I. Renal transplantation against a positive crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal – Case report
- What is the type of this study and what is the level of evidence this study provides?
- What are CLASS I and CLASS II antigens.
- Is there any difference in expression between both?
What is the type of this study and what is the level of evidence this study provides?
case report ( case series)
level of evidence is 4
What are CLASS I and CLASS II antigens.
HLA class I : A, B, C
HLA Class II : DR ,DP, DQ
Is there any difference in expression between both?
HLA class I is expressed in all nucleated cells
HLA class II is expressed on antigen presenting cells including dendritic cells , B lymphocytes and macrophages
1. What is the type of this study and what is the level of evidence this study provides?
Case report ( case series ) , level 4 evidence
2. What are CLASS I and CLASS II antigens.
Class I and II HLA Ag are group of Ag (glycoproteins) on the cell surface encoded on a group of closely linked genes known as (MHC , major histocompitability complex) located on the short arm of chromosome 6
MHC Class I Ag are:HLA-A, HLA-B, HLA-C
Minor classI: HLA-E , HLA-F, HLA-G
MHC Class II:HLA- DP, HLA- DR., HLA- DQ
Minor Class II: HLA- DM , HLA DO
3. Is there any difference in expression between both?
MHC class Icomplexes
· are presented on nucleated cells and are recognized by cytotoxic CD8+ T cells.
· present endogenous antigens
· formed of 3 α subunits and one B2 microglobulin , with the Antigen binding site lying between α1 and α2 subunits
MHCII
· presented on antigen-presenting cells [e.g., dendritic cells (DCs), macrophages, or B cells], on the other hand, can activate CD4+ T cells
· present exogenous antigens that originate extracellularly from foreign bodies such as bacteria.,and has to be digested then processed
· Formed of α (α1,α2) and β chains (β1, β2)
**What is the type of this study and what is the level of evidence this study provides?
Cases series level 4
**What are CLASS I and CLASS II antigens. HLA class I molecules are expressed on the surface of almost all nucleated cells. Class II molecules are expressed only on B lymphocytes, antigen-presenting cells (monocytes, macrophages, and dendritic cells), and activated T lymphocytes .
~Major class 1 antigen are HLA-A ,HLA-B and
HLA-C .
~Minor class 1 antigen are HLA-E ,HLA-F and HLA-G
~Major class 11 antigen HLA-DR ,HLA-DP and HLA-DQ .
~Minor class 11 antigen are HLA-DM and
HLA-DO .
**Is there any difference in expression between both?
MHC class I and class II molecules are similar in function: they deliver short peptides to the cell surface allowing these peptides
to be expressed by CD8+ (cytotoxic) and CD4+ (helper) T cells, respectively. The difference is that the peptides originate from different sources – endogenous, or intracellular, for MHC class I; and exogenous, or extracellular for MHC class II. There is also so called cross-presentation in which exogenous antigens can be presented by MHC class I molecules.
References:
[1] F. Kissmeyer-Nielsen, S. Olsen, V.P. Petersen, O. Fjeldborg, Hyperacute rejection of
kidney allografts, associated with pre-existing humoral antibodies against donor
cells, Lancet 2 (7465) (1966 Sep 24) 662–665.
[2] J.C. Scornik, W.M. LeFor, J.C. Cicciarelli, M.E. Brunson, T. Bogaard, R.J. Howard,
et al., Hyperacute and acute kidney graft rejection due to antibodies against B cells,
Transplantation 54 (1) (1992 Jul) 61–64.
[3] S.V. Fuggle, P. Errasti, A.S. Daar, J.W. Fabre, A. Ting, P.J. Morris, Localization of
major histocompatibility complex (HLA-ABC and DR) antigens in 46 kidneys.
Differences in HLA-DR staining of tubules among kidneys, Transplantation 35 (4)
(1983 Apr) 385–390.
[4] J. Mytilineos, A. Deufel, G. Opelz, Clinical relevance of HLA-DPB locus matching
for cadaver kidney retransplants: a report of the Collaborative Transplant Study,
Transplantation 63 (9) (1997 May 15) 1351–1354.
[5] T.L. Bugawan, A.B. Begovich, H.A. Erlich, Rapid HLA-DPB typing using
enzymatically amplified DNA and nonradioactive sequence-specific
oligonucleotide probes, Immunogenetics 32 (4) (1990) 231–241.
Case series with level of evidence 4.
HLA class I: Major antigens are HLA-A, B, C
Minor antigens are HLA-A, F, G.
HLA class II: Major antigens are HLA-DR, DR, DP, and DQ.
Minor Ags are HLA -DM and Do.
Class I are expressed on the surface of all nucleated cell and activated CD8 +T helpers but class II are expressed on B cells APCs like monocyte, macrophage and dendritic cells and activates CD4+T helpers.
●Case series
●Class 4 evidence
●class 1
Represent all nucleated cells activates t helper cd8
Major . HlA A,B,C
Minor. E,F,G
●Class II
Major.HLADr ,Dp, Dq
Minor . Dm, DO
Represent antigens present cells
(Dendritic-cell macrophages)
Renal transplantation against a positive crossmatch due to HLA-DP donor specific antibodies without prior antibody removal -case report
What is the type of the study and what is the level of evidences this study provides?
