As to the first part of the question which is the (mechanism of non complement fixing antibody injury ).those are IGg 2 ,4
Two routes:
1.Innate immunity where the following cells bind to the Fc fragment of the DSA ab causing degranulation of the cells ,release of lytic enzymes that cause endothelial injury ending in sub clinical rejection or cABMR.These cells are NK, neutrophils ,macrophages.
2.DSAs directly act on endothelial cells leading to proliferation and growth factors production as VEGF ,fibroblast GF ending in vascular intimacy proliferation and TG.
As for the phenotypes:
Most of you have the correct information you can please refer to my comment for Dr .Lomatayo,
A very informative ,simple and clear table is presented by Dr. Mai Shawky look at it.
Lefaucheur et al. explored the association of DSA IgG subclasses with various phenotypes of AMR: 1.iDSAs (iDSAs= immunodominant DSA; the single DSA with the highest MFI) of the IgG3 subclass had the strongest association with acute AMR (P= 0.002). ====================================================== 2.iDSAs of the IgG4 subclass were strongly associated with subclinical ABMR (P= 0.001) & showed features of chronic AMR, including TG & IF/TA. ====================================================== 3.IgG3 iDSAs & C1q1 iDSAs were strongly associated with allograft failure.
Reference Stanley C. Jordan Donor-Specific HLA Antibody IgG Subclasses Are Associated with Phenotypes of Antibody-Mediated Rejection in Sensitized Renal Allograft Recipients J Am Soc Nephrol 27: 6–8, 2016.doi: 10.1681/ASN.2015060608
IgG3 DSAs were associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
• IgG4 was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
• IgG3 and C1q binding DSAs were strongly and independently associated with graft loss.
• IgG4 DSAs were associated subacute and chronic phenotypes of AMR consistent with complement- independent pathogeneses.
References:
1-Applied Transplant Immunology; Case-based Discussion (Part 1) By Professr Ahmed Halawa.
To differentiate between complement fixing and non complement fixing DSAs address the following points systematically:
1.class of HLA
2.class of IGg
3.time of appearance
4.circumstances of their appearance eg.non compliance ,etc
5.along with the subclass are there predisposing factor as IRI, infection,TCMR all these cause ischemia predisposing to their injurious effect.
Alongside with the rest of the battery for work up try to make your report or answer analytical as a clinician to help in decision taking for each patient.
Again there are many tables to demonstrate the different phenotypes but the one presented by Dr.Mai Shawky is fine.
IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy .
Reference ;
1. Schaub S, Hönger G, Amico P: The complexity of the humoral immune response against HLA antigens. Transpl Int 27: 249–250, 2014 [PubMed] [Google Scholar
with class 1 and 3 IgG causes acute and accelerated Acute rejection presented with abrupt deterioration of allograft function, histologically MVI {acute active cappilaritis [glomerulitis and peri tubular capillaritis} with C4d staining in PTC as its complement fixing antibodies.
Meanwhile IgG2 and IgG4 [non complement fixing] related to Chronic AMR presented with subtle deterioration of allograft function and proteinuria. Histologically, presented as Transplant Glomerulopathy TG with double contouring of glomerular basement membrane membrano proliferaive pattern of glomerulopathy, and PTC multilayring.
The phenotype may not differ; what is important is the ability to fix the complement, the strength of antibody, specificity of antibody, and the antigen expression . We know now IgG1& IgG3 had the capacity to fix the complement more than IgG2 & IgG4
No Ben the phenotype is different:
Type1
DSA 1,3 class1HLA IGg 1,3
Effector cells are memory B cells ,Plasma cells.
Complement fixing C1q.
Pathology:microvasculitis,ptc
Timing. Early aggressive ABMR with C4d+.
Type 2.
Class2.HLA eg.DQ
IGg 2;4
Not complement fixing
Effector cells NK ,neutrophils, macrophage
Direct lytic action on endothelial cells.
Timing. Late.
Need ischemia as IRI, infections ,TCMR
Effects sub clinical rejection, chronic rejection TG
So as you see there are major differences!,
Yes,
▪︎ Acute ABMR is mainly driven by IgG3 DSA, whereas subacute ABMR is driven by IgG4 DSA.
▪︎IgG3 DSA is associated with a shorter time to rejection, increased microcirculation injury , and C4d capillary deposition
▪︎IgG4 iDSA is associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions
A quicker time to rejection, greater microcirculation damage, and positive C4d deposits were seen in patients with IgG3 DSAs, indicating that the DSAs were causing cytotoxicity that was reliant on the complement system.
• DSAs with IgG3 and C1q binding were shown to be significantly and independently linked with graft loss.
• IgG4 DSAs were shown to be related to both subacute and chronic forms of AMR, indicating that they are connected with complement-independent pathogens.
