production by facilitating T-cell response through a combination of antigen presentation, cytokine production, and costimulation
1) Loupy A, Hill GS, Jordan SC: The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol 8: 348–357, 2012
2) Noorchashm H, Reed AJ, Rostami SY, Mozaffari R, Zekavat G, Koeberlein B, Caton AJ, Naji A: B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J Immunol 177: 7715–7722, 2006 [PubMed] [Google Scholar] [Ref list]
3) Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, Burlingham WJ, Marks WH, Sanz I, Lechler RI, Hernandez-Fuentes MP, Turka LA, Seyfert-Margolis VL; Immune Tolerance Network ST507 Study Group: Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest 120: 1836–1847, 2010
Esmat MD
3 years ago
Dear All What are the Antigen-Presenting Cells (APC) and how do they work? What is the percentage of B cells in the peripheral blood?
APCs consist of dendritic cells, macrophages, B lymphocytes, and activated human endothelial cells, but among them, dendritic cells are the most potent. APCs provide the means by which HLA-peptide complexes are presented to T-cell receptors and provide necessary signals required for T-lymphocyte proliferation and differentiation. The percentage of B cells in the peripheral blood is about 5-10%.
MICHAEL Farag
3 years ago
B cells >>>>> plasma cells produce antibodies
In the past these antibodies against ABO and/or HLA antigens were the cause of hyperacute rejection but nowadays after Careful ABO matching of donors and recipients and careful testing of the recipient‘s serum for antibodies against the donor‘s HLA prior to transplantation have
eliminated hyperacute rejection in the clinic.
More recently, however, the significance of donor-specific antibodies (DSA) that arise after transplantation has come to the fore. These antibodies, usually against donor HLA but sometimes directed against non-HLA, are associated with poor renal allograft outcomes by causing acute or chronic antibody-mediated rejection (ABMR), often in combination with an ongoing T lymphocyte–mediated (cellular) rejection.
B-Lymphocyte Activation and Differentiation
Naïve B-lymphocyte activation is dependent on antigen recognition by the B-cell receptor (BCR) and on (T-helper) CD4+ T lymphocytes inside secondary lymphoid organs.
Antigen degraded into peptides which bound to MHC II forming MHCII–peptide complexes on B cell surfacethen certain mechanisms occurs lead to differentiation of B cells to plasma cells (which are the factories for the antibodies) and B memory cells; both of them are responsible about maintaining Humoral immunity
Plasma cells exit secondary lymphoid organs and reside for a long time in the bone marrow. They rely on IL-6 for survival.
Memory B lymphocytes, on the other hand, populate secondary lymphoid tissues and circulate in the blood. In humans, they are marked by expression of the surface protein CD27. Similar to memory T lymphocytes, memory B lymphocytes respond much more vigorously than their naïve counterparts to the antigen to which they are specific and produce antibodies of higher affinity
Antibody-Independent Functions of B Lymphocytes
In addition to producing antibodies, B lymphocytes contribute directly to T-lymphocyte immunity by three known mechanisms: (1) they serve as APCs that enhance T-lymphocyte differentiation to memory T lymphocytes; (2) they function as bona fide cellular effectors that produce inflammatory cytokines (for example, TNFα); and (3) a subgroup of them, known as regulatory B lymphocytes (Breg) characterized by IL-10 secretion, modulate immune responses
Targeting B Lymphocytes and Plasma Cells in Transplantation
Since all human B lymphocytes express the surface marker CD20, monoclonal antibodies against CD20 (Rituximab) are quite effective at depleting B lymphocytes in the circulation and to a lesser extent in lymphoid organs. Plasma cells, however, do not express CD20, providing one explanation why Rituximab has not been particularly successful at reversing DSA or ABMR in renal transplant recipients. More recently, proteasome inhibitors, originally developed for the treatment of multiple myeloma, have been employed to inhibit plasma cell function in sensitized patients or those with DSA/ABMR. Finally, B-lymphocyte depletion at the time of transplantation can increase the incidence of acute rejection because of nonselective depletion of both pathogenic and regulatory B lymphocytes.
Dalia Ali
3 years ago
The main functions of B cells are:
1-to make antibodies against antigens
2-to perform the role of antigen-presenting cells (APCs),
3-to develop into memory B cells after activation by antigen interaction.
To generate an effective antibody response B cells need to
1-Recognize antigen through their BCR (signal 1)
2-Receive help from activated CD4 T cells which provide signal 2
These two conditions are actually linked. When antigen binds to the BCR B cells will be activated, This will then be recognized by T cells that have already been activated in response to the same antigen .
B cells contribute to allograft rejection after differentiating into antibody-secreting plasma cells .
Post-transplant donor-specific antibody (DSA) and de novo DSA (dnDSA) are major risk factors to long-term graft survival. Once DSA develops, almost 40% of affected patients lose their graft in contrast to patients with no dnDSA
Furthermore, patients with preformed DS , showed higher risk of rejection, either acute or chronic antibody-mediated rejection (ABMR) regardless of type of organ transplantation
The innate immune system contains cells that detect potentially harmful antigens, and then inform the adaptive immune response about the presence of these antigens. An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells.
1-Schmitz R,,Zachary W. B cells in transplant tolerance and rejection: friends or foes?. Transpl Int. 2020 January ; 33(1): 30–40. doi:10.1111/tri.13549.
2-Renal Transplantation, Oxford Medicine
Amit Sharma
3 years ago
What are the Antigen-Presenting Cells (APC) and how do they work?
APC are a group of cells involved in immune system with the primary function of processing and presenting antigens to lymphocytes like T cells for triggering an immune response. These include B cells, dendritic cells, macrophages and Langerhans cells.
What is the percentage of B cells in the peripheral blood? B cells account for 2-10% of all lymphocytes in the peripheral blood
Heba Wagdy
3 years ago
B cells are precursors of antibody producing plasma cells, secrete cytokines, present alloantigens to T cells, give rise to humoral immune memory through memory B cells
Antibody response in kidney transplant
Studies reported that de novo and pre existent IgG DSAs are associated with acute and chronic allograft rejection. (1)
recipients developing DSA post transplant have lower rates of graft survivalthan those without DSA (2)
memory B cells provide long lasting humoral immunity responsible for rapid release of antigen specific antibodies have low threshold of activation (3)
Studying donor specific B cell response in transplant is gaining more importance. (4)
Role of B cells in antigen presentation to alloreactive T cells
They are potent APCs because
activated B cells express high level of MHC class II and costimulaory molecules
can take up antigens with B cell receptor
Able to clonally expand (5)
The possible role of B cells as APCs in T cell mediated rejection was reported in studies on renal biopsies.
A study showed that in biopsies of acute cellular rejection, there were dense B cell clusters that didn’t correlate with C4d deposition and was associated with low graft survival (6)
CD20+ B cell clusters were present in cases of T cell mediated rejection in absence of ABMR suggesting the role of B cells other than antibody production. (7)
B cells infiltration of chronically rejected allografts
A study showed that lymphoid neogenesis was present in explanted kidney allograft due to chronic rejection. (8) the grafts were infiltrated with B cells and were organized into nodules similar to B cell follicles. (9)
B cells as immune regulators
The role of B cells in tolerance was suggested after identification of B cell signature in operationally tolerant kidney transplant recipients. (10)
Tolerant patients have increased peripheral blood B cells with shift to the naïve and transitional phenotype. (11)
(1) Loupy A, Hill GS, Jord Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest (2010) 120(6):1836–47.an SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol (2012) 8(6):348–57.
(2) Loupy A, Lefaucheur C, Vernerey D, Prugger C, Duong van Huyen JP, Mooney N, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med (2013) 369(13):1215–26.
(3) Lanzavecchia A, Bernasconi N, Traggiai E, Ruprecht CR, Corti D, Sallusto F. Understanding and making use of human memory B cells. Immunol Rev (2006) 211:303–9.
(4) Lucia M, Luque S, Crespo E, Melilli E, Cruzado JM, Martorell J, et al. Preformed circulating HLA-specific memory B cells predict high risk of humoral rejection in kidney transplantation. Kidney Int (2015) 88(4):874–87.
(5) Lanzavecchia A. Pillars article: antigen-specific interaction between T and B cells. 1985. J Immunol (2007) 179(11):7206–8
(6) Sarwal M, Chua MS, Kambham N, Hsieh SC, Satterwhite T, Masek M, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med (2003) 349(2):125–38
(7) Hippen BE, DeMattos A, Cook WJ, Kew CE II, Gaston RS. Association of CD20+ infiltrates with poorer clinical outcomes in acute cellular rejection of renal allografts. Am J Transplant (2005) 5(9):2248–52.
(8) Thaunat O, Patey N, Caligiuri G, Gautreau C, Mamani-Matsuda M, Mekki Y, et al. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J Immunol (2010) 185(1):717–28.
(9) Cheng J, Torkamani A, Grover RK, Jones TM, Ruiz DI, Schork NJ, et al. Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal. Proc Natl Acad Sci U S A (2011) 108(14):5560–5.
(10) Heidt S, Wood KJ. Biomarkers of operational tolerance in solid organ transplantation. Expert Opin Med Diagn (2012) 6(4):281–93.
(11)Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest (2010) 120(6):1836–47.
Mahmud Islam
3 years ago
B cells have an important role in transplantation. They act both as antigen presentation cells and transform into plasma cells secreting antibodies. They also have a role in transplantation tolerance. As many colleagues said. APCs (antigen-presenting cells) in simple words process antigens to be recognized by T cells. Dendritic cells and macrophages are also examples. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184555/figure/F1/
Doaa Elwasly
3 years ago
T cell cross match / Bcell cross match /interpretition
-VE /-VE /No DSAb to HLA class I or II OR DSAb titre lower than a level that can cause positive reaction OR DSAb that is not complement-fixing – relevance unclear)
+VE /+VE /DSAb/s to HLA class I OR
Multiple DSAbs to HLA class I +/− II
-VE /+VE /DSAbs to HLA class II OR Low level DSAb/s to HLA class I
+VE /-VE /Technical error ( related to B-cell viability). The test should be repeated
Mullery W R et al.Understanding crossmatch testing in organ transplantation: A case-based guide for the general nephrologist.Nephrology 16 (2011) 125–133
Doaa Elwasly
3 years ago
Types of HLA presented by B cells and T cells; Class I MHC molecules ; T cells that express CD8 molecules react with class I MHC molecules. These have a cytotoxic function, need to recognize any infected cell. Because every nucleated cell expresses class I MHC molecules, all infected cells can act as antigen-presenting cells for CD8 T cells . Class II MHC molecules ; present only on professional antigen-presenting cells (B cells, macrophages, dendritic cells, Langerhans cells), thymic epithelium, and activated (but not resting) T cells; most nucleated cells can express class II MHC molecules by interferon (IFN)-gamma. T cells reactive to class II molecules express CD4 and are helper cells.(1)
T cells have dual specificity, so they recognize bothMHC I or MHC II and peptide antigens displayed by those MHC molecules.
So the T cell receptor actually recognizes the combination of the MHC molecule and the peptide. Once bound to the MHC molecule, the T cell can begin its role in the immune response.(2)
Naive and memory B cells concentrate HLA-DR, -DM and -DO into compartments dispersed under the cell surface, which are identifed by their expression of lysosome-associated membrane protein (Lamp)-1 as late endosomes/lysosomes. B cell subsets appear to have distinct mechanisms of antigen processing. The naive and memory B cells display small superfcial MIIC that contain HLA-DM and -DO
T lymphocytes have HLA class I antigens while B lymphocytes have both HLA class I and class II antigens. If the recipient’s serum contains antibodies against any of these HLA antigens, the antibodies will target such lymphocytes. This will activate the complement via the classical pathway, causing cell lysis.(3)
References
1-Delves P J ,Human Leukocyte Antigen (HLA) System.MSD manual professional version, Sept 2021
2-Lodge A , Immunolgay for nonimmunologist T cell antigen recognition , Hema care 2018
3- Chalouni C et al .Human germinal center B cells differ from naive and memory B cells by their aggregated MHC class II-rich compartments lacking HLA-DO. International Immunology, 2002 Vol. 15, No. 4, pp. 457±466
AHMED Aref
3 years ago
Dear Dr Ahmed,
What are the Antigen-Presenting Cells (APC) and how do they work?