-Case series and level 4
What are the class 1 and class 2 antigens
HLA class 1(Major) – HLA-A,B,C
HLA class 1 (Minor) – HLA-E,F,G
HLA class 2 (Major)– HLA-DR,DQ and DP
HLA class 2 (Minor)-HLA-DM and DO
Is there any differences in expression between both?
MHC class 1 proteins are expressed on most uncleared cells, albeit at variable levels and they are generally responsible for activating CD8+ T cell
• they largely acquired from intracellular environment.
MHC class 2 molecules present peptides and activate CD4 expressing helper T cells, bering expressed only by B lymphocytes, DCs, and some endothelial
• lately present peptides acquired from the extra cellular environment
Cross presentations might occur in the context of specialised antigen presentation by DCS
REFERENCE
Kidney transplantation- principles and practice by Stuart J Knechtle
This is a case series
Level of evidence is 4
HLA is composed mainly of class I and class II antigens.
class I molecules are expressed on the surface of almost all nucleated cells.
Class II molecules are expressed only on B lymphocytes, antigen-presenting cells (monocytes, macrophages, and dendritic cells), and activated T lymphocytes.
Class I genes are composed of A, B and C antigens .
Class II genes consists of DP , DQ and DR genes
What is the type of this study and what is the level of evidence this study provides?
Cases series level 4
What are CLASS I and CLASS II antigens. HLA class I molecules are expressed on the surface of almost all nucleated cells. Class II molecules are expressed only on B lymphocytes, antigen-presenting cells (monocytes, macrophages, and dendritic cells), and activated T lymphocytes .
Major class 1 antigen are HLA-A ,HLA-B and HLA-C .
Minor class 1 antigen are HLA-E ,HLA-F and HLA-G .
Major class 11 antigen HLA-DR ,HLA-DP and HLA-DQ .
Minor class 11 antigen are HLA-DM and HLA-DO .
Differences in expression:
Class I major antigens: expressed on all nucleated cells, present non self antigens to cytotoxic T cells controlling its activation and function
Class I minor antigens:
expression is restricted to specific tissues and play a role in controlling function of NK cells
Class II major antigens: expressed on APC and B lymphocytes and can be induced on activated T cells and endothelial cells
present antigens to CD4 T helper cells
Class II minor antigens: not expressed on the cell surface, but are involved in peptide exchange and loading onto class II molecules
Case series study with level of evidence 4
HLA are cell surface glycoprotein encoded in the short arm of chromosome6 .
Class I HLA consist of highly polymorphic alpha chain and present in all nucleated cells and consists of HLA- A ,B and C class I responsible for cytotoxic CD+8 T cells activation .
Class II HLA consists of both alpha and beta chains and consists of HLA -DR,DQ and DP class II is more restricted and present in only Antigen presenting cells like B cells ,endothelial cells and dendritic cells, class II is the cause of CD +4 helper T cells activation.
Short and sweet Tahani
What is the type of this study and what is the level of evidence this study provides?
Cases series level 4
What are CLASS I and CLASS II antigens. HLA class I molecules are expressed on the surface of almost all nucleated cells. Class II molecules are expressed only on B lymphocytes, antigen-presenting cells (monocytes, macrophages, and dendritic cells), and activated T lymphocytes .
Major class 1 antigen are HLA-A ,HLA-B and HLA-C .
Minor class 1 antigen are HLA-E ,HLA-F and HLA-G .
Major class 11 antigen HLA-DR ,HLA-DP and HLA-DQ .
Minor class 11 antigen are HLA-DM and HLA-DO .
Is there any difference in expression between both? MHC class I and class II molecules are similar in function: they deliver short peptides to the cell surface allowing these peptides to be recognised by CD8+ (cytotoxic) and CD4+ (helper) T cells, respectively. The difference is that the peptides originate from different sources – endogenous, or intracellular, for MHC class I; and exogenous, or extracellular for MHC class II. There is also so called cross-presentation in which exogenous antigens can be presented by MHC class I molecules. Endogenous antigens can also be presented by MHC class II when they are degraded through autophagy.
Thanks Dalia
This is a case report (4 cases) , normally althogh not united concept, case series is morte than 4 cases. In the title as written this is acse report. Both level of evedince is thus four.
HLA-antigens are classified into major and minor. Class I&II are major
Both class I and 2 are subdivided into classic and non classic
classic HLA class I antigens are : HLA -A/-B/-C vs non classic (-E/-F/G)
classic HLA class II antigens are: HLA DR, DQ, DP vs non classical (-M, -O)
class I antigens are found nearly in all cnucleated cells (so the are not present in RBCs)
class II antigesn are found mainly on proffesional cells of the immune system, namely the APCs (antigen peresenting cells like denditic cells , macrophages
class I proteins present peptides that are endogenous like viruses to cytotoxic T celels (CD8+), while class II antigens present peptides of extracelleuar pathogens to T helper celles (CD4+). Both are of central role for generation of immune response (https://www.frontiersin.org/articles/10.3389/fimmu.2011.00048/full)
Thanks
Renal transplantation against a positive crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal – Case report
What is the type of this study and what is the level of evidence this study provides?
Case series, level 4 of evidence, this paper did not require ethical committee approval (
What are CLASS I and CLASS II antigens.
Is there any difference in expression between both?
The human leukocyte antigen locus (HLA) located in the short arm of chromosome 6 contain more than 200 genes with high polymorphismrestricted to class1,11 .