Only IgG3,IgG4 subclasses correlated with the ABMR phenotyping
1-IgG 3 subclass associated with early aggressive type of AMR ( phenotype 1)with lower GFR at time of rejection with C1q complement binding activity and positive C4D staining. Histologically shows microvascular inflammation with typical g, PTCS its independent risk of early graft loss.
2- IgG4 class correlated with phenotype 2 less aggressive subclinical AMR non-complement binding activity and occur late with better GFR at time of presentation but associated with more chronic damage characterized by histological finding of chronic Tg and IFTA, ,less responsive to treatment and associated with progressive late graft loss.
References:
1-Lefaucheur C, Viglietti D, Bentlejewski C, et al. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury. J Am Soc Nephrol. 2016;27(1):293-304. doi:10.1681/ASN.2014111120
Yes there is a difference in the rejection phenotype between the different IgG classes.
IgG3 DSA are associated with shorter time to rejection, increased microcirculation injury, positive C4d deposits, all indicating complement dependent cytotoxicity.
IgG4 is associated with late graft injury with increased transplant glomerulopathy and interstitial fibrosis, tubular atrophy.
IgG3 and C1q binding DSA are strongly and independently associated with graft loss.
IgG4 DSA are associated with subacute and chronic phenotypes of AMR, indicating complement independent pathogenesis.
IgG class 1, 3 usually involved in type 1 AMR, which is usually mediated by complement fixing antibodies , with memory B cells and plasma cells are main effector cells, it if formed due to preformed DSA (directed against HLA class I) and presented as hyper-acute , acute rejection with rapid progression of graft loss. it is characterized histologically by positive c4d in ptc, plus presence of c1q which indicated complement activation. it respond well to anti rejection therapy as PEX, IVIG and rituximab. however, IgG class 2, 4 are involved in type 2 ABM, which mediated by non complement fixing antibodies, formed denovo after transplantation against HLA class II and cause graft damage through antibody mediated cellular toxicity or direct endothelial activation. it is usually presented later or as as chronic AMR, with slow progressive course and less response to anti-rejection therapy , but eventually TG and graft loss.
Phenotype 1 AMR usually caused by sensitization events.caused by DSA class 1 IgG 1&3 subclasses.
It is Complement fixing
The effector cells are memory B cells and plasma cells
Crossmatching result usually positive T cells
Occurs early with C4d positive in ptc
It is complement- dependent cytotoxicity
Lead to acute ABMR with rapid graft dysfunction and rapid graft loss
Phenotype 2 AMR
Caused by ischemia-reperffusion injury
No adherence to IS or viral infection
Caused by DSA class ll IgG 2 &4
It is non-complement fixing with effector cells NK, neutrophils and macrophages
Cause positive B cells crossmatching
With negative C4d in ptc
Late in presentation lead to late AMR or chronic active ABMR
Mechanism of action antibody -mediated cellular cytotoxicity or direct endothelial injury and swelling.
It slowly progress but lead eventually to graft loss.
Does the phenotype of the rejection differ between the 4 types of IgG classes?
Yes phenotype of rejection differs according to the IgG subclass
Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury.
*IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
*IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
*whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy.
Yes, The phenotype of rejection difference with sub class of IgG :
Acute ABMR was mainly driven by IgG3 DSA, whereas subclinical ABMR was driven by IgG4 DSA.
IgG3 DSA was associated with a shorter time to rejection , increased microcirculation injury , and C4d capillary deposition .
IgG4 DSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions .
Integrating DSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses revealed IgG3 DSA and C1q-binding DSA were strongly and independently associated with allograft failure.
IgG3 subclass DSA has associted with ABMR and characterized by intense micro vascular inflammation and higher C4d deposition in allograft and has great risk of graft loss,
IgG4 subclass DSA exhibit specific phenotype of antibody mediated injury as represent by transplant glommularpathy , interstitial fibrosis and tubular atrophy. References1. Sellarés J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, Hidalgo LG, Famulski K, Matas A, Halloran PF: Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 12: 388–399, 2012 [PubMed] [Google Scholar]
2. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B: Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 4: 378–383, 2004 [PubMed.
What are the classes of IgG DSA?what is the mechanism of the injury they cause?IgG has several subclasses IgG1,2,3 and 4 and thy have various ability to activates complement and recruit effector cells through the FC receptor. IgG1 and IgG 3 usullaly complement binding subclasses IgG3 binding to C1q and activate complement cascade also increased microcirculation and postive C4d deposit indicate complement depented cytotoxcity . IgG2 can activate complement weakly IgG4 does not activate complement at all but both can recruit effector cells through the FC receptors and associttted with advanced stage of rjection such as TG , IF and TA associtted with subacute and chronic ABMR. Referenc PROF.Ahmed H alawa
Several phenotypes of ABMR are determşned by the timing and extent of humoral response and various characteristics of DSAs. they differ in terms of strength and complement-fixing capacity.