Antigen-Presenting Cells (APC) as we can expect from the name are highly specialized cells that are responsible for sampling and processing the foreign antigens to present them later to T cells resulting in the initiation of immune response and activation of memory cells. They are characterized by the presence of HLA class II antigens (1).
They are not only presenting the processed antigens via the HLA-peptide complexes but they also provide the necessary signals required for T-lymphocyte proliferation and differentiation.
Dendritic cells, macrophages, B lymphocytes, and activated human endothelial cells are all known to function as APCs (1).
What is the percentage of B cells in the peripheral blood?
The B cells in the peripheral blood are about 10% of the lymphocyte population in healthy controls as mentioned in one study (2).
2) Elmér E, Smargianaki S, Pettersson Å, et al. Increased Frequencies of Switched Memory B Cells and Plasmablasts in Peripheral Blood from Patients with ANCA-Associated Vasculitis. J Immunol Res. 2020 Nov 28; 2020: 8209737.
What are the Antigen-Presenting Cells (APC) and how do they work? What is the percentage of B cells in the peripheral blood?
APCs are cells mediate immune response by processing and presenting antigen to T cells e.g B cells, dendritic cells , langerhans cells, and macrophages
B cells represent 2-10 % of peripheral blood cells
Role of B cell in transplantation
B cells can regulate cellular immunity, participate to the genesis of tolerance, and accommodation in transplantation.
Besides producing antibodies, B cells enhances lymphoid organogenesis. B cells increase the development of dendritic cells, acting as antigen-presenting cells, in secondary lymphoid tissues.
T cells known to provide help for B cells, mean while currently the opposite is most probable , Bcells enable thymocytes to mature into T cells. B cells produces signals for keeping T cells in the periphery and regulating it’s functions
B cells present antigen and enhance activation of T cells and participates inT-cell tolerance and to accommodation that protects target tissues when tolerance fails.
Bound antibody can enhance cellular immunity and cellular rejection, and it can block or depress cellular immunity and rejection in tumor transplants (i.e., enhancement).
B-cell responses to some polysaccharides, such as blood groups, are emerging from newly activated B cells and do not get more effective with repeated exposure. These responses do not require T-cell help, and accordingly they are called T independent.
B-cell responses to protein antigens require T-cell help, requiring activation of T cells responding to peptides with MHC class II.
The activation of T cells and the recruiting of T-cell help is consolidated if B cells recognize a foreign protein via the antigen receptor, engulf it , and present peptides to T cells.On the other hand , B-cell responses to proteins manifest both memory and progressive increase in affinity of the B-cell receptor to the antigen.
Reference;
-Dijke E I etal . B cells in transplantation. J Heart Lung Transplant. 2016 June ; 35(6): 704–710.
Reem Younis
3 years ago
Many transplanted patients require retransplantation or even die of graft rejection. Thus, the prevention of graft rejection is a critical step in improving outcomes in organ transplantation.
Chronic antibody-mediated rejection is considered the main cause of late allograft loss.
Several mechanisms have been attributed to B cells during graft rejection. The most important function of B cells is producing antibodies against HLA and nonHLA antigens. These antibodies contribute to complement fixation and cell lysis,antibody-dependent cellular cytotoxicity by NK, increasing the thickness of endothelial and smooth muscle cells, activating platelet, developing inflammatory conditions, thrombosis, and overall reducing of graft function.1,2
B cells present antigens to T cells and can activate them by providing costimulatory signals through CD28-B7 and CD 40L-CD40 interactions.
Additionally, B-cells produce cytokines such as IL-6 and IFNɣ and contribute to T cell activation. Moreover, B cells present antigens to T cells and can activate them by providing costimulatory signals through CD28-B7 and CD40L-CD40 interactions. Additionally, B cells produce cytokines, such as interleukin- (IL-) 6 and interferon- (IFN-) γ, and contribute to T cell activation.
Also, B cells produce IL-17 that stimulates endothelial, epithelial, and fibroblast cells to produce chemokines and cytokines, leading to recruitment of neutrophils and establishment of inflammatory conditions.
Moreover, by producing TNF-α, B cells directly promote inflammation, endothelial and epithelial cell injuries, as well as inflammatory renal disorders that cause allograft rejection 3.
B cells are also involved in the development of lymphoid-like structures, named tertiary lymphoid organs (TLOs) at the side of inflammation that contain both B and T cells. In TLOs B cells undergo affinity maturation, clonal expansion, and class switching which result in efficient antibody production 4.
B cell-activating factor( BAFF) is a cytokine that belongs to the TNF family. It is a membrane-bound protein that can undergo proteolytic cleavage and convert into a soluble form. The activation of BAFF leads to B cell differentiation and survival and IgE and Igg class switching, as well as plasma cell survival 5.
References
1.G. E. Karahan, F. H. Claas, and S. Heidt, “B cell immunity in solid organ transplantation,” Frontiers in Immunology, vol. 7, p. 686, 2016.
2.X. Zhang and E. F. Reed, “Effect of antibodies on endothelium,” American Journal of Transplantation, vol. 9, no. 11, pp. 2459–2465, 2009.
3.W. Hoffman, F. G. Lakkis, and G. Chalasani, “B cells, antibodies, and more,” Clinical Journal of the American Society of Nephrology, vol. 11, no. 1, pp. 137–154, 2016.
4. C. Pitzalis, G. W. Jones, M. Bombardieri, and S. A. Jones, “Ectopic lymphoid-like structures in infection, cancer and autoimmunity,” Nature Reviews. Immunology, vol. 14, no. 7, pp. 447–462, 2014.
5.N. Thompson, D. A. Isenberg, E. C. Jury, and C. Ciurtin, “Exploring BAFF: its expression, receptors and contribution to the immunopathogenesis of Sjögren’s syndrome,” Rheumatology (Oxford), vol. 55, no. 9, pp. 1548–1555, 2016.
fakhriya Alalawi
3 years ago
B cells are by far the largest population of antigen-presenting cells (APCs) found in vivo. Though T lymphocytes are the primary targets of immunotherapy in clinical transplantation, B lymphocytes are detrimental to graft survival by virtue of their capacity to present antigen to T cells via the indirect pathway of allorecognition and the generation of donor-specific alloantibody. Furthermore, the long-term survival of organ allografts remains challenged by chronic rejection, a process in which activated B cells have been found to play a significant role. Moreover, B cells as APCs can impact T cell function both in a positive as well as a negative manner, leading to either T cell activation or tolerance.
The presence of dense intra-graft B cell infiltrates in renal allograft biopsies is associated with poor outcomes. Preemptive B cell depletion (anti-CD20, Rituximab) is reported to prolong the survival of islet and cardiac allografts in non-human primates. In humans, Rituximab induction has been shown to reduce the incidence of acute rejection in kidney recipients.
References:
Redfield RR 3rd, Rodriguez E, Parsons R, Vivek K, Mustafa MM, Noorchashm H, Naji A. Essential role for B cells in transplantation tolerance. Curr Opin Immunol. 2011 Oct;23(5):685-91. doi: 10.1016/j.coi.2011.07.011. PMID: 21982511; PMCID: PMC5351416.
Ban Mezher
3 years ago
Both HLA class I & II are present on all nucleated cell surface accept RBC, but HLA class II expression found only B cells, certain myeloid cell & subset of activated T cells.
The role of B cells in renal transplant still incomplete & growing. Numerous studies had focused on B cells role in antibodies production that can affect transplant outcome, but it is found that not all DSA are harmful & in some situation can induce tolerance by accommodation. B cells have an important role in activation of CD4 T cells & CD8 T cells & differentiation into memory T cells.
There is an evidence that B cells can induce chronic rejection which is not depends on antibody production. Another role in transplant is interaction with T cells ( APC), cytokine production & co stimulation.
Also B cells respond to ischemic re perfusion injury which associated with chronic kidney injury & rejection in absence of alloimmune response.
References:
Danovitch M. Handbook of Kidney Transplantation. 6th ed.
Schmitz R., Fitch Z., Schroder P., et al. B cells in transplant tolerance and rejection: friends or foes?.Transpl Int. 2020; 33(1): 30-40.
Alfaro R., Legal I., Gonzalez-Martinez G., et al. Monitoring of B cells in Kidney Transplantation : Development of a Novel Clusters Analysis and Role of Transitional B cells in Transplant Outcome. Diagnostics. 2021, 11:641.
Amit Sharma
3 years ago
What is the role of B cells in transplantation?
B cells have multiple functions in addition to producing antibodies. (1) They play an important role in kidney transplant rejection.
The major functions of B cells include:
a) Produce antibodies,
b) Enable lymphoid organogenesis, (2)
c) Enable thymocytes to mature into T cells, (3)
d) Contribute to T-cell tolerance and accommodation tha protects target tissues when tolerance fails, (4)
e) Regulatory B cells exert immunosuppressive effect through IL-10, IL-35, TGF beta. (5)
References:
1) Dijke EI, Platt JL, Blair P, et al. B cells in transplantation. J Heart Lung Transplant 2016;35:704-710.
2) . Lakkis FG, Arakelov A, Konieczny BT, et al. Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med. 2000;6:686-688.
3) Joao C, Ogle BM, Gay-Rabinstein C, et al. B cell-dependent TCR diversification. J Immunol. 2004;172:4709–4716.
4) Koch CA, Khalpey ZI, Platt JL. Accommodation: preventing injury in transplantation and disease. J Immunol. 2004; 172:5143–5148.
5) Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015; 42:607–612
B lymphocytes and plasma cells are the immune cells that are responsible for antibody production. If a recipient harbor performed antibodies against donor antigens in advance, the consequence is hyperacute rejection, so ABO matching and careful screening for antibodies against donor antigens in the serum of recipients prior to kidney transplantation are mandatory. In addition, performing donor specific antibody after kidney transplantation can lead to acute or chronic ABMR. ABMR cause allograft damage via two principal ways: activation of the classical pathway of complement that leads to accumulation of C4d in tissues and stimulation of macrophages and other immune cells. Raising IgG antibodies is more concern than IgM antibodies in transplantation.
In addition to producing antibodies, B lymphocytes directly contribute to T lymphocytes immunity by at least three mechanisms: they serve as APC that enhance effector T-lymphocyte differentiation to memory T lymphocytes, they function as true effectors that produce inflammatory cytokines and, a subgroup of them known as regulatory B cells, modulate immune response. So the cellular function of B lymphocytes can contribute to allograft rejection or conversely diminish the alloimmune response. As a result, B lymphocyte depletion at the time of transplantation can increase the incidence of acute rejection because of nonselective depletion of both pathogenic and regulatory B lymphocytes.
Since all human B lymphocytes express CD 20, Rituximab is significantly effective at depleting B lymphocytes. On the other hand, plasma cells do not express CD 20, providing an explanation why rituximab are not completely successful at reversing ABMR. Proteosome inhibitors such as Bortezumib have been employed to inhibit plasma cell function in sensitized patients or in ABMR.
Mohamed Essmat
3 years ago
· Needless to say that B lymphocytes play a major role in transplantation , being a part of the humoral and adaptive immunity. · B lymphocytes , secrete antibodies through plasma cells differentiation , act as memory B cells lasting for life , secrete cytokines and inflammatory mediators which stimulate T lymphocytes or act independently . · MHC 1 is presented on all body cells , blessed by the MHC 2 receptors as other APCs , B
Lymphocytes act as Antigen presenting cells , to T lymphocytes as well.
co-interaction between T and B lymphocytes is evident as mentioned . · B and T cross match detect the presence of antibodies in the recipient serum against the donor lymphocytes . If only B lymphocytes cross match is positive then anti HLA class 1 (low titre) or 2 may be present , but if T lymphocytes cross match is +ve only that means antibodies against class 1 with low titre is present , but if both +ve then it means antibodies against class 1 and may be class 2 is also present. · Hoffman W., Lakkis F.G., Chalasani G. B Cells, Antibodies, and More. cjas. 2016; · Jan.,Vol.11.pouliquen
E, Koenig A, Chen CC, et al. Recent advances in
renal transplantation: antibody-mediated rejection takes centre stage. F1000Prime Rep 2015; 7: 51.
Ahmed Faisal
3 years ago
B cells function in many ways, some of which promote rejection, and some of which have the potential to promote tolerance
B cells play an important role in graft rejection by producing donor-specific antibodies.
B cells may contribute to allograft rejection independently of antibody production by shaping the T-cell response through a combination of antigen presentation, cytokine production, and costimulation.