Class1 HLA antigen, expressed on all nucleated cells at variable densities except erythrocytes and trophoblasts with three major antigens HLA A, B C, and three minor HLA-E, HLA-F, HLA-G, class1 antigens have heavy chain (alfa chain) combined with light non-polymorphic B chain
Class1 antigens bind to CD8 cytolytic subsets of T- cells – innate immune response
Class11 antigens include HLADR, DQ, DP, expressed by APC mainly dendritic cells, macrophage B -cells,
HLDR -B chain carries the polymorphism characteristic. While HLDQ AND DP each have polymorphic alfa and beta chains.
CD4 Subsets of T cells restricted to MHC class11, adaptive immune response
this article reported outcome of three cases of highly sensitized recipients due to previous transplantation with complex HLA mismatch and low chance to get compatible donor, second and third case their waiting list > 10 years, two of them had high-levels of DSAs against specific class11 HLA-DP3 with positive T and B FCXM, while the third had a high level DSA against HLA-DP13 and HLA –DP19. Despite high DSA with high MFI values they decide to go ahead with DBD transplantation. With high risk of early and late ABMR, one of the explanations given in this report that the clinical importance of MFI values can be different for different HLA like HLA-DP is variably expressed on renal endothelium and their effect on the graft survival still not clearly understood.
T cell FCXM was weakly positive in two cases with no clear explanation The autologous FCXM testing was negative, which doesn’t account for the T cell positivity.
explanation for the T cell positivity is that not all class I antibody specificities have been identified due to the complexity of the profile.
(Case 2). It could also be caused by non-HLA, non-auto antibodies binding to a target on the T cells.No one underwent desensitization protocol despite positive XM and high DSA level, only induction as high risk with ATG in first two cases and one case with alemtuzumab followed by maintenance triple therapy with targeting higher tacrolimus trough level above 8, the outcome of the three not optimal one with transplant glomerulopathy , all three cases GFR < 30ml/min. one may ask why they not offered desensitization? Ii it feasible? Would it make difference in the outcome in term of reduced the risk of rejection or clearnce of de novo DSA ? All three cases on long waiting list all had previous transplantation so very difficult to get compatible donor and even desensitization will be very challenging and not with out side effects ( infection , malignancy )and may not improve the longterm graft outcome based on the available limited evidence from many studies all small from local centres with different protocals and restrosepctive designs . so in conclusion the Current sensitazation protocals are not standardized not effective in decreasing the AMR rate, and less effective in decreasing the DSA espression especially in patients with strong DSAs (1).
1-In depth
Desensitization Protocols and Their Outcome
Kwaku Marfo,* Amy Lu,* Min Ling*† and Enver Akalin*Clin J Am Soc Nephrol 6: 922–936, 2011. doi: 10.2215/CJN.08140910.
Thanks, Saja for your reflection. We will discuss this later in detail. Time is an important factor. We can not run desensitisation for deceased donor transplants. Also, HLA DP and also DQ expression may be incomplete. This would give an advantage where there is no enough HLA DP antigen expressed on the kidney for the antibodies to react against
Renal transplantation against a positive cross match HLA-DP donor specific antibodies without prior antibodies removal.
What is the type of this study ?
Case series.
What is the level of evidence this study provide ?
Level 4 .
What are class 1 antigen ?
Major class 1 antigen are HLA-A ,HLA-B and HLA-C .
Minor class 1 antigen are HLA-E ,HLA-F and HLA-G .
What are class 2 antigen?
Major class 11 antigen HLA-DR ,HLA-DP and HLA-DQ .
Minor class 11 antigen are HLA-DM and HLA-DO .
Is there is any difference in expression between both ?
Class 1 is found on the cell surface of all nucleated cell .it is responsible for presentation of intracellular antigen to CD8 .
Class 11 is found on the cell surface of antigen presenting cells ( dendritic cells, B-cell , macrophage and thymic epithelial cells ) .it is responsible for presentation of extra cellular antigen to CD4.
Dear All
How easy to perform desensitisation in cadaveric transplantation?
What is the chance of HLA DP not being expressed on the kidney?
i have no experience with DD desesitisation but i think its not easy espcaily there is no standardized desensitisation protocals , not free from side efffects , adding more cost with doutful benefit in regards to reduce rate of acute or chronic ABMR based on avialable evidnce .
Also, time is a major factor. The kidney has to be transplanted ASAP. We can not run a desensitization protocol for a deceased donor transplant involving 5/6 sessions of plasmapheresis.
It is a case report with the level 5 of evidence.
The HLA class I cluster comprises three classical class I genes (HLA-A, -B, -C), and three nonclassical class I genes (HLA-E, -F, -G) and two class I-like genes (MICA, MICB). The classical class I gene are expressed by all nucleated cells.
The HLA class II cluster comprises classical class II genes (HLA-DR, DP, DQ), nonclassical class II genes (HLA-DM, -DO), and several pseudogenes.
HLA class II molecules expressed by antigen presenting cells (dendritic, macrophage, and monocyte cells) and B lymphocytes.
The class I antigens (HLA-A, -B, -C) consist of an α heavy chain and β2 microglobulin. The class II antigens (HLA-DR, DP, DQ), consist of two chains, α chain (encoded by DRA, DQA1, DPA1) and β chain (encoded by DRB1, DRB3, DRB4, DRB5, DQB1, DPB1).
Thanks, Esmat
Any difference in expression between class I and II?