For example, Denovo DSAs are usually related to late Acute AMR.
Preformed DSAs can lead to hyperacute, accelerated acute and early acute rejection.
IgG subclasses have different affinities and capabilities to activate complement and recruit effector cells. For instance, IgG3 are frequently associated with acute rejection, while IgG4 subclass is mostly associated with chronic or subclinical rejection
yes,
IgG3 C1q binding DSA is commonly associated with acute AMR, more severe graft injury and early graft loss while IgG4 C1q non binding DSA is more related to subclinical, chronic AMR and transplant glomerulopathy.
Zhang R. Donor-specific antibodies in kidney transplant recipients. Clinical Journal of the American Society of Nephrology. 2018 Jan 6;13(1):182-92.
There is IgG 1,3 which is usually secreted in response to HLA class 1 mismatch and usually causes early post-transplant graft acute ABMR by Complement fixing C1q. causing severe microvascular inflammation and C4D +ve in immunohistochemistry microscopy. There is IgG 2;4 which is usually secreted in response to HLA class2 mismatch and usually causes late post-transplant graft subacute and chronic TG by not complement-fixing by direct lytic action on endothelial cells. this is usually precipitated by ischemia as IRI, infections,TCMR as class II not usually expressed on the surface except after stress conditions.
yes sir
in one study
After analysis of iDSAs and their subclasses, there was an interested association.
1. iDSAs of the IgG3 subclass had the strongest association with acute ABMR.
2. iDSAs of the IgG4 subclass were strongly associated with subclinical ABMR and showed features of CABMR, including TGand interstitial fibrosis/tubular atrophy.
This study found that IgG3iDSAs and C1q1 iDSAs were strongly associated with allograft failure.
This finding is of paramount importance as it is show that iDSA characteristics
can predict risk for developing different phenotypes of ABMR.
These data help to characterize the specific phenotype of ABMR and may help to specify specific treatment for each phenotype .
phenotype of rejection is different between IgG subclasses. IgG3 and IgG4 were the most discriminating IgG subclasses for identifying ABMR phenotypes.Studies revealed that IgG immunodominant DSA(iDSA) subclasses identify phenotypes of kidney allograft ABMR.IgG3 iDSA was associated with a shorter time to rejection, increased microvascular injury and C4d capillary deposition. IgG4 iDSA was associated with later graft injury, increased transplant glomerulopathy and IFTA
Wee Leng Gan
2 years ago
Ig G DSA can be divided into Ig G 1 , Ig G 2, Ig G 3, Ig G 4.
IgG1 comprises 60 to 70 percent of total IgG
IgG2 comprises 20 to 30 percent of total IgG
IgG3 comprises 5 to 8 percent of total IgG
IgG4 comprises 1 to 4 percent of total IgG
IgG1 and IgG3 fix C1q most effectively, while IgG2 does so weakly. IgG4 does not bind complement at all.
Reference.
Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol 2010; 125:S41.
Carsetti R, Plebani A, Ugazio AG, et al. B lymphocytes and immunoglobulins. In: Immunology IV: Clinical Application in Health and Disease, Bellanti JA (Ed), Care Press, Bethesda, MD 2012. p.163.
van der Berg M, Weemaes CMR, Cunningham-Rundles C. Isotype defects. In: Immune Deficiencies, Sullivan KE, Stiehm ER (Eds), Academic Press Elsevier, Amsterdam 2014. p.389.
AMAL Anan
2 years ago
There are 4 types of IgG classes:
IgG 1 and 3 which leads to acute antibody mediated rejection
Where IgG 2 and 4 lead to chronic antibody mediated rejection
Alyaa Ali
2 years ago
IgG has several subclasses (IgG1, -2, -3, and -4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor. IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade.
Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor.
Phenotype 1 AMR related to IgG class 1 and 3
Phenotype 2 related to IgG class 2 and 4
Assafi Mohammed
2 years ago
IgG classes:
There are four sub-classes of IgG: IgG1, IgG2, IgG3, and IgG4.
What is the mechanism of the injury they cause?
IgG1: in response to anaphylaxis or allergic reaction along with IgE.It is also involved in opsonization and activation of the complement cascade and strong association was found between the C1q-binding ability and the IgG1 strength. It has been observed in cardio-pulmonary responses to anaphylaxis. These responses being mediated by the Fc portion of the IgG1.
IgG2:found in relation with the host reaction to bacterial capsular polysaccharide antigens.
IgG3:found to be associated with effector responses to foreign antigens. It’s a complement-binding subclass. It has been hypothesized that it might play a role in the acquirement of protective immunity.