Kidney injury in ischemia/reperfusion injury and transplantation are both mediated by a B-cell response to dysfunctional tissue repair.
Patients who developed chronic rejection already showed elevated B-cell activities and other common gene signatures for acute kidney injury including genes related to fibrosis (e.g., COL1A1, DPT, and MMP7) and inflammation (e.g., CD52, CXCL10, and CCL21).
Recently, there is growing evidence which demonstrates that B cells may play a pivotal role in the induction and maintenance of transplant tolerance through regulatory B cells (Bregs).
Regulatory B (Breg) cells, an immunosuppressive subset of B cells, may secret inhibitory cytokines such as IL-10 which potently downregulate the immune response, ameliorating allograft rejection.
Reference:
Schmitz, Robin et al. “B cells in transplant tolerance and rejection: friends or foes?.” Transplant international : official journal of the European Society for Organ Transplantation vol. 33,1 (2020): 30-40. doi:10.1111/tri.13549
Cherukuri, A, Mohib, K, Rothstein, DM. Regulatory B cells: TIM-1, transplant tolerance, and rejection. Immunol Rev. 2021; 299: 31– 44. https://doi.org/10.1111/imr.12933
Still waiting for replies
Dear All
What are the Antigen-Presenting Cells (APC) and how do they work?
What is the percentage of B cells in the peripheral blood?
Dear All
Of course B cells are important in the immune response to transplantation. It acts as antigen presenting cell and secrete antibodies. B cell interact with T cells also.
The question here
What are the types of HLA presented by B cells and T cells?
What is meant by B cell and T cell crossmatch?
B cells express both MHC I AND MHC II while T cells express only MHC I.
The crossmatch is essential step for determination of DSA. when using complement dependent technique, lymphocytes from the donor are added to recipipient’s serum which may contain antibodies against the host cells. but yo identify against which MHC (HLA) the antibodies are direct, there is initially separation of donor’s lymphocytes into CD 19+ <–>B and CD 3= <–>T cells. after mixing the recipients serum with the separated lymphocytes, complement is added with viability dye. so if there are DSA against MHC I , B and T lymphocytes will undergo lysis, If only against MHC II, only B cells will undergo lysis, if absent -no DSAs are present.
HLA class I are expressed on the surface of both B cells and T cells; On the other hand, HLA class II expression is restricted to B cells.
A positive B cell cross match demonstrates the presence of HLA class I and/or HLA class II antibodies, but a positive T cell crossmatch determines the presence of HLA class I antibodies. So, if the B cell cross match is positive and the T cell cross match is negative, we can conclude there are HLA class II antibodies. On the other hand, since B cells express a higher amount of class I HLA antigens, a positive B cell cross match concomitant with a negative T cell cross match may indicate low levels of class I antibodies.
Excellent
T cell has class I HLA which is expressed in all nucleated cells
B cell has class I and II HLA….class II is expressed in APCs (antigen presenting cells).
T cell crossmatch positive means antibodies antibodies against class I
B cell crossmatch positive means antibodies against class I or II
B cell crossmatch has much false positive results because it may be related to B cell viability , also antibodies against class II HLA are less likely to induce hyperacute rejection than class I antibodies
so T cell crossmatch is more linked to hyperacute rejection ; if positive , should take it seriously and will go for desensitization protocol.
WILLIAM R MULLEY, JOHN KANELLIS. Understanding crossmatch testing in organ transplantation: A case-based guide for the general nephrologist. Nephrology 16 (2011) 125–133.
What are the types of HLA presented by B cells and T cells?
HLA Class I are present on all nucleated cells, hence present on both B cell and T cell.
HLA Class II is present on antigen presenting cells (e.g. B cells).
So, B cells present both class I and class II, while T cells present class I.
What is meant by B cell and T cell crossmatch?
Crossmatch includes T cell crossmatch and B cell crossmatch.
T cell crossmatch: If positive, Implies presence of HLA class I antibodies
B cell crossmatch: If positive, implies presence of HLA class I or Class II antibodies.
If B cell cross match is positive, with T cell Crossmatch positive: Either class I alone or class I and II antibodies present.
If B cell cross match is positive, with T cell Crossmatch negative: Class II antibodies or low level of class I antibodies (as B cells express higher levels of class I antigens) (1,2)
Reference:
1)Pellegrino MA, Belvedere M, Pellegrino AG, et al. B peripheral lymphocytes express more HLA antigens than T peripheral lymphocytes, Transplantation 1978;25:93-95.
2) Mulley WR, Kanellis J. Understanding crossmatch testing in organ transplantation: a case based guide for the general nephrologist. Nephrology 2011;16:125-133.
B cells express both class I & II HLA
T cells express class I HLA
Positive B cell crossmatch indicate the presence of class II HLA ab & to lesser extent class I HLA ab
Positive T cell crossmatch indicate the presence of class I HLA ab
T cell and B cell +XM
T lymphocytes express HLA class I and B lymphocytes HLA class I and II.
DSA directed against HLA class I give rise to a +T and +B cell XM.
Since HLA class I is expressed by all nucleated cells (e.g. graft EC and RTEC), there has been broad agreement that a +T cell XM prohibits transplantation.
• Only B cells express HLA class II. Therefore a B+/T– XM may indicate the presence of HLA class II DSA • B cells may express HLA class I at higher levels than T cells
. Thus a B+/T– XM may reflect low levels of HLA class I DSA
• B cells express cell surface Ig and Fc receptors. For this reason circulating immune complexes and autoantibodies may give rise to a false positive B cell XM, particularly by flow cytometry (FC). In these circumstances no DSA would be detectable by solid phase assay.
False + B-cell XM (no detectable DSA – >50% of +B-cell XM in some reports) do not ↑risk of poor outcomes.
Reference
Renal Transplantation, Oxford Medicine
HLA-class I antigens are expressed on T cells and B cells, and some but not all studies
suggest that the cell surface expression of HLA-class I antigens is higher on B than T cells.
HLA-class II antigens are expressed on B cells but not on resting T cells
Thus, a T+B+ FCXM, rather than a T+B-, is the expected result in the presence of HLA-
class I antibodies.
A T-B+ FCXM is the anticipated result in the presence of HLA-class II antibodies only
since HLA-class II antigens are expressed on B cells but not on resting T cells
Antigen-presenting cells:
Antigen-presenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells.
Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.
percentage of B cells in the peripheral blood 5-10%.
the primary antigen presenting cells are macrophages , dendritic cells and B lymphocytes , they have four primary functions
1-monitor the intracellular and extracellular environment
2-processing antigens by specific pathway
3-transporting the antigens from tissues to the peripheral lymphoid organs for interaction with T-cells.
4-provide activating signals to stimulate CD8 + cytotoxic T cell resulting in killing the intercellular pathogens like viruses also APCs activate c4+helper cells leading to specific AB production and humoral immune response this type of immune response important in defense against extracellular bacteria , parasites and allergic disease
5- T-cell priming and cross priming which reflect the cooperation between T-cells and B cells , as antigen presentation by B cells plays critical role in the development of acute humoral response through the MHC class 2 restricted pathway
the understanding of the critical role of the APC for normal immune response as well as their response to pathogenesis with in infection , autoimmune , allergic response , organ and tissue rejection this help in the developing of APC cell – based cancer immunotherapy , vaccination ,biological agents like abatacept that block costimulation by APCS , rituximab , B lymphocyte CD20 depleting agent.
sorry my previous contribuation to the below Questions and the second part regarding the % of lymphocytes in the peripheral blood its in the range of 8-33% of WBC count in adult .
What are the Antigen-Presenting Cells (APC) and how do they work?
What is the percentage of B cells in the peripheral blood?
*HLA Class I are presented on all nucleated cells, so it present on both B cell and T cell.
HLA Class II is present on antigen presenting cells APCs like B cells.
So that B cells present in both class I and class II, but T cells present class I.
What is meant by B cell and T cell crossmatch?
Crossmatch includes T cell crossmatch and B cell crossmatch.
Positive T cell crossmatch reflects presence of HLA class I antibodies.
Positive B cell crossmatch reflects presence of HLA class I or Class II antibodies.
When B cell cross match is positive, with T cell Crossmatch positive this meant that it will be class I alone or class I and II antibodies present.
When B cell cross match is positive, with T cell Crossmatch negative this meant that it will be Class II antibodies or low level of class I antibodies (as B cells express higher levels of class I antigens despite Tcells )
What is the percentage of B cells in the peripheral blood?
5-10%
What are the Antigen-Presenting Cells (APC) and how do they work?
Classical antigen presenting cells (APCs) are dendritic cells (DCs) and B cells . To mount an immune response, APCs must first recognize and bind their target. To do so, APCs express antigen-specific surface receptors including pattern recognition receptors (PRRs).
PRRs detect pathogen-associated molecular patterns (PAMPs), which are produced by microbes, and damage-associated molecular patterns (DAMPs), which are produced by damaged or mutated host cells (1).
One major family of PRR is the Toll-like receptors (TLRs). TLRs are typically expressed on the cell surface or within endosomes and are type I transmembrane proteins whose extracellular domains express leucine-rich repeats that are used to recognize and bind to specific PAMPs (14–16). Once the extracellular domain binds its target, the TLR activates a cytosolic signaling cascade which is initiated by an adaptor protein that interacts with the intracellular domain of the TLR. Depending on the TLR, the two adaptor sets that can be activated are TIRAP-MyD88 and TRAM-TRIF .
Another group of PRR is the nucleotide binding oligomerization domain (NOD)-like receptors (NLRs). NLRs are present in the cytoplasm and, like TLRs, initiate signaling cascades upon binding to microbial PAMPs .
After binding to their appropriate PAMP or DAMP, APCs internalize their target by initiating phagocytosis, pinocytosis, or clathrin-mediated endocytosis. The pathway by which molecules are endocytosed determines how they will be degraded and then displayed by major histocompatibility complex (MHC) for T cell recognition 2.
1 ten Broeke T, Wubbolts R, Stoorvogel W. MHC class II antigen presentation by dendritic cells regulated through endosomal sorting. Cold Spring Harb Perspect Biol. (2013) 5:a016873.
2 Fukata M, Vamadevan AS, Abreu MT. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Semin Immunol. (2009) 21:242–53.
What are the types of HLA presented by B cells and T cells?
What is meant by B cell and T cell crossmatch?
HLA class I are expressed on all nucleated cells including B cells and T cells but B cells shows a high number of class I HLA antigens than T cells .
HLA class II is expressen only ob APCS including B cells surface .
positive T cell crossmatch means presence of HLA class I antibodies only .
positive B cell cross match means the presence of both of HLA classes or one of them but
if the B cell cross match is positive and the T cell cross match is negative, it means there are HLA class II antibodiesonly or with low levels of class I antibodies.
B-cells participate in the cellular immunity through the following;
-act as Ag presenting cells, they present the Ag to the T-cells, lead to their activation with subsequent graft damage(CMR).
-they secret cytokines (IL2 &TNFa),that activate T-cells.
B-cells play a major role in humeral immunity through ;
-they differentiate into plasma cells, secret antibodies leading to (AMR)
B-cells ( regulator ) have a role in immunological tolerance ,as they can suppress others B-cells .
B-cells can differentiate into memory B cells, can induce memory response once reactivated.
Reference:
1- Pouliquen E, Koenig A, Chen CC, et al. Recent advances in renal transplantation: antibody-mediated rejection takes center stage. F1000Prime Rep 2015; 7: 51.
2- William Hoffman, Fadi G. Lakkis, and Geetha Chalasani B Cells, Antibodies, and More Clin J Am Soc Nephrol 11: 137–154, 2016. doi: 10.2215/CJN.09430915
B cell responsible for Anti-body production and plasma cell proliferation which lead to antibody mediated projection and sensitization
HLA class I Ags are expressed on the surface of both B &T cells; but HLA class II Ags are expressed on B cells .A positive B cell cross XM denotes presence of HLA class I and/or HLA class II antibodies, but a positive T cell XM denotes presence of HLA class I antibodies. So, if the B cell XM is positive and the T cell XM is negative, that denotes that there are HLA class II antibodies. As B cells express a higher amount of class I HLA antigens, a positive B cell cross match with a negative T cell cross match may denote low levels of class I antibodies.