Class l expressed on all neucleatef cells
Class ll expressed on B lymphocytes, plasma cells and myaloid cells (macrophages and neutrophils) APC
also it expressed on endothelial cells during inflammation and T cell activation and cytokines release
As I mentioned in my comment, classical HLA class I antigens are expressed by all nucleated cells, and HLA class II molecules are expressed by antigen presenting cells (dendritic, macrophage, and monocyte cells) and B lymphocytes.
In addition, donor antigen frequency is different between HLA antigens. For example, HLA-A2 antigen is the most common HLA antigen in whites. Other common HLA antigens are HLA-B7, HLA-DQ6, and particularly HLA-DR52.
On the other hand, the number of variant alleles at class I loci (HLA-A, -B, and -C) and at class HLA-DRB1 (of class II HLA) is high.
In class I they present self Ag which are unrecognized by CD 4+ T cells while class II presenting non self Ag to CD+8 T cells class I present in all nuclear cells while class II in antigen presenting cells like macrophages and dendritic cells.
· Case series , level of evidence 4
· Class I and II (HLA class I and II )
Are glycoprotients encoded by MHC genes present on short arm of chromosome 6
HLA class I presents on all nucleated cells and classified as
Major classes : HLA-A, B,C
Minor classes :HLA E, F, G
while HLA class II are present on APCs and classified as
Major classes are HLA DR, DQ, DP
Minor classes are DM, DO
Expression of HLA class I Ag is higher on T cell compared with b cell specially HLA C (1).
Their primary role is to present foreign antigen to the immune system.
1- Putheti P , Sharma K , Friedlander R, Menon A, Dadhania D, Muthukumar T, Suthanthiran (2021).T Cell Positive B Cell Negative Flow Cytometry Crossmatch (FCXM): Frequency, HLA-Locus Specificity, and Mechanisms Among 3073 Clinical FCXM Tests. DOI:10.1101/2021.05.20.21257541
Expression of class 1 and II is incomplete
case series report
level 5
class 1 HLA found in all nucleated cell ,A_B_C
expressed in all cells (t cell)
they are responsible for innate immunity mainly cellular
class 2 HLA found in specific cells as B cell
DR_DP_DQ
responsible for humoral immunity and also natural killer
Class II is mainly on antigen-presenting cells which are?
Case series, level 4
Class I antigens:
classical: HLA-A, B, C, classical genes are expressed on all nucleated cells, present non self antigens to cytotoxic T cells controlling its activation and function
non classical: HLA-E, F, G
non classical gene expression is restricted to specific tissues and play a role in controlling function of NK cells
Class II antigens:
classical: HLA-DP, DQ, DR
expressed on APC and B lymphocytes and can be induced on activated T cells and endothelial cells
present antigens to CD4 T helper cells
non classical: HLA-DM, DO
not expressed on the cell surface, but are involved in peptide exchange and loading onto class II molecules
Handbook of kidney transplantation, M. Danovitch, sixth edition
Excellent
(1) case series – level of evidence 4
(2)(3) HLA system had 2 major sets of antigens :
-It is a case-series report and level of evidence 4.
1-Major HLA class I antigens are HLA-A, HLA-B, HLA-C, and minor antigens are HLA-E, HLA-F, and HLA-G.
-Class I is expressed by all nucleated cells and platelet.
-Class I can present peptides from inside the cell.
-it consists of one polymorphic polypeptide α chain and monomorphic β2 microglobulin chain which unlike HLA proteins is encoded by a gene on chromosome 15.
-It is recognized by TCRs on CD8 + lymphocytes
2. Major HLA class II antigens are HLA-DP, HLA-DQ, HLA-DR, and minor antigens HLA- DM, and HLA-DO.
-it is expressed in B lymphocytes, antigen-presenting cells, and human endothelial cells during inflammation in response to cytokines interferon-gamma.
-It consists of 2 polymorphic chains alpha and beta chain encoded by genes in the HLA complex
– It is recognized by TCRs on CD4 + lymphocytes
1- What is the type of this study and what is the level of evidence this study provides?
observational non invasive report of cases series
level 4
2- What are CLASS I and CLASS II antigens?
class I antigens :HLA-A,B &C
class II antigens :HLA-DP, DQ &DR
3- Is there any difference in expression between both?
yes . the expression of both classes is upregulated by cytokines(IFNγ, TNF) but the expression of class II can be induced in cells that do not normally have them and this is mediated by INFγ
HLA class I is present in all nucleated cells except RBCs, and they display peptides from intracelluar antigens to CD8 T cells.
HLA class HLA class class II are present in small amount in antigen presenting cells but the level is high in activated APC( dendritic cells, B cells ,macrophagesand thymic epithelial cells . they present peptides from extra cellular origin to CD4
Excellent answer
NB
RBCs are not nucleated cells
This case series study.
Level of evidence 4.
The HLA histocompatibility system in humans represents a complex of
MHC class I molecules distributed on essentially all nucleated cells of the body , The
class I region consists of HLAA, HLA-B, and HLA-C loci.
MHC class II molecules that are distributed on B lymphocytes, macrophages, and a few
other cell types.
the class II region consists of the D region which is subdivided into HLA-DP, HLA-DQ,
and HLA-DR sub region.
Class II molecules play an important role in the induction of an immune response, since
antigen-presenting cells must complex an antigen with class II molecules to present it in
the presence of interleukin-1 to CD4+ T lymphocytes.