IgG4: has been associated with chronic exposure to an antigen and also auto-immune disease.
Ahmed Fouad Omar
2 years ago
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
o There are 4 IgG classes that differ in their ability to activate complement and recruiting effector cells through their Fc receptor.
IgG1 and IgG3:
o IgG1 and IgG3 are the complement binding subclasses.IgG1 is the most common subclass. Whereas, IgG3 has the greatest ability to activate the complement cascade.
o IgG1 and IgG3 results in type 1 ABMR directed against HLA class 1
o Clinically presents with hyper acute or acute graft loss and increased microcirculation injury
o Histologically, C4d in the PTC and C1q can be detected indicating complement activation.
o Shows better response to treatment that includes PP,IVIG +/- Rituximab
IgG2 and IgG4:
o IgG2 can weakly activate complement. On the other side,IgG4 does not activate complement completely. Graft injury results from Antibody-dependent cellular cytotoxicity or direct endothelial activation.
o IgG2 and IgG4 results in type 2 ABMR directed against HLA class 2
o Clinically presents with more chronic, sub-acute forms of graft loss and TG
o Histologically, it results in C4d negative rejection or direct endothelial activation.
o Shows poor response to anti-rejection treatment
References:
1. Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. CJASN January 2018, 13 (1) 182-192
2. Update June 2020
Balaji Kirushnan
2 years ago
The donor specific IgG antibodies belong to various classes namely IgG1,IgG2, IgG3 and IgG4….They have variable expression and belong to different classes and have different complement binding capacity…..
IgG1 – It is the most common IgG which causes complement dependent damage and they belong to de-novo class 1 DSA…They have a strong complement affinity potential…They cause ABMR very early after transplant and respond to the usual treatment..They are responsible for the classical C4d positive ABMR
IgG2 – They are responsible for complement independent injury and are weekly bound to complement…They are usually de novo class II DSA and bind to the endothelium and cause chronic ABMR which is resistant to treatment and occurs late in the course of the treatment…They cause C4d negative ABMR
IgG3 – It has high complement binding capacity and they are similar to IgG1 in the features of ABMR..
IgG4 – It is similar to IgG2 and it causes late onset ABMR…It is associated with similar features to IgG2 and causes long term graft damage due to complement dependent cell cytotoxicity and direct endothelial cell damage..
Mahmoud Hamada
2 years ago
There are 4 classess of IgG : IgG1,IgG2, IgG3 and IgG4.
IgG4 was associated with delayed allograft injury, high risk of allograft glomerulopathy, and interstitial fibrosis/tubular atrophy IFTA.
on the other hand, early rejection, higher microvascular injury, more C4d capillary deposition, and graft failure.
Hamdy Hegazy
2 years ago
What are the classes of IgG DSA? What is the mechanism of the injury they cause? DSA IgG 1, 2, 3, 4. IgG 1, 3 are usually against class I HLA, usually are performed antibodies that leads to early acute ABMR via complement fixation, are usually associated with C4d positive staining in IF and IHC microscopy, usually associated with poor graft outcome, however it responds to treatment. IgG 2, 4 are usually directed against class II HLA, usually denovo antibodies, non-complement fixing but direct lytic effect that leads to late (after first year post TX) subacute graft dysfunction.
Abdullah Raoof
2 years ago
Serum IgG can be divided into 4 subclasses (IgG1, IgG2, IgG3, IgG4).
These sub classes has different ability to activate complement system with (IgG1 & IgG3) has higher ability than (IgG2 & IgG4).
A study done by Lefaucheur et al. report that diferent DSA IgG subclasses associated with various phenotypes of ABMR.
In this study there was , 125 patients with positive DSAs .
40.8% of patients had acute ABMR.
28.8% had subclinical ABMR.
30.4% remained free of ABMR.
Immunodominant DSA (iDSAs) the single DSA with the highest mean fluorescence intensity [MFI]) were 6724 , and 41.6%of patients had C1q1DSAs.
After analysis of iDSAs and their subclasses, there was an interested association.
1. iDSAs of the IgG3 subclass had the strongest association with acute ABMR.
2. iDSAs of the IgG4 subclass were strongly associated with subclinical ABMR and showed features of CABMR, including TGand interstitial fibrosis/tubular atrophy.
This study found that IgG3iDSAs and C1q1 iDSAs were strongly associated with allograft failure.
This finding is of paramount importance as it is show that iDSA characteristics
can predict risk for developing different phenotypes of ABMR.
These data help to characterize the specific phenotype of ABMR and may help to specify specific treatment for each phenotype .
Kamisawa et al in his study shows that
· patients withIgG4related disease present with a spectrum of autoimmune
·disorders characterized by storiform fibrosis, phlebitis, levels. These patient are known to respond well to rituximab.