B cells are related to plasma cell production &antibody formation essentially responsible for humoral immunity; leading to ABMR and sensitization.
REFERENCES
Danovitch, GM; Handbook of kidney transplantation, Sixth edition,2018
What is the role of B cells in transplantation?
Functions of B-cells include:
1- Antibodies production.
2- Thymocytes maturation into T-cells.
3- Lymphoid organogenesis.
4- T-Cell tolerance.
5- Regulatory B cells immunosuppressive effect via IL10, IL35, TGF-B.
6- B-cells express HLA-I and HLA-II, however T-cells express only HLA-I.
B- lymphocytes play an important role in kidney transplant rejection.
So, B-cell positive cross match means presence of antibodies against either HLA-I or HLA-II.
What is the percentage of B cells in the peripheral blood?
2-10 % of peripheral blood cells.
What are the Antigen-Presenting Cells (APC) and how do they work?
An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection.
When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen.
Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells.
Dendritic cells are immune cells that process antigen material; they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, thus functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs.
After phagocytosis by APCs, the phagocytic vesicle fuses with an intracellular lysosome forming phagolysosome. Within the phagolysosome, the components are broken down into fragments; the fragments are then loaded onto MHC class I or MHC class II molecules and are transported to the cell surface for antigen presentation.
Note that T lymphocytes cannot properly respond to the antigen unless it is processed and embedded in an MHC II molecule. APCs express MHC on their surfaces, and when combined with a foreign antigen, these complexes signal a “non-self” invader. Once the fragment of antigen is embedded in the MHC II molecule, the immune cell can respond. Helper T- cells are one of the main lymphocytes that respond to antigen-presenting cells. Recall that all other nucleated cells of the body expressed MHC I molecules, which signal “healthy” or “normal.”
Reference:
· Biology 2e. Provided by: OpenStax. Located at: http://cnx.org/contents/185cbf87-c72e-48f5-b51e-f14f21b5eabd@10.8. License: CC BY: Attribution. License Terms: Access for free at https://openstax.org/books/biology-2e/pages/1-introduction
What are the Antigen-Presenting Cells (APC) and how do they work?
APC are mainy three categories:
What is the percentage of B cells in the peripheral blood?
15-20%
B cell responsible for plasma cell production and AB formation .
Mainly responsible fo humoral immunity
So it’s role in transplantation that it make AB lead to AMR and sensitization
b cell are responsible for antibody production therefor is responsible for AMR .
CREFULL CROSMATCH ( fo patient serum with donor Ag ) was resposible of elimination of this complication.
anti ABO Ab and anti HLA Ab ( especially DSA ) are important in this field .
B cell activation needs Ag presentation by T cells . the Ag attach to b cell recepter then internalized and degraded to peptide . this peptide is expressed in ( ag- MHC) complex in the cell wall which activate t cell.
the resultant of this activation is plasma cell ( Ab factory ) in the bone marrow and the memeory cell ( cd 27 positive ) in secondary lymphoid tissue .
the IgM ab HAS LOW ( MINIMUM ) ROLE IN KIDNEY TRANSPLANTATION ( LOW AFFINITY AB WHLE the IG g ab ( high affinity ) has important role in transplantation .
Targeting B Lymphocytes and Plasma Cells in Transplantation
Since all human B lymphocytes express the surface marker CD20, monoclonal antibodies against CD20 (Rituximab)
are quite effective at depleting B lymphocytes in the circulation and to a lesser extent in lymphoid organs.
Plasma cells, however, do not express CD20, THEREFORE IT IS NOT EFFECTIVE in treatment of AMR .
proteasome inhibitors, IS USED IN THE TREATMENT OF AMR AND SENSITIZED PATIENT .
Finally, B-lymphocyte depletion at the time of transplantation can increase the incidence of
acute rejection because of nonselective depletion of both pathogenic and regulatory B lymphocytes.
Functions of B cell in transplantation
B-cells participate in the cellular immunity through the following;
-act as Ag presenting cells, they present the Ag to the T-cells, lead to their activation with subsequent graft damage(CMR).
-they secret cytokines (IL2 &TNFa),that activate T-cells.
B-cells play a major role in humeral immunity through ;
-they differentiate into plasma cells, secret antibodies leading to (AMR)
B-cells ( regulator ) have a role in immunological tolerance ,as they can suppress others B-cells .
B-cells can differentiate into memory B cells, can induce memory response once reactivated.
Reference:
1- Pouliquen E, Koenig A, Chen CC, et al. Recent advances in renal transplantation: antibody-mediated rejection takes center stage. F1000Prime Rep 2015; 7: 51.
2- William Hoffman, Fadi G. Lakkis, and Geetha Chalasani B Cells, Antibodies, and More Clin J Am Soc Nephrol 11: 137–154, 2016. doi: 10.2215/CJN.09430915
●What are the types of HLA presented by B cells and T cells?
HLA presented b cells class 1/11
HLA presented by T cells class 1 only
●What is meant by B cell and T cell crossmatch?
If positive crossmatch for both B and T cells this means that HlA type 1 and type present .
But if possible B positive cross match and negative T crossmatch,
This means HLA type 2 only present.
●Antigen-presenting cells (APCs) are a heterogeneous group of immune cells that mediate the cellular immune response by processing and presenting antigens for recognition by certain lymphocytes such as T cells. Classical APCs include dendritic cells, macrophages, Langerhans cells and B cells.
●
What is the percentage of B cells in the peripheral blood?
Up to 10 % in prepheral blood
B cells and their downstream effector plasma cells (PCs) play a major role in acute and chronic ABMR [1].
Memory B cells rapidly differentiate to PCs following a secondary anamnestic response [2].
Post-transplant donor-specific antibody (DSA) and de novo DSA (dnDSA) are major risk factors and barriers to long-term stable graft survival .
Once DSA develops, almost 40% of affected patients lose their graft in contrast to patients with no dnDSA [3].
patients with preformed DSA, who comprise 40% of transplant waitlists, showed higher risk of rejection, either acute or chronic antibody-mediated rejection (ABMR) [4]. Alloantibody is also a major barrier to transplant tolerance.
Accommodation
Recent studies have shown that 30% of nonsensitized patients develop de novo DSA post-transplantation without demonstrating clinical signs of rejection [5]. This condition is referred to as accommodation [78,79]. Accommodation describes a biologic state in which grafts function despite noxious stimuli, like alloantibodies, against them.
B cells as antigen-presenting cells
Although chronic rejection is commonly considered an antibody-mediated process, Zeng et al. [6] have provided evidence that B cells are capable of promoting chronic rejection independently of antibody production.
Noorchasm and colleagues reported that indirect alloantigen presentation by recipient B cells plays a critical role in the activation of alloreactive CD4+ T cells [7]
cells may contribute to allograft rejection independently of antibody production by shaping the T-cell response through a combination of antigen presentation, cytokine production, and costimulation [8].
Additionally, one important role of B cells may include supporting the basic architecture of lymphoid tissue to allow optimal interaction between T cells, dendritic cells, and other components of the immune response [9].
B cells may play a pivotal role in the induction and maintenance of transplant tolerance [10].
Regulatory B cells (Bregs) have proven their importance in controlling immunity
Bregs function through IL-10 and through secretion of other cytokines (TGF-β, IL-35) to suppress CD4+ T-cell proliferation, suppress CD8+ effector T-cell function, induce T-cell apoptosis through binding the FAS and PD-1 receptors, induce Tregs, suppress antigen-presenting and cytokine secretion by dendritic cells and M1 macrophages, and suppress natural killer (NK) cells and neutrophils [11].
Reference
1 Clatworthy MR, Targeting B. Cells and antibody in transplantation. Am J Transplant 2011; 11: 1359.
2 Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol 2015; 15: 149.
3 Wiebe C, Gibson IW, Blydt-Hansen TD, et al. Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody. Am J Transplant 2015; 15: 2921.
4 Lefaucheur C, Loupy A, Hill GS, et al. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol 2010; 21: 1398.
5 Gill JS, Landsberg D, Johnston O, et al. Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection. Transplantation 2010; 89: 178.
6 Zeng Q, Ng YH, Singh T, et al. B cells mediate chronic allograft rejection independently of antibody production. J Clin Invest 2014; 124: 1052.
7 Noorchashm H, Reed AJ, Rostami SY, et al. B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J Immunol 2006; 177: 7715.
8 Lund FE, Randall TD. Effector and regulatory B cells: modulators of CD4+ T cell immunity. Nat Rev Immunol 2010; 10: 236.
9 Nolte MA, Arens R, Kraus M, et al. B cells are crucial for both development and maintenance of the splenic marginal zone. J Immunol 2004; 172: 3620.
10. Chong AS, Sciammas R.Matchmaking the B-cell signature of tolerance to regulatory B cells. Am J Transplant 2011; 11: 2555.
11 Peng B, Ming Y, Yang C. Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation. Cell Death Dis 2018; 9: 109
What are the Antigen-Presenting Cells (APC) and how do they work?
Antigen presenting cells (APC)
CD4 activation requires presentation of antigen of MHC-2 and the role carried out by APC
Examples of APC – B cells, Dendritic Cells (DC) , macrophages, activated human endothelial cells but DC is the most potent APC
DC present in all organs that are transplanted and in secondary lymphoid organs
Expression of CD11c and MHC-2 are useful markers to recognise classical DC in human tissues
After transplantation, DC cells migrate out of the organ( transplanted) into blood stream and will recognise recipient lymphoid system in which they interact and stimulate immune response
Mechanisms of antigen presentation by Dc in Alloimmunity
Donor tissue-resident DCs and shed antigens from transplanted allograft together activate recipient T cells for alloimmunity
Direct antigen presentation – migrating donor derived DCs within local lymphoid tissue
Indirect antigen presentation- recipient DCs acquiring shed antigens from damaged tissues
Semi direct antigen presentation -shed allo- MHC /peptide exosomes being acquired by recipient Dcs for presentation to recipient T cells
What is the percentage of B cells in the peripheral blood
Lymphocytes in human circulating blood are approximately 80 to 90 percent T cells and 10 to 20 percent B cells
References
Knechtle, S., n.d. Kidney Transplantation: Principles and Practice.
B cell functions and its role in transplantation
Role of B cell
B cells is always called as antibody secreting cells but they are multifunctional leukocyte population.
B cells can act as Antigen presenting cells because they express and co stimulators molecules such as CD40.
As APC, B cells engage T cells via TCR and vocal stimulatory molecules which in turn creates a cel cluster that enables cytokines secreted by T cell to influence B cell activation, differentiation and antibody production.
B cell express complement receptors, so can interact with complement coated damaged cells, facilitating antigen presentation and induces regulation of adaptive immunity
B cells mostly T cell dependant for activation and antibody production and encounter antigen in secondary lymphoid tissue
B cell and its role in Antibody mediated rejection (AMR)
B cells may be contributing to rejection process as B cells, B cell clusters and B cell, those have been described as being present in immunosuppression free transplantation recipient that showed operational tolerance to donor alloantigens
B cell may have the ability to regulate the alloimmunity response depending on the specific circumstances in transplantation recipient
Mechanism
When B cell encounter an antigen, it bind their surface BCR – may either develop into short lived germ line encoded antibody or becoming center B cell
Then, B cell divide and mutate region genes ( somatic hyper stimulation) to produce antibody with a higher affinity for antigen
B cell also undergo class switching the heavy chain present in antibody changes from mu to other isotypes
When multiple division and hyper stimulation happens, B cells with high affinity BCR are positively selected and differentiation into either B cell or plasma cells
Tfh after engaged by germinal centre which presented antigen to them , stimulating progress of GC reaction and development of memory B cell(CD27) and plasma cells
Small proportion of plasma cells arising from GC become long lived plasma cells in bone marrow
References
Knechtle, S., n.d. Kidney Transplantation: Principles and Practice.
~An antigen-presenting cell or accessory cell is a cell that displays antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T-cells.
~Almost all cell types can present antigens in some way. They are found in a variety of tissue types. Professional antigen-presenting cells, including macrophages, B cells and dendritic cells, present foreign antigens to helper T cells, while virus-infected cells (or cancer cells) can present antigens originating inside the cell to cytotoxic T cells. In addition to the MHC family of proteins, antigen presentation relies on other specialized signaling molecules on the surfaces of both APCs and T cells.