Class I molecules are important in presentation of intracellular antigen to CD8+ T
lymphocytes as well as for effector functions of target cells.
Well done
1- case-series.
The level of evidence is Level 4
2-Two types
MHC l
HLA, A, B, and C
All nucleated cells and platelets express class l proteins.
Heterodimers of a polymorphic alpha chain and invariant B2 microglobulin
They provide proteins to CD8 cells.
MHC ll
HLA DR, DP, DQ
Class ll proteins are exclusive to antigen-presenting cells.
These proteins are likewise heterodimers but have two polymorphism chains alpha and beta.
They deliver antigen to CD4 cells.
3-Is there a difference in their expression?
yes
Class l proteins are found in all nucleated cells, but class ll proteins are only found in antigen-presenting cells.
Excellent
This is a case series, of 3 case reports. Level of evidence: Level 4
HLAs corresponding to MHC class I (A, B, and C). MHC class I proteins form a functional receptor on most nucleated cells of the body. There are 3 major and 3 minor MHC class I genes in HLA.
Major MHC class I: HLA-A, HLA-B, HLA-C
Minor genes are HLA-E, HLA-F, and HLA-G.
Similarly, there are 3 major and 2 minor MHC class II proteins encoded by the HLA. The genes of class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen-presenting cells.
Major MHC class II proteins only occur on antigen-presenting cells, B cells, and T cells.
1. HLA-DP: has α-chain encoded by HLA-DPA1 locus and β-chain encoded by HLA-DPB1 locus
2. HLA-DQ has α-chain encoded by HLA-DQA1 locus and β-chain encoded by HLA-DQB1 locus
3. HLA-DR has α-chain encoded by HLA-DRA locus and 4 β-chains (only 3 possible per person), encoded by HLA-DRB1, DRB3, DRB4, DRB5 loci
The other MHC class II proteins, DM and DO, are used in the internal processing of antigens, loading the antigenic peptides generated from pathogens onto the HLA molecules of the antigen-presenting cells.
Please comment on the expression of Class I and Class II antigens
What is the type of this study and what is the level of evidence this study provides?
Case report of 3 patients
Level of evidence is 4
What are CLASS I and CLASS II antigens.?
MHC
In humans these genes are encoded in a cluster on chromosome 6 and code for a set of proteins called HLA.
They are very polymorphic.
There main function is the presentation of the antigens to T lymphocytes.
They are 2 type
Class l MHC
This includes HLA,A,B and C
Class l proteins are expressed on all nucleated cells
Class l proteins are heterodimers, consisting of the polymorphic alpha chain and invariant B2 microglobulin
They are responsible for the presentation of proteins produced within the cell cytosol to CD8 lymphocytes
Class ll MHC
This includes HLA DR,DP and DQ
Class ll proteins have a much more restricted distribution,being confined to antigen-presenting cells
Class ll proteins are also heterodimers but in contrast to class l there are 2 polymorphic chains alpha and beta .
They are responsible for presentation of antigen to CD4 cells
Is there any difference in expression between both?
Yes .
Class l proteins are expressed on all nucleated cells,while class ll proteins have much more restricted distribution,being confined to antigen-presenting cells.
Any role of CD8 in the expression of Class I antigen
1. What is the type of this study and what is the level of evidence this study provides?
This is a case-series.
Level of evidence: Level 4
2. What are CLASS I and CLASS II antigens.
Human Leukocyte Antigen (HLA) is a gene complex located on short arm of chromosome 6 (6p21.3). It contains many genes and can be classified into class I, II and III.
Class I and II have important role in immune regulation.
HLA Class I has 3 major loci (HLA-A, HLA-B and HLA-C) and 3 minor loci (HLA-E, HLA-F, HLA-G)
HLA Class II has 3 major loci (HLA-DP, HLA-DQ, HLA-DR) and 2 minor loci (HLA-DM, HLA-DO)
3. Is there any difference in expression between both?
Class I Antigen: They are present on all nucleated cells. They present ‘self-antigens’ which are not recognized by the T cell receptors (TCRs). They are recognized by TCRs only in conjunction with CD8 cells. These are responsible for innate immunity.
Class II Antigen: They are present on antigen presenting cells (APCs): B cells, dendritic cells, macrophages., vascular endothelial cells. They present exogenous (foreign) antigens. These are recognized by TCRs in conjunction with CD4 cells. These are responsible for adaptive immunity.
Good answer, any comments on Prof Ala’s questions
Most studies shows no risk of AMR in patient with HLA DP antibodies ,many
have successful transplant ,as reported in UCLA institute by DR.RAJ.(yesterday
in his histocompatibility report) without
sensitization ,so i think , as no evidence of risk its, ethical to transplant
without sensitization ,case report here are small to make final judgment.
1) In my opinion, it is unethical to go ahead without desensitization in such cases. If we have a look at the outcomes, the GFR is less than 30, one patient had TG in less than 3 years and one patient had AMR on day 10. Explaining such results to the patient, when desensitization as an option for sensitized patient is available and not utilized becomes difficult.
2) In such patients, monitoring would involve DSA monitoring as well as protocol biopsies at regular interval.
Ethical means without prior antibody removal and without aggressive induction
In this case series
What are your thoughts on having pretransplant removal of antibodies?
Do you think it’s ethical to go without desensitization in such cases? Please have a look at the outcomes?