· Patients with predominant IgG3 iDSAs and C1q1 iDSAs will likely require a combination of antibody reduction therapies and complement inhibitors to control the ABMR process.
REFRENCESS
Stanley C. Jordan Donor-Specific HLA Antibody IgG Subclasses Are Associated
with Phenotypes of Antibody-Mediated Rejection in Sensitized Renal Allograft
RecipientsJ Am Soc Nephrol 27: 6–8, 2016.doi: 10.1681/ASN.2015060608
Ramy Elshahat
2 years ago
What are the classes of IgG DSA? What is the mechanism of the injury they cause?there is IgG 1,3 which is usually secreted in response to HLA class 1 mismatch and usually causes early post-transplant graft acute ABMR by Complement fixing C1q. causing severe microvascular inflammation and C4D +ve in immunohistochemistry microscopy. There is IgG 2;4 which is usually secreted in response to HLA class2 mismatch and usually causes late post-transplant graft subacute and chronic TG by not complement-fixing by direct lytic action on endothelial cells. this is usually precipitated by ischemia as IRI, infections,TCMR as class II not usually expressed on the surface except after stress conditions.
Ahmed Omran
2 years ago
IgG has four subclasses: IgG1-4.IgG 1&3 are complement fixing. They work against class I HLA through complement binding leading to more rapid rejection ,more microcirculation damage in addition to C4d deposition.
DSAs with IgG3 & C1q binding are significantly and independently linked with graft loss.
• IgG4 DSAs were shown to be associated with both subacute and chronic AMR, indicating that they are connected with complement-independent pathogens and they are HLA class II antibodies .
Dalia Eltahir
2 years ago
IgG is composed of four subclasses: IgG1, IgG2, IgG3, and IgG4
IgG 1 and 3 are complement-fixing subclasses. They are class I HLA antibodies, strong complement binding, associated with quicker time to rejection, greater microcirculation damage, and positive C4d deposits • DSAs with IgG3 and C1q binding were shown to be significantly and independently linked with graft loss.
• IgG4 DSAs were shown to be related to both subacute and chronic forms of AMR, indicating that they are connected with complement-independent pathogens and they are HLA class II antibodies .
MICHAEL Farag
3 years ago
There are several phenotypes of antibody-mediated rejection that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity.
de novo class I DSA are of subclass IgG1 and IgG3 while class II are IgG2 and IgG4
▪︎DSA IgG Subclasses:
*IgG has 4 subclasses (IgG1, -2, -3, and -4), with different abilities to activate complement and recruit effector cells through the Fc receptor.
▪︎IgG1 and IgG3
*IgG1 and IgG3 are usually complement binding subclasses.
* IgG1 is the most abundant subclass and mirrors the total IgG level.
* IgG3 has the greater binding efficiency to C1q and activate complement cascade.
*acute antibody-mediated rejection is mainly caused IgG3 iDSA.
*IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
*IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
▪︎IgG2 and IgG4
* IgG2 can activate complement weakly, IgG4 does not activate complement at all.
*both can recruit effector cells through the Fc receptor.
*IgG4 is a biomarker of matured alloresponse and associated with advanced stage of rejection.
* IgG4 iDSA usually associated with subclinical AMR.
* IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
*IgG4 iDSA–associated subacute and chronic of antibody-mediated rejection with complement-independent pathogeneses.
Rubin Zhang.Donor-Specific Antibodies in Kidney Transplant Recipients.CJASN January 2018, 13 (1) 182-192
Dear Dr Farag This is a copy and paste from a colleague’s reply. This is very unethical; therefore, you have been referred to the Academic Integrity officer for investigation. Please see below:
Shereen Yousef
15 days ago
■What are the classes of IgG DSA? What is the mechanism of the injury they cause?
There are several phenotypes of antibody-mediated rejection that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity.
de novo class I DSA are of subclass IgG1 and IgG3 while class II are IgG2 and IgG4
▪︎DSA IgG Subclasses:
*IgG has 4 subclasses (IgG1, -2, -3, and -4), with different abilities to activate complement and recruit effector cells through the Fc receptor.
▪︎IgG1 and IgG3
*IgG1 and IgG3 are usually complement binding subclasses.
* IgG1 is the most abundant subclass and mirrors the total IgG level.
* IgG3 has the greater binding efficiency to C1q and activate complement cascade.
*acute antibody-mediated rejection is mainly caused IgG3 iDSA.
*IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
*IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
▪︎IgG2 and IgG4
* IgG2 can activate complement weakly, IgG4 does not activate complement at all.
*both can recruit effector cells through the Fc receptor.
*IgG4 is a biomarker of matured alloresponse and associated with advanced stage of rejection.
* IgG4 iDSA usually associated with subclinical AMR.
* IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
*IgG4 iDSA–associated subacute and chronic of antibody-mediated rejection with complement-independent pathogeneses.