Antigen-presenting cells are vital for effective adaptive immune response, as the functioning of both cytotoxic and helper T cells is dependent on APCs. Antigen presentation allows for specificity of adaptive immunity and can contribute to immune responses against both intracellular and extracellular pathogens. It is also involved in defense against tumors. Some cancer therapies involve the creation of artificial APCs to prime the adaptive immune system to target malignant cells.
~ Antigen-presenting cells fall into two categories: professional and non-professional. Those that express MHC class II molecules along with co-stimulatory molecules and pattern recognition receptors are often called professional antigen-presenting cells.The non-professional APCs express MHC class I molecules.
Professional APCs specialize in presenting antigens to T cells. They are very efficient at internalizing antigens, either by phagocytosis (e.g. macrophages), or by receptor-mediated endocytosis (B cells), processing the antigen into peptide fragments and then displaying those peptides (bound to a class II MHC molecule) on their membrane. The T cell recognizes and interacts with the antigen-class II MHC molecule complex on the membrane of the antigen-presenting cell.
The main types of professional antigen-presenting cells are dendritic cells, macrophages and B cells.
~Non-professional antigen presenting cells include all nucleated cell types in the body. They use an MHC class I molecule coupled to beta-2 microglobulin to display endogenous peptides on the cell membrane. These peptides originate within the cell itself, in contrast to the exogenous antigen displayed by professional APCs using MHC class II molecules.
References:
***Kambayashi T, Laufer TM (November 2014). “Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell?”. Nature Reviews. Immunology. 14 (11): 719–30. doi:10.1038/nri3754. PMID 25324123. S2CID 22184839.
***den Haan JM, Arens R, van Zelm MC (December 2014). “The activation of the adaptive immune system: cross-talk between antigen-presenting cells, T cells and B cells”. Immunology Letters. 162 (2 Pt B): 103–12. doi:10.1016/j.imlet.2014.10.011. PMID 25455596.
***Hivroz C, Chemin K, Tourret M, Bohineust A (2012). “Crosstalk between T lymphocytes and dendritic cells”. Critical Reviews in Immunology. 32 (2): 139–55.
Previously, it was thought that T cells are the corner stone of graft rejections, but nowadays the interest in the role of B cells increased markedly.
In the indirect way to recognize the allograft, the B cells act as APCs and represent the donor antigens to the recipient T cells triggering the rejection process.
B cells activity in renal transplantation can be detected by markers such as C4d deposition in peritubular capillaries and the presence of DSAs in the patient circulation.
CDC cross matching is done by mixing the patient serum with the donor lymphocytes.
If CDC T cells crossmatch is positive , it means that the recipient have antibodies against HLA class l antigen, while if CDC B cells is positive, it means that he has antibodies against both class I and class II antigens.
Ref:
B cells in renal transplantation: pathological aspects and therapeutic interventions | Nephrology Dialysis Transplantation | Oxford Academic (oup.com)
What is the role of B cells in transplantation
B cell are subtype of adaptive immunity
B cell recognize antigen by b cell receptors (antibody itself) presented to it by follicular tcell in the 2ry lymphoid organs differentiate to plasma cell (effector b cell) which secrets the antibodies which results in ABMR (acute and chronic) which identified in the pathology by microvascular inflammation (PTC and G) plus C4d stain in PTC and TMA
And identified in the serum by circulating DSA
Role of B cell is not restricted on antibodies formation it also act as APC as it has MHC class 2 and present antigens to Tcell so play role in Tcell mediated rejection
B cell is divided into subtypes(Naïve,effector which is plasma cell, memory, regulatory)
Breg secrets IL10 which plays important role in tolerance and identification of transcriptional signature had been seen in tolerant patients which showed upregulation of b cell related genes
Target therapeutics targeting b cell
1)ATG depleting induction which produces both tcell and b cell lysis but it has been shown that it affect Breg and inhibit tolerance
2) rutiximab which anti CD20 on Naïve bcell not on effector (plasma cell)…so it shouldn’t be used alone as its functions limited only also its efficacy is limited due to anti rutiximab antibodies so CD19level it’s better to be measured
3) obnitozomab(gazyva) which is also CD20 but more potent than rutiximab and studies giving promising results but still on small size and lack of randomization
4)bortezomib which is antiplasma cell which theoretical was thought to be effective but results were disappointing
5)IVIG which is widely used and block BCR and antibodies and its very effective drug in both desensitization and treatment of ABMR
What are the Antigen-Presenting Cells (APC) and how do they work?
b cell , macrophages and denderitic cells
What is the percentage of B cells in the peripheral blood
Its around 5-10%0of total peripheral blood
References:
1- Schmitz R, Fitch ZW, Schroder PM, Choi AY, Jackson AM, Knechtle SJ, et al. B cells in transplant tolerance and rejection: friends or foes? Transpl Int. 2020;33(1):30–40.
2- Clatworthy MR. B-cell regulation and its application to transplantation. Transpl Int. 2014;27(2):117–28.
3- Karahan GE, Claas FHJ, Heidt S. B cell immunity in solid organ transplantation. Front Immunol.
Nowadays the role of Bcells are more prominent in kidney transplantation. Bcells can cause allograft rejection by producing alloantibodies, induction of Tcells trigger macrophages, Natural Killer cells and activating complement. The preformed antibody includes anti-ABO and also anti-HLA antibodies play a significant role in hyperacute rejection. After the transplantation, donor specific antibodies that were against HLA and sometimes even non-HLA antigens of donor, play a major part in chronic and acute ABMRs. Bcells became mature in secondary lymphoid organs, with the help of TFH. Ag is detected by Bcell Receptor and is internalized and transformed into peptides and is bounded to MHC class 2 at the surface of B lymphocytes and is detected by CD4+ T lymphocytes. T lymphocytes help this process by cytokines and costimulatory ligands. In germinal center, B cells are proliferated and transformed to plasma cells and memory Bcells. Memory Bcells react vigorously and fast in response to antigens that previously produced antibodies. Antibodies attached to donor antigens can induce antibody mediated rejection by complement activation and stimulation of NK cells and macrophages attaching FC reseptors.
B cells can play role of antigen presenting cells and secret inflammatory cytokines like TNF-α. Immunomodulatory function of B regulatory cells (B regs) and secretion of IL-10 may play role in chronic rejection or reversely tolerance. Referances:
1. Dijke, E. I., Platt, J. L., Blair, P., Clatworthy, M. R., Patel, J. K., Kfoury, A. G., & Cascalho, M. (2016). B cells in transplantation. In Journal of Heart and Lung Transplantation (Vol. 35, Issue 6).
2. Schmitz, R., Fitch, Z. W., Schroder, P. M., Choi, A. Y., Jackson, A. M., Knechtle, S. J., & Kwun, J. (2020). B cells in transplant tolerance and rejection: friends or foes? In Transplant International (Vol. 33, Issue 1).
Beside producing antibodies , B cells can regulate cellular immunity and can contribute to the genesis of tolerance , B cell response is one of obstacles for transplantation .
B cells triggers humoral immunity ( antibody mediated rejection ) through formation of donor specific antibodies against HLA antigens .
response of B cells to antigens:
if the antigen is foreign polysaccharides such as blood group , the response will be T cell independent , but if the antigen is foreign proteins such as HLA antigen that need T cell help.
B-cell responses to proteins manifest both memory of and progressive increase in affinity of the B-cell receptor to the antigen and this occur due to mutations in the variable regions of immunoglobulin genes followed by selection and survival of the mutated B cells that compete more effectively for antigen and T-cell help( affinity maturation) these form memory B cells then they can be differentiated to plasma cells.
they lead to acute and chronic antibody mediated rejection , transplant tolerance
Dijke, Esme I et al. “B cells in transplantation.” The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation vol. 35,6 (2016): 704-10. .
The role of B cells in transplantation:
HLA class I genes are expressed by all nucleated cells and control the activation, function of cytotoxic T cells so express both T cells and B cells .
HLA class II molecule expression is restricted to antigen presenting cells (dendritic cells, macrophages, monocytes), and B cells. so during acute graft rejection both class I and II HLA can be expressed by vascular endothelial cell.
B cells activation and differentiation to antibody-secreting plasma cells play major role in acute and chronic ABMR .
B cells shape the T-cell response through a combination of APC, cytokine production,
and costimulation , complement activation .
in acute ischemic hypo perfusion injury B cells activation have direct effects on the allograft and induce acute humeral rejection.
interesting growing evidence from recent studies demonstrates that B cells may play a pivotal role in the induction and maintenance of transplant tolerance through accommodation effect of the regulatory B cells.
References
1-handbook of transplantation ,Fifth Edition. Gabriel M.Danovitch.
2-Understanding crossmatch testing in organ transplantation: A case-based guide for the general nephrologistnep_1414 125..133 WILLIAM R MULLEY1,2 and JOHN KANELLIS1,
3-B cells in transplant tolerance and rejection: friends or foes? Robin Schmitz, Zachary W. Fitch, Paul M. Schroder, Ashley Y. Choi, Annette M. Jackson, Stuart J. Knechtle & Jean Kwun.
B cells in transplant rejection:
1–Differntiate to antibody secreting plasma cells.
2-Bcell shape t-cell response through a combination of antigen presenting cell, cytokine
production and co stimulation.
3- Direct B-cell effect by initiate ischemic injury.
B cells as antigen-presenting cells:
B cells are capable of promoting chronic rejection independently of antibody production,
by shaping the T-cell response through a combination of antigen presentation, cytokine
production, and costimulation. (1)
B-cell response to tissue injury:
Kidney injury in ischemia/reperfusion injury and transplantation are both mediated by a
B-cell response to dysfunctional tissue repair.
Role of B cells in promoting tolerance:
Growing evidence demonstrates that B cells may play a pivotal role in the induction and
maintenance of transplant tolerance. Upregulation of B-cell-related genes and their
molecular pathways were associated with tolerance.
References:
1- Bo Peng, Yangzi et al .Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation. Cell Death & Disease volume 9, Article number: 109 (2018)
What are the types of HLA presented by B cells and T cells?
What is meant by B cell and T cell crossmatch?
B cells express both class I & II HLA (class I is expressed in all nucleated+ it is one of APCs so additionally it has class II HLA)
T cells express class I HLA( class I is expressed in all nucleated cells)
Positive B cell crossmatch indicate the presence of class II HLA AB & to lesser extent class I HLA AB
Positive T cell crossmatch indicate the presence of class I HLA AB
What are the Antigen-Presenting Cells (APC) and how do they work?
Antigen presenting cells (APCs) are critical for the initiation of adaptive immune responses and for maintenance of peripheral tolerance.
APCs are cells that can process a protein antigen, break it into peptides, and present it in conjunction with class II MHC molecules on the cell surface where it may interact with appropriate T cell receptors(CD4+ TH cells.. However APCs including DCs can also present exogenous antigens to the MHC I receptor to activate CD8+ T cells during a process called cross-presentation).
Professional APCs include dendritic cells, macrophages, and B cells, whereas nonprofessional APCs that function in antigen presentation for only brief periods include thymic epithelial cells and vascular endothelial cells
Dendritic cells, macrophages, and B cells are the principal APCs for T cells, whereas follicular dendritic cells are the main antigen presenting cells for B cells.
What is the percentage of B cells in the peripheral blood?
Lymphocytes in human circulating blood are approximately 80 to 90% T cells and 10 to 20 % B cells. They represent 10-15% of the peripheral blood mononuclear cells and carry the marker CD19
Cross-Talk Between Antigen Presenting Cells and T Cells Impacts Intestinal Homeostasis, Bacterial Infections, and Tumorigenesis
Stephen J. Guadino and Pawan Kumar Front. Immunol., 06 March 2019
B lymphocytes (BL) play an essential role in the biological processes mediating renal graft rejection and tolerance through various effector mechanisms
B cells can perpetuate alloimmune responses in multiple ways:
§ Differentiation into antibody-producing plasma cells that can secrete antibodies that can cause hyper acute rejection in sensitized patients
§ sustaining long-term humoral immune memory(memory B cells)
§ serving as antigen-presenting cells to CD4 TH cells
§ organizing the formation of tertiary lymphoid organs with lymphotoxin expression
§ secreting pro- as well as anti-inflammatory cytokines to trigger polarization of naïve T lymphocytes into Th1 or Th2 cells
§ Maintenance of the fine equilibrium required for tolerance(Breg cells)
The cross-talk between B cells and T cells in the course of immune responses forms the basis of these diverse functions
B cell subsets: Naïve, transitional, plasma cells, memory B cells and B regular cells
Targeting B cells should take into consideration their different functions and the consequences as simple depletion of all B cells can interfere with beneficial effects of certain B cell subpopulations.