What are the monitoring strategies for such patients?
Would you please reflect your own thoughts
if we have DSA , should do desensitization first before going to transplantation , it is non ethical to go without removal of DSA because of high incidence of HAR, and AMR which may leads to graft loss.
I think if a patient is highly sensitized with a high level of PRA, positive DSA should have desensitization therapy.
Though the 3 cases were transplanted successfully, and part of the third case who suffer AMR and get treated, still their outcomes, in general, are low with a GFR of less than 30ml/min.
1) Pre-transplant removal of antibodies should be performed in a sensitized patient with positive crossmatch and elevated DSAs.
2) In my opinion, it is unethical to go ahead without desensitization in such cases. If we have a look at the outcomes, the GFR is less than 30, one patient had TG in less than 3 years and one patient had AMR on day 10. Explaining such results to the patient, when desensitization as an option for sensitized patient is available and not utilized becomes difficult.
3) In such patients, monitoring would involve DSA monitoring as well as protocol biopsies at regular interval.
Excellent
For those cases with very high high PRA and positive DSA (significant level) and positive crossmatch, I think it is mandatory to desensitize them before transplantation, Am not happy with their outcome as 2 of them had delayed graft function with late discharge( day 12-16) , the third one had ABMR in day 10. All of them now had low eGFR ( 28, 26, 32 respectively). The first patient had transplant glomerulopathy 2 years post transplant. They should be followed by DSA monitoring and protocol biopsy and they need high level of immunosuppression.
Excellent
Presence of DSA befor transplantation indicates desensitization and its unethical to transplant patient knowing that his at high risk for acute rejection which appears clear on the outcome of the cases
Monitor is by transplantation monitor of DSA and biopsy at 1, 3 months
This question give us a dilemma of reducing Cold ishaemia timing vs desensitise patients
For me, highly sensitised patient ( high DSA, cPRA, positive crossmatch) should undergoes desensitisation because high likelihood that the allograft would fail. so its unethical to transplant without desensitisation
some studies suggest for DSA monitoring in highly sensitised patient for early detection of rejection. i would suggest for protocol biopsy and DSA monitoring might aid in detecting the early graft rejection
3.HLA Class 1 antigen are expressed in all nucleated cells, hence they are involved in innate immunity, immunity towards cancer and self antigen recognition. HLA Class II antigens are expressed in APC an B cells thereby presenting the foreign antigen to the immune systems.
1- What is the type of this study and what is the level of evidence this study provides?
2- What are CLASS I and CLASS II antigens.
A- class I called HLA-I. it include HLA- A to G subtypes.
– they are expressed on all nucleated cells, the most important of them
in transplantation are HLA-A and HLA-B
B- class II called HLA-II. it include HLA-DP,DQ,DR, DM,DO subtypes.
– they are expressed on antigen presenting cells, the most important
in transplantation is HLA-DR
3- Is there any difference in expression between both?
Thanks
What is the type of this study and what is the level of evidence this study provides?
Case series. level of evidence 4
What are CLASS I and CLASS II antigens AND Is there any difference in expression between both?
A- HLA class I which is present in all nucleated cells which are subdivided into
• Major antigens which include HLA -A, HLA- B, HLA-C
• Minor antigens which include HLA-E, HLA-F and HLA-G
B- HLA class II which is present in APCS (macrophages, denderitic cells, vascular endothelial cells and B cells) they are further subdivided into
• Major antigens which include HLA-DR, HLA-DQ, HLA-DP
• Minor antigens which include HLA-DM, HLA DO
1 What is the type of this study and what is the level of evidence this study provides?
This is a case series study its level of evidence is 4.
2 What are CLASS I and CLASS II antigens.
Classification of HLA classes:
HLA system complex it is encoded by genes located on short arm of chromosome 6.
HLA molecules are the major trigger for immune response against foreign oragan .
They are classified into 2 MHC proteins; Class I, Class II
Class I ; is expressed on surface of all nucleated cell it has 3 major HLA types A, B and C, and 3 minor E, F, and G.
They are composed of polymorphic heavy alpha chain (including alpha 1,2 and 3) and non polymorphic light chain ;beta 2 micro globulin and recognized by cytotoxic CD8+ T cells.
Class II; is expressed only on surface of antigen presenting cells as dendritic cells (DCs), macrophages, or B cells which can activate CD4+ T cells.
it include 3 major types DR, DP and DQ and 2 minor DM and DO.
They are composed of polymorphic alpha and beta chains.
HLA II is also expressed on vascular endothelial cells of the renal graft .
its expression may be increased on epithelial cell and vascular endothelial cell after exposure to inflammatory cytokines.
Transplantation with no mismatch was associated with the most favourable outcoms not only on patient and graft survival but also on reduction of immunosuppression with all its complications .
The HLA-DP α and β chain are both polymorphic although the β chain exhibits the most polymorphism with well over 100 DPB1 alleles described.
the anti-DP antibody-positive patients had a higher rate of rejection when compared with anti-DP antibody-negative patients,
In sensitised patients, anti HLA antibodies to DP were estimated to be 35% lower than that of A, B and DR and mostly due to previous transplantation rather than pregnancy .
There are controversies about the impact of HLA DP antibodies in allograft outcome.
Patients waiting for a deceased allograft with HLA-DP DSA and a positive FCXM can be transplanted with reasonable outcome with ATG or Alemtuzumab induction followed by Tacrolimus, MMF and prednis-olone without prior antibody removal.