Rubin Zhang.Donor-Specific Antibodies in Kidney Transplant Recipients.CJASN January 2018, 13 (1) 182-192
Mohamed Essmat
3 years ago
IgG1 is the most prevalent subclass in the pre- & post transplant sera.
IgG1 & IgG3( associated with high incidence of ABMR , and poor graft outcome) are strong complement binding antibodies which occur early in post transplant period and are associated with anti-HLA class I antibodies.
IgG2 & IgG4 ( Chronic transplant glomerulopathy ) are non complement binding antibodies which take part late in post transplant period & associated with anti-HLA class II antibodies.
nawaf yehia
3 years ago
IgG DSA classes : IgG 1 ,2,3,4
IgG1, IgG3 : complement binding Abs , activate the classical complement pathway by binding to c1q , resulting in cell damage
these are directed against class 1 HLA , leading to acute ABMR and early graft loss
IgG2 , IgG4 : Complement non-fixing DSA ,they are commonly targeting class 2 HLA on graft endothelium and can induce cell damage by the following mechanisms : 1- Ab dependant cellular cytotoxicity , by recuitinmg immune cells namely neutrophils , macrophages & NK cells that by degranulation and release of their lytic enzymes cause cell damage 2- direct endothelial cell activation and proliferation resulting in vasculopathy in general it tends to occur later than the complement binding type , more associated with chronic changes and subclinical presentation and thereby slower graft loss
nawaf yehia
3 years ago
Subclasses of IgG DSA : 4 subclasses IgG 1 , 2,3,4
IgG1 & IgG3 : these are complement binding Abs ( after binding to their target Ag , they activate the classical complement pathway by binding to C1q ) resulting in cell damage .
they are directed to class 1 HLA , associated with Acute ABMR , early presentation , rapid graft dyysfunction & graft loss , C4d +ve in graft biopsy
IgG 2 , IgG4 : they are commonly targeting class 2 HLA on graft endothelium and can induce cell damage by the following mechanisms :
1- Ab dependant cellular cytotoxicity , by recuitinmg immune cells namely neutrophils , macrophages & NK cells that by degranulation and release of their lytic enzymes cause cell damage
2- direct endothelial cell activation and proliferation resulting in vasculopathy
in general it tends to occur later than the complement binding type , more associated with chronic ABMR and subclinical presentation and thereby slower graft loss . C4d is negative in graft biopsy
Jamila Elamouri
3 years ago
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
IgG subclasses are IgG1, 2, 3, and 4.
IgG1 and 3 are complement-fixing subclasses. They are class I HLA antibodies, strong complement binding, associated with early (acute) AMR, and rapid graft dysfunction. C4d positivity.
IgG1 is a more abundant subclass and it mirrors the total IgG level. While IgG3 has a greater binding affinity to C1q and complement activation.
IgG2 and 4 are weak or non-complement fixing. They are class ii HLA antibodies. Associated with late (chronic) AMR and late graft loss. C4d negative biopsy. Both make injury through the recruitment of the effector cells through the Fc receptor.
manal jamid
3 years ago
Yes
Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas non complement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses. They are associated with acute antibody-mediated rejection and early graft loss. Class 2 de novo DSAs appear later and are commonly non complement binding IgG2 or IgG4 subclass. They tend to be persistent and are associated with chronic antibody-mediated rejection and transplant glomerulopathy.
manal jamid
3 years ago
What are the classes of IgG DSA?
IgG has several subclasses (IgG1, -2, -3, and-4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor
what is the mechanism of the injury they cause The major three mechanism of graft injury are complement-dependent mechanisms 1.Binding of DSA to antigen expressed on allograft endothelial cells can activate classic complement pathway, a key pathologic process of acute antibody-mediated rejection phenotypes. complement-independent mechanism 2. DSAs can cause graft damage through antibody-dependent cellular cytotoxicity. The innate immune cells, including neutrophils, macrophages, and natural killer cells, can bind to Fc fragments of DSAs, trigger degranulation, and release lytic enzymes, which cause tissue injury and cell death. This process can mediate smoldering damages to the endothelial cells and is proposed as an important pathogenesis in subclinical and chronic antibody-mediated rejection phenotypes. 3. DSAs can cause graft injury by direct activation of endothelial proliferation through increasing vascular endothelial growth factor production, upregulating fibroblast growth factor receptor, and increasing its ligand binding as well as other signaling pathways for cellular recruitment. This pathogenesis may contribute to transplant glomerulopathy and vasculopathy that feature vascular intima thickness with smooth muscle cell invasion. The latter two complement-independent mechanisms can explain the clinical phenotypes of antibody-mediated rejection with negative C4d staining in peritubular capillaries.