Why are B Cells Important in renal Transplantation?
Currently available immunosuppressive regimens are centered on T cells to reduce acute rejection rates and hence improved short-term graft survival but they are not effective in controlling humoral immune responses since antibody-mediated rejection (ABMR)
Depletion of B cells at the time of kidney transplantation seemed to enhance acute T cell-mediated rejection as they may eliminate a population of B cells with regulatory properties (B regulatory cells (Breg)), thus enhancing the T cell allo-response
Moving forward rational strategies to target B cells need to maximize the tolerogenic capacity of B cells while minimizing their immunostimulatory effects.
Essential role for B cells in transplantation tolerance.
Robert R Redfield, III, Eduardo Rodriguez, Ronald Parsons, Kumar Vivek, Moiz M Mustafa, Hooman Noorchashm, Curr Opin Immunol. 2011 Oct; 23(5): 685–691
B cells in renal transplantation: pathological aspects and therapeutic interventions
Nicholas Barnett, Anthony Dorling, Nizam Mamode. Nephrology Dialysis Transplantation, Volume 26, Issue 3, March 2011, Pages 767–774
Monitoring of B Cell in Kidney Transplantation: Development of a Novel Clusters Analysis and Role of Transitional B Cells in Transplant Outcome.
Rafael Alfaro et al, Diagnostics 2021, 11, 641.
What are the Antigen-Presenting Cells (APC) and how do they work?
What is the percentage of B cells in the peripheral blood?
Antigen-presenting cell is cell that displays antigen bound by MHC proteins on its surface. Antigen-presenting cells include macrophages, dendritic cells and B cells. APCs present foreign antigens to helper T cells. Antigen-presenting cells are vital for effective adaptive immune response, as the functioning of both cytotoxic and helper T cells is dependent on APCs.
Among all peripheral blood lymphocytes, B cells account for 2–10% of all lymphocytes.
Professional APC include dendritic cells, macrophage & B cells , & non professional APC ( function temporary as APC) include thyme epithelial cells & vascular endothelial cells.
It can process the protein antigen & break it to peptide & present it with class II MHC on cell surface to interact with T cells receptor.
B cells compromised 5-10% of peripheral blood mononuclear cells.
B cells are part of immune system cells that are proliferate and differentiate in the bone marrow ,they are characterized by expression of antibody through antigen surface receptors BCR ,after many levels of division and differentiation B cells will be divided into either memory B cells or plasma cells .
B cells are responsible in the immune system to activate and produce antibodies (humoral)response leading to hyperacute rejection ,acute ABMR and chronic ABMR .
Also they play a role in initiating cellular response or immunity by presenting antigens to CD 4+ T cells and regulate other immune cells to produce cytokines .
ABMR caused from pathway of alloantibody effector function by direct activation of endothelial cells to MHC leading to complement activation (classical pathway) or immune cells activation that express complement receptors like macrophages,neutrophils,money and natural killer cells .
ABMR treatment usually difficult and it’s diagnosed by alot of methods mainly by detection alloantibodies and complement activation in graft biopsy through C4d staining although in chronic ABMR C4d may be negative ,also ABMR can be detected by graft function detorioration and DSA detection .
Regarding HLA types question :
Class I is present in all nuclaeted cells also T and B cells
Class II is restricted in bone marrow derived cells ,B cells and present mainly in antigen presenting cells APC which are ;macrophages, mesengial cells and dendritic cells these will make antigens present peptides to CD4+ T cells leading to their activation and by this it will activate CD8+ cell.
An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytosethe pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells. Dendritic cells are immune cells that process antigen material; they are present in the skin (Langerhans cells) and the lining of the nose, lungs, stomach, and intestines. Sometimes a dendritic cell presents on the surface of other cells to induce an immune response, thus functioning as an antigen-presenting cell. Macrophages also function as APCs. Before activation and differentiation, B cells can also function as APCs
percentage of B cellin prripheralbloof about 5–10/
Thank you for emphasizing Dendritic cells
//B cells play a role in graft rejection via several mechanisms. Specifically, B cells produce high-affinity antibodies to alloantigens including allogeneic major histocompatibility complex (MHC) with the help of follicular helper T cells. B cells also function as antigen-presenting cells for alloreactive T cells, resulting in the activation of alloreactive T cells. Conversely, the frequency of regulatory B cells increases under inflammatory conditions and suppresses the rejection process. Here, the differential roles of the major B cell subpopulations (B-1, follicular B, marginal zone B, and regulatory B cells) involved in transplantation rejection
Role of the B-cell in transplantation:
B-cells express surface antibody (Ig) as BCR, and variable surface markers during their development, to adapt and facilitate their function.
Ex: CD20, CD19, CD27, CD32B (FcyRIIB).
The function of B-Cell:
1- Act as a precursor to Antibody producing plasma cells, these antibodies react with proteins and peptide Ag (T-dependent Ag), also, interact with carbohydrate/polysaccharide antigens (T-independent Ag).
2- Act as immune effector
3- Negatively regulate or modulate the immune response.
4- T-cell activation via Ag presentation leads to immune response.
5- Formation of an ectopic germinal center.
(As they can clonally expand, they can form a nucleus of lymphoid tissue in the inflamed tissue and allograft.) (Arrangement (orchestration) of the microarchitecture of the secondary lymphoid tissues).
6- Enhancing innate immune response.
B-Cell subsets:
B1-cell:
· Produce natural antibodies (that have a low affinity, poly-reactive) to T-cell independent Ag, as the first line of defence, as well, these antibodies are protective in atherosclerosis which may be of relevant role in vasculopathy in transplantation.
· Have a phagocytic and microbiocidal activity.
B2-cell:
Formed in the bone marrow released as immature B-cells and circulate through 2RY lymphoid organs (spleen and lymph nodes) as naïve B cells which express IgM and IgD. These cells are either:
· Follicular B cell (T-dependent response)
· Marginal Zone B cell (T-independent response), express CD21(CR2), and memory marker CD27.
Plasma cell
Memory B Cell
Regulatory B cell (Bregs) has regulatory immune inhibitory function via the production of IL-10 (also called B10 cell), it expresses CD24, CD38, CD5, and CD27.
B-cell also expresses CD19 which is a co-receptor that can lower the threshold for B-cell activation.
B-cell activation can also be facilitated by complement components (C3b, C3d) that bind to CD21.
B-cell expresses- TLR (Toll-like receptor 12, 6,7,9,10)
B-cell may also receive pro-activation and survival signals via cytokines (BAFF= TNF tumor necrosis factor family), overexpression of it can cause hypergammglobulinemia.
B-cells express either Co-activating receptors or inhibitory receptors (FcyRIIB)
The inhibitory receptors, in their cytoplasmic domain, have tyrosine protein, ligation of it with BCR, negatively regulates B-cell activation. This protein is called immunoreceptor tyrosine inhibitory motifs (ITIM receptor). The inhibitory receptors are important in terminating germinal center (GC) responses once sufficient antigen-specific IgG has been generated. (Overexpression of them results in reduced autoimmunity.
CD22, is a glycoprotein of Ig superfamily, co-ligation of CD22 to BCR reduces B-cell activation while sequestratingCD22 away from the BCR, resulting in B-cell hyperactivity.
· B-cells with high affinity for antigen are differentiated to either memory or plasma cells.
· within the B-cell follicles there is CD4T-cell (expresses Bcl-6) which is known as follicular helper cell (Tfh). The Tfh cells are essential for the development of the germinal centre B-cell response. Inhibition of these cells may represent a possible strategy in future attempts to inhibit humoral alloimmunity.
· Small proportion of plasma cells arising from the germinal centre become established as long-lived plasma cells in the bone marrow and act as long-term antibody factories, producing IgG. They do not proliferate, and they reside within a number of limited niches, like the inflamed tissue in autoimmunity and within the allografts.
From that, we can conclude that the B –cell has multiple roles in transplant immunology
In summary, the B-cell have roles in:
1- Acute T-cell mediated rejection.
2- Acute and chronic antibody-mediated rejection.
3- Immunomodulatory role via interleukin production (IL10).
4- Transplant tolerance.
Transplanted graft tolerance might allow patients to wean off immunosuppression and maintain normal graft function.
Regulatory B-cell (Brgs) has an important role in promoting and maintaining tolerance.
Identification of transcriptional signature intolerant patients shows upregulation of B cell-related gene.
The majority of biomarkers associated with tolerance were found to be B-cell related.
the body underwent several mechanisms to adapt for tolerance, like changing the harmful type of IgG to IgG2 that is not harmful to the graft, if true to say that.
# So, B-cell has harmful (rejection) and beneficial (tolerance)effects in transplantation, by cell depletion, the benefit of B-cell can be lost.
· De novo donor-specific antibodies (DSA) production is frequently associated with acute antibody-mediated rejection (AMR) which has a deleterious effect on the transplantation outcome.
· DSA and non-HLA Abs may contribute to the long-term allograft exhaustion in chronic AMR.
References:
1- Schmitz R, Fitch ZW, Schroder PM, Choi AY, Jackson AM, Knechtle SJ, et al. B cells in transplant tolerance and rejection: friends or foes? Transpl Int. 2020;33(1):30–40.
2- Clatworthy MR. B-cell regulation and its application to transplantation. Transpl Int. 2014;27(2):117–28.
3- Karahan GE, Claas FHJ, Heidt S. B cell immunity in solid organ transplantation. Front Immunol.
What are the Antigen-Presenting Cells (APC) and how do they work?
What is the percentage of B cells in the peripheral blood?
APCs are immune cells , that present antigens to T lymphocytes, they process antigens and present it on its surface in conjugation with Class II MHC .
Types of APCs include , dendritic cells , B cells and macrophages
Percentage of B cells in peripheral blood as a total 2.5% in other articles up to 10%
( peripheral B cells are subclassified into naive , memory , plasmablast and immature B cells )
Perez-Andres M, Paiva B, Nieto WG, Caraux A, Schmitz A, Almeida J, Vogt RF, Marti GE, Rawstron AC, Van Zelm MC, Van Dongen JJM, Johnsen HE, Klein B, Orfao A. Human peripheral blood B-cell compartments: A crossroad in B-cell traffic. Cytometry Part B 2010; 78B (Suppl. 1): S47–S60.
B cells have multifactorial role in initiating and regulating allograft injury
B cells and their progeny of plasma cells , were thought initially to have the main function of DSAs production and so mediating ABMR (1)
Now B cells are recognized to present donor antigens to T cells ,thus mediating T cell mediated allograft injury ( 2)
Moreover, some animal studies ,showed that B cells may have immunoregulatory functions , through secretion of IL 10 , they can suppress Effector T cells , and upregulate Treg ( regulatory T cells ) and hence their role in transplantation tolerance , and so the idea of complete B cell depletion that may be harmful as it depletes regulatory B cells .
Studies also proved that tolerant recepient ,exhibit B cell derived gene products not found in recipients receiving immunosuppression
Generally B cells may cause allograft rejection independently of antibody production by facilitating T-cell response through a combination of antigen presentation, cytokine production, and costimulation
1) Loupy A, Hill GS, Jordan SC: The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol 8: 348–357, 2012
2) Noorchashm H, Reed AJ, Rostami SY, Mozaffari R, Zekavat G, Koeberlein B, Caton AJ, Naji A: B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J Immunol 177: 7715–7722, 2006 [PubMed] [Google Scholar] [Ref list]
3) Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, Burlingham WJ, Marks WH, Sanz I, Lechler RI, Hernandez-Fuentes MP, Turka LA, Seyfert-Margolis VL; Immune Tolerance Network ST507 Study Group: Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest 120: 1836–1847, 2010
Dear All
What are the Antigen-Presenting Cells (APC) and how do they work?
What is the percentage of B cells in the peripheral blood?
APCs consist of dendritic cells, macrophages, B lymphocytes, and activated human endothelial cells, but among them, dendritic cells are the most potent. APCs provide the means by which HLA-peptide complexes are presented to T-cell receptors and provide necessary signals required for T-lymphocyte proliferation and differentiation. The percentage of B cells in the peripheral blood is about 5-10%.