M. H¨ormann, G. Dieplinger, L.M. Rebellato, K.P. Briley, P. Bolin, C. Morgan, et al., Incidence and impact of anti-HLA-DP antibodies in renal transplantation, Clin. Transpl. 30 (9) (2016 Sep) 1108–1114.
A.A. Vo, O. Aubert, M. Haas, E. Huang, X. Zhang, J. Choi, et al., Clinical Relevance of Posttransplant DSAs in Patients Receiving Desensitization for HLA-incompatible Kidney Transplantation, Transplantation 103 (12) (2019 Dec) 2666–2674.
L. Dani¨els, F.H.J. Claas, C.S.M. Kramer, A. Senev, M. Vanden Driessche, M. P. Emonds, et al., The role of HLA-DP mismatches and donor specific HLA-DP antibodies in kidney transplantation: a case series, Transpl. Immunol. 16 (2020 Mar), 101287.
M. Ling, K. Marfo, P. Masiakos, A. Aljanabi, J. Lindower, D. Glicklich, et al., Pretransplant anti-HLA-Cw and anti-HLA-DP antibodies in sensitized patients, Hum. Immunol. 73 (9) (2012 Sep) 879–883.
Renal transplantation against a positive crossmatch due to HLA-DP donor-specific antibodies without prior antibody removal – Case report .Yazin Marie a,1,* , Tim Key b,2 , Ahmed Halawa a,c,3 .Sheffield Kidney Institute, Sheffield, UK.
What is the type of this study and what is the level of evidence this study provides?
Case series with level of evidence 4
What are CLASS I and CLASS II antigens?
Class I classical antigens: HLA- A, B, C , non classical: HLA-E, F, G
Class II Classical antigens: HLA-DR, DP, DQ , non classical: HLA-DM, DO
Is there any difference in expression between both?
Class I molecules are expressed on all nucleated cells, whereas class II molecules are expressed primarily on antigen-presenting cells (such as B cells, dendritic cells, and macrophages) but can be expressed under inflammatory conditions on a variety of cell types including endothelial cells and epithelial cells. This means that only HLA type i are present on T lymphocyte , however B lymphocytes express both HLA type I and II.
Type of study:
Case series
Level of evidence:
this study provides level 4c
CLASS I and CLASS II antigens:
Classification of HLA antigens
HLA (human leucocyte antigen) are encoded for by genes on chromosome 6 :
MHC class I proteins form a functional receptor on most nucleated cells of the body.
There are 3 major and 3 minor MHC class I genes in HLA:
The genes of the class II combine to form heterodimeric (αβ) protein receptors that are typically expressed on the surface of antigen-presenting cells.
There are 3 major and 2 minor MHC class II proteins encoded by the HLA:
MHC class I Antigens are expressed onr on most nucleated cells of the body.
Class II Antigens are typically expressed on the surface of antigen-presenting cells.
Case report study with level 4 evidence
MHC class I & II are proteins that play a major role in adaptive response. Both classes proteins have a role in presenting peptides on cell surface that recognized by T cells.
HLA class I classifies into classical genes ( HLA-A, -B, -C), & non classical genes (HLA -E, -F, -G), and class I like gene( MICA, MICB). Classical expressed in all nucleated cells& activate CD8 T cells, non classical genes expressed in special tissues while class I like gene expressed only in physiological stress.
HLA class II classifies into classical genes (HLA-DR, -DP, -DQ), non classical genes ( HLA-DM& DO), & pseudogenes. HLA class II expressed in APC ( DC, macrophage) & B cells.
References:
Level of evidence 5 case report
Class I and II antigens are protein expressed on the surface of cells, class I expressed on all nucleated cells, but class II expressed on the surface of antigen presenting cells APCs like B cells, dendritic cells, macrophages, and endothelial cells.
Class I antigen protein is composed of complex of 3 α chains (α1, α2, α3) and one β2 microglobulin. And can be recognized by CD8.
Class II antigen protein is composed of complex of 2 alpha and 2 beta chains. Can be recognized by CD4.
Marek Wieczorek, Jana Sticht, Miguel Álvaro-Benito, Esam T. Abualrous, Sebastian Stolzenberg. Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Front. Immunol., 17 March 2017.
1-Type of Study: Case series with level of evidence of 4.
2-HLA I&II: are the major alloantigens in charge of triggering T lymphocytes.
HLA I : They are glycoproteins encoded by linked genes on short arm of chromosome 6.
HLA class I :including HLA-A to G ;of which the most clinically important are HLA-A,B and C. polymorphic They are composed of polymorphic heavy alpha chain (including alpha 1,2 and 3) and non polymorphic light chain ;beta 2 micro globulin.
HLA II: composed of polymorphic alpha and beta chains including ;the classical ones :HLA-DP,HLA-DQ and HLA-DR. They are encoded by DPA, DPB, DQA, DQB, DRA, and DRB genes.
3 Expression :
HLA class I : are expressed on all nucleated cells and platelets ,but not on RBCS and trophoplasts .
HLA class II :are expressed only on antigen presenting cells ;dendritic cells ,macrophages ,and B lymphocytes.