REF:1. Donor-Specific Antibodies in Kidney Transplant Recipients Rubin Zhang CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
Heba Wagdy
3 years ago
IgG is divided into 4 subclasses IgG 1,2,3 and 4 and can initiate different effector functions based on their structure
IgG1 and IgG3 are usually complement binding, IgG1 is the most abundant while IgG3 has higher binding affinity to C1q
IgG1 and 3 are are likely to be class I DSA, detected sooner post transplant and are associated with acute AMR and early graft loss
IgG2 can weakly activate complement but IgG4 is unable to activate it, they can recruit effector cells through Fc receptor
IgG4 is considered a biomarker of advanced stage of rejection.
IgG2 and 4 subclasses are likely to be class II DSA that appear late post transplant and are commonly persistent and associated with chronic AMR
Zhang R. Donor-specific antibodies in kidney transplant recipients. Clinical Journal of the American Society of Nephrology. 2018 Jan 6;13(1):182-92.
Theepa Mariamutu
3 years ago
DSA IgG class
IgG has subclasses IgG1,2,3,4
Have various abilities to activate complement and recruit effector cells through Fc receptor
IgG1 and 3 – usually complement binding subclasses
IgG1- most abundant subclass and mirrors total IgG1 level
IgG3
has greater binding efficiency to C1q and activate complement cascade
Leads to acute ABMR
Associated with shorter time for rejection
Increased micro vascular injury
Positive C4d deposits
IgG3 and C1q binding iDSA were strongly and independently associated with graft loss
IgG2- weakly activate complement pathway, but can recruit effector cells thru Fc receptors
IgG4
do not activate complement cascade, but can recruit effector cells thru Fc receptors
Considered bio marker for matured alloresponse and associated with advance stage of rejection
Leads to subclinical rejection
Later graft injury with increased transplant glomerulopathy and interstitial fibrosis and tubular atrophy
IgG4 iDSA associated with subacute and chronic phenotypes of ABMR were consistent with complement non-fixing pathogeneses
Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. CJASN January 2018, 13 (1) 182-192.
Esmat MD
3 years ago
In addition to MFI strength and complement binding ability, another important characteristic of DSAs that influences their effects on graft damage is IgG subclasses.
IgG has several subclasses (IgG1, -2, -3, and -4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
There is a sequential IgG subclass switching, typically from IgG3 to IgG1 to IgG2 to IgG4 in the process of the immune response and antibody production. The pathogenicities of DSAs are a dynamic course and vary based on different IgG subclass profile.
IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and reflects the total IgG level, but IgG3 has the greater binding capability to C1q and activate complement cascade. Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor. IgG4 is also considered as a biomarker of matured alloresponse and is associated with an advanced stage of rejection.
Cytotoxic IgG antibodies are usually complement-binding IgG1 or IgG3 subclasses and can lead to a positive T cell crossmatch.
Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses and are associated with acute AMR and early graft loss. Class 2 de novo DSAs appear later and are commonly non-complement binding IgG2 or IgG4 subclasses, which tend to be persistent and are related to chronic AMR and transplant glomerulopathy.
IgG3 immune-dominant DSA (iDSA) is associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
IgG4 iDSA is associated with subacute and chronic phenotypes of antibody-mediated rejection, later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy that is consistent with complement independent pathogeneses including recruitment of innate immune cells (NK cells, macrophages, and neutrophils) through Fc receptors that lead to antibody-dependent cellular toxicity, and direct stimulation and pleotrophic effects on endothelial cells that cause tissue injury, cellular recruitment, and endothelial proliferation.
Ahmed Abd El Razek
3 years ago
IgG has several subclasses (IgG1, -2, -3, and -4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor. There is a sequential IgG subclass switching, typically from IgG3 to IgG1 to IgG2 to IgG4 IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor. IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection It was found that acute antibody-mediated rejection was mainly driven by IgG3 iDSA, whereas subclinical antibody-mediated rejection was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity. IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy. IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss.
Nasrin Esfandiar
3 years ago
IgG subclasses are IgG 1, 2, 3, 4. IgG subclass switching from IgG3 to IgG1, to IgG2 or IgG4 occurs during antibody production.
IgG1 and IgG3 are complement binding subclass with IgG3 more binding affinity To C19.
IgG2 weakly activates complement but IG4 can’t activate complement. They are effective in recruitment of immune cells.
IgG3 DSA is associated with early rejection, ↑ MVI and C4d+ or complement dependent cytotoxicity but IgG4 DSA is associated with later rejection and TG and IF/TA.
IgG3 and C19 binding DSAs are associated with graft loss but IgG4 DSAs are associated with subacute & chronic AMR with complement independent way. Immunological risk assessment a is improved with determining DSA strength,
IgG3 subclass or C1q binding capacity and harmful DSAs could be recognized.