B cells >>>>> plasma cells produce antibodies
In the past these antibodies against ABO and/or HLA antigens were the cause of hyperacute rejection but nowadays after Careful ABO matching of donors and recipients and careful testing of the recipient‘s serum for antibodies against the donor‘s HLA prior to transplantation have
eliminated hyperacute rejection in the clinic.
More recently, however, the significance of donor-specific antibodies (DSA) that arise after transplantation has come to the fore. These antibodies, usually against donor HLA but sometimes directed against non-HLA, are associated with poor renal allograft outcomes by causing acute or chronic antibody-mediated rejection (ABMR), often in combination with an ongoing T lymphocyte–mediated (cellular) rejection.
B-Lymphocyte Activation and Differentiation
Naïve B-lymphocyte activation is dependent on antigen recognition by the B-cell receptor (BCR) and on (T-helper) CD4+ T lymphocytes inside secondary lymphoid organs.
Antigen degraded into peptides which bound to MHC II forming MHCII–peptide complexes on B cell surface then certain mechanisms occurs lead to differentiation of B cells to plasma cells (which are the factories for the antibodies) and B memory cells; both of them are responsible about maintaining Humoral immunity
Plasma cells exit secondary lymphoid organs and reside for a long time in the bone marrow. They rely on IL-6 for survival.
Memory B lymphocytes, on the other hand, populate secondary lymphoid tissues and circulate in the blood. In humans, they are marked by expression of the surface protein CD27. Similar to memory T lymphocytes, memory B lymphocytes respond much more vigorously than their naïve counterparts to the antigen to which they are specific and produce antibodies of higher affinity
Antibody-Independent Functions of B Lymphocytes
In addition to producing antibodies, B lymphocytes contribute directly to T-lymphocyte immunity by three known mechanisms: (1) they serve as APCs that enhance T-lymphocyte differentiation to memory T lymphocytes; (2) they function as bona fide cellular effectors that produce inflammatory cytokines (for example, TNFα); and (3) a subgroup of them, known as regulatory B lymphocytes (Breg) characterized by IL-10 secretion, modulate immune responses
Targeting B Lymphocytes and Plasma Cells in Transplantation
Since all human B lymphocytes express the surface marker CD20, monoclonal antibodies against CD20 (Rituximab) are quite effective at depleting B lymphocytes in the circulation and to a lesser extent in lymphoid organs. Plasma cells, however, do not express CD20, providing one explanation why Rituximab has not been particularly successful at reversing DSA or ABMR in renal transplant recipients. More recently, proteasome inhibitors, originally developed for the treatment of multiple myeloma, have been employed to inhibit plasma cell function in sensitized patients or those with DSA/ABMR. Finally, B-lymphocyte depletion at the time of transplantation can increase the incidence of acute rejection because of nonselective depletion of both pathogenic and regulatory B lymphocytes.
The main functions of B cells are:
1-to make antibodies against antigens
2-to perform the role of antigen-presenting cells (APCs),
3-to develop into memory B cells after activation by antigen interaction.
To generate an effective antibody response B cells need to
1-Recognize antigen through their BCR (signal 1)
2-Receive help from activated CD4 T cells which provide signal 2
These two conditions are actually linked. When antigen binds to the BCR B cells will be activated, This will then be recognized by T cells that have already been activated in response to the same antigen .
B cells contribute to allograft rejection after differentiating into antibody-secreting plasma cells .
Post-transplant donor-specific antibody (DSA) and de novo DSA (dnDSA) are major risk factors to long-term graft survival. Once DSA develops, almost 40% of affected patients lose their graft in contrast to patients with no dnDSA
Furthermore, patients with preformed DS , showed higher risk of rejection, either acute or chronic antibody-mediated rejection (ABMR) regardless of type of organ transplantation
The innate immune system contains cells that detect potentially harmful antigens, and then inform the adaptive immune response about the presence of these antigens. An antigen-presenting cell (APC) is an immune cell that detects, engulfs, and informs the adaptive immune response about an infection. When a pathogen is detected, these APCs will phagocytose the pathogen and digest it to form many different fragments of the antigen. Antigen fragments will then be transported to the surface of the APC, where they will serve as an indicator to other immune cells.
1-Schmitz R,,Zachary W. B cells in transplant tolerance and rejection: friends or foes?. Transpl Int. 2020 January ; 33(1): 30–40. doi:10.1111/tri.13549.
2-Renal Transplantation, Oxford Medicine
What are the Antigen-Presenting Cells (APC) and how do they work?
APC are a group of cells involved in immune system with the primary function of processing and presenting antigens to lymphocytes like T cells for triggering an immune response. These include B cells, dendritic cells, macrophages and Langerhans cells.
What is the percentage of B cells in the peripheral blood?
B cells account for 2-10% of all lymphocytes in the peripheral blood
B cells are precursors of antibody producing plasma cells, secrete cytokines, present alloantigens to T cells, give rise to humoral immune memory through memory B cells
Antibody response in kidney transplant
Studies reported that de novo and pre existent IgG DSAs are associated with acute and chronic allograft rejection. (1)
recipients developing DSA post transplant have lower rates of graft survivalthan those without DSA (2)
memory B cells provide long lasting humoral immunity responsible for rapid release of antigen specific antibodies have low threshold of activation (3)
Studying donor specific B cell response in transplant is gaining more importance. (4)
Role of B cells in antigen presentation to alloreactive T cells
They are potent APCs because
The possible role of B cells as APCs in T cell mediated rejection was reported in studies on renal biopsies.
A study showed that in biopsies of acute cellular rejection, there were dense B cell clusters that didn’t correlate with C4d deposition and was associated with low graft survival (6)
CD20+ B cell clusters were present in cases of T cell mediated rejection in absence of ABMR suggesting the role of B cells other than antibody production. (7)
B cells infiltration of chronically rejected allografts
A study showed that lymphoid neogenesis was present in explanted kidney allograft due to chronic rejection. (8) the grafts were infiltrated with B cells and were organized into nodules similar to B cell follicles. (9)
B cells as immune regulators
The role of B cells in tolerance was suggested after identification of B cell signature in operationally tolerant kidney transplant recipients. (10)
Tolerant patients have increased peripheral blood B cells with shift to the naïve and transitional phenotype. (11)
(1) Loupy A, Hill GS, Jord Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest (2010) 120(6):1836–47.an SC. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol (2012) 8(6):348–57.
(2) Loupy A, Lefaucheur C, Vernerey D, Prugger C, Duong van Huyen JP, Mooney N, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med (2013) 369(13):1215–26.
(3) Lanzavecchia A, Bernasconi N, Traggiai E, Ruprecht CR, Corti D, Sallusto F. Understanding and making use of human memory B cells. Immunol Rev (2006) 211:303–9.
(4) Lucia M, Luque S, Crespo E, Melilli E, Cruzado JM, Martorell J, et al. Preformed circulating HLA-specific memory B cells predict high risk of humoral rejection in kidney transplantation. Kidney Int (2015) 88(4):874–87.
(5) Lanzavecchia A. Pillars article: antigen-specific interaction between T and B cells. 1985. J Immunol (2007) 179(11):7206–8
(6) Sarwal M, Chua MS, Kambham N, Hsieh SC, Satterwhite T, Masek M, et al. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N Engl J Med (2003) 349(2):125–38
(7) Hippen BE, DeMattos A, Cook WJ, Kew CE II, Gaston RS. Association of CD20+ infiltrates with poorer clinical outcomes in acute cellular rejection of renal allografts. Am J Transplant (2005) 5(9):2248–52.
(8) Thaunat O, Patey N, Caligiuri G, Gautreau C, Mamani-Matsuda M, Mekki Y, et al. Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J Immunol (2010) 185(1):717–28.
(9) Cheng J, Torkamani A, Grover RK, Jones TM, Ruiz DI, Schork NJ, et al. Ectopic B-cell clusters that infiltrate transplanted human kidneys are clonal. Proc Natl Acad Sci U S A (2011) 108(14):5560–5.
(10) Heidt S, Wood KJ. Biomarkers of operational tolerance in solid organ transplantation. Expert Opin Med Diagn (2012) 6(4):281–93.
(11)Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest (2010) 120(6):1836–47.
B cells have an important role in transplantation. They act both as antigen presentation cells and transform into plasma cells secreting antibodies. They also have a role in transplantation tolerance. As many colleagues said. APCs (antigen-presenting cells) in simple words process antigens to be recognized by T cells. Dendritic cells and macrophages are also examples. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184555/figure/F1/
T cell cross match / Bcell cross match /interpretition
-VE /-VE /No DSAb to HLA class I or II OR
DSAb titre lower than a level that can cause positive reaction OR DSAb that is not complement-fixing – relevance unclear)
+VE /+VE /DSAb/s to HLA class I OR
Multiple DSAbs to HLA class I +/− II
-VE /+VE /DSAbs to HLA class II OR
Low level DSAb/s to HLA class I
+VE /-VE /Technical error ( related to B-cell viability).
The test should be repeated
Mullery W R et al.Understanding crossmatch testing in organ transplantation: A case-based guide for the general nephrologist.Nephrology 16 (2011) 125–133
Types of HLA presented by B cells and T cells;
Class I MHC molecules ; T cells that express CD8 molecules react with class I MHC molecules. These have a cytotoxic function, need to recognize any infected cell. Because every nucleated cell expresses class I MHC molecules, all infected cells can act as antigen-presenting cells for CD8 T cells .
Class II MHC molecules ; present only on professional antigen-presenting cells (B cells, macrophages, dendritic cells, Langerhans cells), thymic epithelium, and activated (but not resting) T cells; most nucleated cells can express class II MHC molecules by interferon (IFN)-gamma. T cells reactive to class II molecules express CD4 and are helper cells.(1)
T cells have dual specificity, so they recognize bothMHC I or MHC II and peptide antigens displayed by those MHC molecules.
So the T cell receptor actually recognizes the combination of the MHC molecule and the peptide. Once bound to the MHC molecule, the T cell can begin its role in the immune response.(2)
Naive and memory B cells concentrate HLA-DR, -DM and -DO into compartments dispersed under the cell surface, which are identifed by their expression of lysosome-associated membrane protein (Lamp)-1 as late endosomes/lysosomes. B cell subsets appear to have distinct mechanisms of antigen processing. The naive and memory B cells display small superfcial MIIC that contain HLA-DM and -DO
T lymphocytes have HLA class I antigens while B lymphocytes have both HLA class I and class II antigens. If the recipient’s serum contains antibodies against any of these HLA antigens, the antibodies will target such lymphocytes. This will activate the complement via the classical pathway, causing cell lysis.(3)
References
1-Delves P J , Human Leukocyte Antigen (HLA) System.MSD manual professional version, Sept 2021
2-Lodge A , Immunolgay for nonimmunologist T cell antigen recognition , Hema care 2018
3- Chalouni C et al .Human germinal center B cells differ from naive and memory B cells by their aggregated MHC class II-rich compartments lacking HLA-DO. International Immunology, 2002 Vol. 15, No. 4, pp. 457±466
Dear Dr Ahmed,
What are the Antigen-Presenting Cells (APC) and how do they work?
Antigen-Presenting Cells (APC) as we can expect from the name are highly specialized cells that are responsible for sampling and processing the foreign antigens to present them later to T cells resulting in the initiation of immune response and activation of memory cells. They are characterized by the presence of HLA class II antigens (1).
They are not only presenting the processed antigens via the HLA-peptide complexes but they also provide the necessary signals required for T-lymphocyte proliferation and differentiation.
Dendritic cells, macrophages, B lymphocytes, and activated human endothelial cells are all known to function as APCs (1).
What is the percentage of B cells in the peripheral blood?
The B cells in the peripheral blood are about 10% of the lymphocyte population in healthy controls as mentioned in one study (2).
References:
1) Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
2) Elmér E, Smargianaki S, Pettersson Å, et al. Increased Frequencies of Switched Memory B Cells and Plasmablasts in Peripheral Blood from Patients with ANCA-Associated Vasculitis. J Immunol Res. 2020 Nov 28; 2020: 8209737.
Excellent
What are the Antigen-Presenting Cells (APC) and how do they work?
What is the percentage of B cells in the peripheral blood?