References:
Danovitch, GM: Handbook of kidney transplantation, sixth edition
Case report, Level 4 evidence
A- Major Histocompatibility Antigen MHC = HLA Human Leukocyte Antigen: polymorphic proteins, any given HLA gene is present in many different forms or alleles
1- HLA class I: HLA-A to -G
The most clinically relevant (Classical) are HLA-A, -B, -C
These present on the surface of all nucleated cells and platelets
2- HLA class II: present on B-lymphocytes, myeloid cells, and a subset of activated T-lymphocyte
The most relevant group are HLA-DR, -DQ, -D
Myeloid cells that express HLA class II molecules are antigen-presenting cells (APC) that include dendritic cells and macrophages.
HLA II is also expressed on endothelial cells during inflammation, in response to the cytokine interferon-gamma (IFNץ).
Non-class I- like proteins:
1- (HLA-G); modulate NK-cell function and are targets of alloantibodies.
2- MICA and MICB: stimulate NK cell and some T-lymphocyte subsets, anti-MICA or –MICB antibodies in the recipient correlates with increased incidence of rejection and graft loss.
B- Minor Histocompatibility Antigen (m HA):
1- non-HLA; H-Y Ag (present only in males) affect the survival of the male renal allograft transplanted to a female recipient.
Polymorphic mitochondrial proteins
What is the type of this study and what is the level of evidence this study provides?
Case report, level of evidence: 4
What are CLASS I and CLASS II antigens.
Class I: HLA- A, B, C ( Classical antigens)
HLA-E, F, G ( Non-Classical)
Class II: HLA-DR, DP, DQ ( Classical)
HLA-DM, DO ( Non-Classical)
Is there any difference in expression between both?
HLA Class I antigen expressed by all nucleated cells
HLA Class II antigen expressed by antigen presenting cells ( dendritic cells, macrophages, monocytes) and B lymphocytes.
1- Case report study , level of evidence is 4
2- Class I antigens It is made of a polymorphic alpha chain, which consists of
three external domains,
a transmembrane region, and
an intracellular domain,
noncovalently associated with a non-polymorphic beta-2 microglobulin chain
It is expressed by 3 genes ;HLA A B C which is highly polymorphic
Class II antigens
compromises two polypeptide chains,
an alpha chain and a beta chain,
each with a transmembrane domain, two external domains, and a short intracellular domain.
Which is expressed by 9 genes ; HLA-DRA, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, – DQB1, -DPA1, -DPB1which is highly polymorphic
The majority of the genetic variation within an HLA allele providing that region different specific cities for antigenic peptide binding and T cell antigen receptor interaction.
Studies in recipients of renal transplants from deceased donors showed no major effects on outcome in first transplants but a significant impact on re-transplants
3- Class I is expressed on nucleated cells and are recognized by cytotoxic CD8+ T cells.
Class II is expressed by antigen-presenting cells as dendritic cells (DCs), macrophages, or B cells which can activate CD4+ T cells,also its expression may be increased on epithelial cell and vascular endothelial cell after exposure to inflammatory cytokines.
Reference
-Wieczorick M .etal. Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation .Front. Immunol., 17 March 2017
What is the type of this study and what is the level of evidence this study provides?
Case series.
Level 4 evidence
What are CLASS I and CLASS II antigens. Is there any difference in expression between both?
Class I MHC
• This includes HLA A, B and C
• Class I proteins are expressed on all nucleated cells
• Class I proteins are heterodimers, consisting of the polymorphic alpha chain and invariant
β-2 microglobulin
• They are responsible for the presentation of proteins produced within the cell cytosol to CD8 T cells.
Class II MHC
• This includes HLA DR, DP and DQ
• Class II proteins are confined to antigen presenting cells . However, under the influence of inflammatory cytokines other cells (for example renal epithelial and endothelial cells) can express MHC class II
• Class II proteins are also heterodimers but in contrast to class I there are two polymorphic
chains (α and β )
• Antigen-presenting cells take up antigen from their environment and process this to short
peptides that are then loaded onto class II proteins. These are then expressed on the cell
surface for recognition by lymphocytes.
• They are responsible for presentation of antigen to CD4 cells
Oxford handbook of transplant
In this case series
What are your thoughts on having pretransplant removal of antibodies?
Do you think it’s ethical to go without desensitization in such cases? Please have a look at the outcomes?
What are the monitoring strategies for such patients?
Would you please reflect your own thoughts
Algorithm based on HLA Typing report, CDC, FCXM, SAB Luminex
CDC and FCXM negative
If DSA is negative in recipient will go ahead with basiliximab induction. maintenance Tac, MMF, Prednisolone
If DSA is positive but MFI<1000- will go ahead with ATG induction. maintenance Tac, MMF, Prednisolone
If DSA is positive and MFI 1000-10000- desensitization with ATG, plasmapheresis, Ivig followed by maintenance Tac, MMF, Prednisolone
If DSA is positive and MFI>10000 or multiple DSA >5000-avoid
CDC positive – avoid
CDC negative , FCXM positive
If DSA is negative in recipient will go ahead ATG induction. maintenance Tac, MMF, Prednisolone
If DSA is positive but MFI<1000- will go ahead with ATG induction. maintenance Tac, MMF, Prednisolone
If DSA is positive and MFI 1000-10000- desensitization with ATG, plasmapheresis, Ivig followed by maintenance Tac, MMF, Prednisolone
If DSA is positive and MFI>10000 or multiple DSA >5000-avoid
HLA Desensitization Based on Results of the Luminex Technique in Kidney Transplant
S.B.Bansal et al