APCs are cells mediate immune response by processing and presenting antigen to T cells
e.g B cells, dendritic cells , langerhans cells, and macrophages
B cells represent 2-10 % of peripheral blood cells
Excellent
Role of B cell in transplantation
B cells can regulate cellular immunity, participate to the genesis of tolerance, and accommodation in transplantation.
Besides producing antibodies, B cells enhances lymphoid organogenesis. B cells increase the development of dendritic cells, acting as antigen-presenting cells, in secondary lymphoid tissues.
T cells known to provide help for B cells, mean while currently the opposite is most probable , Bcells enable thymocytes to mature into T cells. B cells produces signals for keeping T cells in the periphery and regulating it’s functions
B cells present antigen and enhance activation of T cells and participates inT-cell tolerance and to accommodation that protects target tissues when tolerance fails.
Bound antibody can enhance cellular immunity and cellular rejection, and it can block or depress cellular immunity and rejection in tumor transplants (i.e., enhancement).
B-cell responses to some polysaccharides, such as blood groups, are emerging from newly activated B cells and do not get more effective with repeated exposure. These responses do not require T-cell help, and accordingly they are called T independent.
B-cell responses to protein antigens require T-cell help, requiring activation of T cells responding to peptides with MHC class II.
The activation of T cells and the recruiting of T-cell help is consolidated if B cells recognize a foreign protein via the antigen receptor, engulf it , and present peptides to T cells.On the other hand , B-cell responses to proteins manifest both memory and progressive increase in affinity of the B-cell receptor to the antigen.
Reference;
-Dijke E I etal . B cells in transplantation. J Heart Lung Transplant. 2016 June ; 35(6): 704–710.
Many transplanted patients require retransplantation or even die of graft rejection. Thus, the prevention of graft rejection is a critical step in improving outcomes in organ transplantation.
Chronic antibody-mediated rejection is considered the main cause of late allograft loss.
Several mechanisms have been attributed to B cells during graft rejection. The most important function of B cells is producing antibodies against HLA and nonHLA antigens. These antibodies contribute to complement fixation and cell lysis,antibody-dependent cellular cytotoxicity by NK, increasing the thickness of endothelial and smooth muscle cells, activating platelet, developing inflammatory conditions, thrombosis, and overall reducing of graft function.1,2
B cells present antigens to T cells and can activate them by providing costimulatory signals through CD28-B7 and CD 40L-CD40 interactions.
Additionally, B-cells produce cytokines such as IL-6 and IFNɣ and contribute to T cell activation. Moreover, B cells present antigens to T cells and can activate them by providing costimulatory signals through CD28-B7 and CD40L-CD40 interactions. Additionally, B cells produce cytokines, such as interleukin- (IL-) 6 and interferon- (IFN-) γ, and contribute to T cell activation.
Also, B cells produce IL-17 that stimulates endothelial, epithelial, and fibroblast cells to produce chemokines and cytokines, leading to recruitment of neutrophils and establishment of inflammatory conditions.
Moreover, by producing TNF-α, B cells directly promote inflammation, endothelial and epithelial cell injuries, as well as inflammatory renal disorders that cause allograft rejection 3.
B cells are also involved in the development of lymphoid-like structures, named tertiary lymphoid organs (TLOs) at the side of inflammation that contain both B and T cells. In TLOs B cells undergo affinity maturation, clonal expansion, and class switching which result in efficient antibody production 4.
B cell-activating factor( BAFF) is a cytokine that belongs to the TNF family. It is a membrane-bound protein that can undergo proteolytic cleavage and convert into a soluble form. The activation of BAFF leads to B cell differentiation and survival and IgE and Igg class switching, as well as plasma cell survival 5.
References
1.G. E. Karahan, F. H. Claas, and S. Heidt, “B cell immunity in solid organ transplantation,” Frontiers in Immunology, vol. 7, p. 686, 2016.
2.X. Zhang and E. F. Reed, “Effect of antibodies on endothelium,” American Journal of Transplantation, vol. 9, no. 11, pp. 2459–2465, 2009.
3.W. Hoffman, F. G. Lakkis, and G. Chalasani, “B cells, antibodies, and more,” Clinical Journal of the American Society of Nephrology, vol. 11, no. 1, pp. 137–154, 2016.
4. C. Pitzalis, G. W. Jones, M. Bombardieri, and S. A. Jones, “Ectopic lymphoid-like structures in infection, cancer and autoimmunity,” Nature Reviews. Immunology, vol. 14, no. 7, pp. 447–462, 2014.
5.N. Thompson, D. A. Isenberg, E. C. Jury, and C. Ciurtin, “Exploring BAFF: its expression, receptors and contribution to the immunopathogenesis of Sjögren’s syndrome,” Rheumatology (Oxford), vol. 55, no. 9, pp. 1548–1555, 2016.
B cells are by far the largest population of antigen-presenting cells (APCs) found in vivo. Though T lymphocytes are the primary targets of immunotherapy in clinical transplantation, B lymphocytes are detrimental to graft survival by virtue of their capacity to present antigen to T cells via the indirect pathway of allorecognition and the generation of donor-specific alloantibody. Furthermore, the long-term survival of organ allografts remains challenged by chronic rejection, a process in which activated B cells have been found to play a significant role. Moreover, B cells as APCs can impact T cell function both in a positive as well as a negative manner, leading to either T cell activation or tolerance.
The presence of dense intra-graft B cell infiltrates in renal allograft biopsies is associated with poor outcomes. Preemptive B cell depletion (anti-CD20, Rituximab) is reported to prolong the survival of islet and cardiac allografts in non-human primates. In humans, Rituximab induction has been shown to reduce the incidence of acute rejection in kidney recipients.
References:
Redfield RR 3rd, Rodriguez E, Parsons R, Vivek K, Mustafa MM, Noorchashm H, Naji A. Essential role for B cells in transplantation tolerance. Curr Opin Immunol. 2011 Oct;23(5):685-91. doi: 10.1016/j.coi.2011.07.011. PMID: 21982511; PMCID: PMC5351416.
Both HLA class I & II are present on all nucleated cell surface accept RBC, but HLA class II expression found only B cells, certain myeloid cell & subset of activated T cells.
The role of B cells in renal transplant still incomplete & growing. Numerous studies had focused on B cells role in antibodies production that can affect transplant outcome, but it is found that not all DSA are harmful & in some situation can induce tolerance by accommodation. B cells have an important role in activation of CD4 T cells & CD8 T cells & differentiation into memory T cells.
There is an evidence that B cells can induce chronic rejection which is not depends on antibody production. Another role in transplant is interaction with T cells ( APC), cytokine production & co stimulation.
Also B cells respond to ischemic re perfusion injury which associated with chronic kidney injury & rejection in absence of alloimmune response.
References:
What is the role of B cells in transplantation?
B cells have multiple functions in addition to producing antibodies. (1) They play an important role in kidney transplant rejection.
The major functions of B cells include:
a) Produce antibodies,
b) Enable lymphoid organogenesis, (2)
c) Enable thymocytes to mature into T cells, (3)
d) Contribute to T-cell tolerance and accommodation tha protects target tissues when tolerance fails, (4)
e) Regulatory B cells exert immunosuppressive effect through IL-10, IL-35, TGF beta. (5)
References:
1) Dijke EI, Platt JL, Blair P, et al. B cells in transplantation. J Heart Lung Transplant 2016;35:704-710.
2) . Lakkis FG, Arakelov A, Konieczny BT, et al. Immunologic ‘ignorance’ of vascularized organ transplants in the absence of secondary lymphoid tissue. Nat Med. 2000;6:686-688.
3) Joao C, Ogle BM, Gay-Rabinstein C, et al. B cell-dependent TCR diversification. J Immunol. 2004;172:4709–4716.
4) Koch CA, Khalpey ZI, Platt JL. Accommodation: preventing injury in transplantation and disease. J Immunol. 2004; 172:5143–5148.
5) Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015; 42:607–612
As in this reference, B cells especially (B reg) thought to have had role and signature intolerance.
Transpl Int. 2020 Jan; 33(1): 30–40.
doi: 10.1111/tri.13549 B cells in transplant tolerance and rejection: friends or foes?
Robin Schmitz, Zachary W. Fitch, Paul M. Schroder, Ashley Y. Choi, Annette M. Jackson, Stuart J. Knechtle, and Jean Kwun
link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184555/
B lymphocytes and plasma cells are the immune cells that are responsible for antibody production. If a recipient harbor performed antibodies against donor antigens in advance, the consequence is hyperacute rejection, so ABO matching and careful screening for antibodies against donor antigens in the serum of recipients prior to kidney transplantation are mandatory. In addition, performing donor specific antibody after kidney transplantation can lead to acute or chronic ABMR. ABMR cause allograft damage via two principal ways: activation of the classical pathway of complement that leads to accumulation of C4d in tissues and stimulation of macrophages and other immune cells. Raising IgG antibodies is more concern than IgM antibodies in transplantation.
In addition to producing antibodies, B lymphocytes directly contribute to T lymphocytes immunity by at least three mechanisms: they serve as APC that enhance effector T-lymphocyte differentiation to memory T lymphocytes, they function as true effectors that produce inflammatory cytokines and, a subgroup of them known as regulatory B cells, modulate immune response. So the cellular function of B lymphocytes can contribute to allograft rejection or conversely diminish the alloimmune response. As a result, B lymphocyte depletion at the time of transplantation can increase the incidence of acute rejection because of nonselective depletion of both pathogenic and regulatory B lymphocytes.
Since all human B lymphocytes express CD 20, Rituximab is significantly effective at depleting B lymphocytes. On the other hand, plasma cells do not express CD 20, providing an explanation why rituximab are not completely successful at reversing ABMR. Proteosome inhibitors such as Bortezumib have been employed to inhibit plasma cell function in sensitized patients or in ABMR.
· Needless to say that B lymphocytes play a major role in transplantation , being a part of the humoral and adaptive immunity.
· B lymphocytes , secrete antibodies through plasma cells differentiation , act as memory B cells lasting for life , secrete cytokines and inflammatory mediators which stimulate T lymphocytes or act independently .
·
MHC 1 is presented on all
body cells , blessed by the MHC 2 receptors as other APCs , B
Lymphocytes act as Antigen presenting cells , to T lymphocytes as well.
co-interaction between T and B lymphocytes is evident as mentioned .
·
B and T cross match
detect the presence of antibodies in the recipient serum against the donor
lymphocytes . If only B lymphocytes cross match is positive then anti HLA class
1 (low titre) or 2 may be present , but if T lymphocytes cross match is +ve
only that means antibodies against class 1 with low titre is present , but if
both +ve then it means antibodies against class 1 and may be class 2 is also
present.
·
Hoffman W., Lakkis F.G.,
Chalasani G. B Cells, Antibodies, and More. cjas. 2016;
·
Jan.,Vol.11.pouliquen
E, Koenig A, Chen CC, et al. Recent advances in
renal transplantation: antibody-mediated rejection takes centre stage. F1000Prime Rep 2015; 7: 51.
B cells function in many ways, some of which promote rejection, and some of which have the potential to promote tolerance
B cells play an important role in graft rejection by producing donor-specific antibodies.
B cells may contribute to allograft rejection independently of antibody production by shaping the T-cell response through a combination of antigen presentation, cytokine production, and costimulation.
Kidney injury in ischemia/reperfusion injury and transplantation are both mediated by a B-cell response to dysfunctional tissue repair.
Patients who developed chronic rejection already showed elevated B-cell activities and other common gene signatures for acute kidney injury including genes related to fibrosis (e.g., COL1A1, DPT, and MMP7) and inflammation (e.g., CD52, CXCL10, and CCL21).
Recently, there is growing evidence which demonstrates that B cells may play a pivotal role in the induction and maintenance of transplant tolerance through regulatory B cells (Bregs).
Regulatory B (Breg) cells, an immunosuppressive subset of B cells, may secret inhibitory cytokines such as IL-10 which potently downregulate the immune response, ameliorating allograft rejection.
Reference:
Schmitz, Robin et al. “B cells in transplant tolerance and rejection: friends or foes?.” Transplant international : official journal of the European Society for Organ Transplantation vol. 33,1 (2020): 30-40. doi:10.1111/tri.13549
Cherukuri, A, Mohib, K, Rothstein, DM. Regulatory B cells: TIM-1, transplant tolerance, and rejection. Immunol Rev. 2021; 299: 31– 44. https://doi.org/10.1111/imr.12933