So, mechanism of injury in IgG3 subclasses is complement dependent and in IgG4 is through cellular cytotoxicity or endothelial proliferation by complement independent pathways.
Manal Malik
3 years ago
What are the classes of IgG DSA?what is the mechanism of the injury they cause?IgG has several subclasses IgG1,2,3 and 4 and thy have various ability to activates complement and recruit effector cells through the FC receptor.
IgG1 and IgG 3 usullaly complement binding subclasses
IgG3 binding to C1q and activate complement cascade
also increased microcirculation and postive C4d deposit indicate complement depented cytotoxcity .
IgG2 can activate complement weakly
IgG4 does not activate complement at all but both can recruit effector cells through the FC receptors and associttted with advanced stage of rjection such as TG , IF and TA
associtted with subacute and chronic ABMR.
Referenc
PROF.Ahmed H alawa
Drtalib Salman
3 years ago
There are 4 subclass of IgG switching from IgG3 to IGg1 to IgG2 and finally after prolong immunization IgG4 .
they are exhibit functional difference such as complement activation and FC binding
IgG1 and 3 are the most effective at complement activation .
interesting IgG 3 the has the greater binding efficiency to complement C1q .
IgG 1 effective in complement dependent cell lysis .
IgG 2 can fix complement weakly but IgG 4 not at all .
.-IgG has several subclasses (IgG1, -2, -3, and -4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
-Over the course of immune response and antibody production, there is a sequential IgG subclass switching, typically from IgG3 to IgG1 to IgG2 to IgG4 .
-IgG1 and IgG3 are usually complement binding subclasses.
– IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activates the complement cascade.
-IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor.
-IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection .
– Studies showed :
-IgG3 -DSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
– IgG4 -DSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
– IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss .
-IgG4 -DSA–associated subacute and chronic phenotypes of antibody-mediated rejection were consistent with complement-independent pathogeneses .
-The advances in complement binding DSA assay and IgG subclass analysis have improved the ability to assess a patient’s immunologic risk and can help clinicians to identify more harmful DSAs, predict the distinct phenotypes of antibody-mediated rejection, and guide the clinical decision for kidney biopsy as well as immunosuppressive management. Reference:
-Rubin Zhang .Donor-Specific Antibodies in Kidney Transplant Recipients
CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
■What are the classes of IgG DSA? What is the mechanism of the injury they cause?
There are several phenotypes of antibody-mediated rejection that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity.
de novo class I DSA are of subclass IgG1 and IgG3 while class II are IgG2 and IgG4
▪︎DSA IgG Subclasses:
*IgG has 4 subclasses (IgG1, -2, -3, and -4), with different abilities to activate complement and recruit effector cells through the Fc receptor.
▪︎IgG1 and IgG3
*IgG1 and IgG3 are usually complement binding subclasses.
* IgG1 is the most abundant subclass and mirrors the total IgG level.
* IgG3 has the greater binding efficiency to C1q and activate complement cascade.
*acute antibody-mediated rejection is mainly caused IgG3 iDSA.
*IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
*IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
▪︎IgG2 and IgG4
* IgG2 can activate complement weakly, IgG4 does not activate complement at all.
*both can recruit effector cells through the Fc receptor.
*IgG4 is a biomarker of matured alloresponse and associated with advanced stage of rejection.
* IgG4 iDSA usually associated with subclinical AMR.
* IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
*IgG4 iDSA–associated subacute and chronic of antibody-mediated rejection with complement-independent pathogeneses.
Rubin Zhang.Donor-Specific Antibodies in Kidney Transplant Recipients.CJASN January 2018, 13 (1) 182-192
IgG has several subclasses (IgG1,-2,-3, and-4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
IgG1 and IgG3 are usually complement binding subclasses.
IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade
IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor. IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection
acute antibody-mediated rejection was mainly driven by IgG3 iDSA (91%), whereas subclinical antibodymediated rejection was driven by IgG4 iDSA (76%).
IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy
IgG subclass analysis have improved our ability to assess patient’s immunologic risk.
They can help clinicians to identify more harmful DSAs, predict the distinct phenotypes of antibody-mediated rejection, and guide our clinical decision for kidney biopsy as well as immunosuppressive management.
Reference
Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol 13: 182–192, 2018. doi: https://doi.org/10.2215/CJN.00700117
Asmaa Khudhur
3 years ago
There are 4 subclasses of IgG DSA 1,2,3and 4.
All have different potentials to activate complement and recruit the effector cells through Fc receptors to produce tissue injury with different spectrum ranging from no damage to severe damage .
IgG3 & IgG1
1-usually strong complement binding antibodies 2-occur early in post-transplant period .
3-associated with anti-HLA class I antibodies. 4-IgG3 associated with high incidence of ABMR, C4d positive & worse graft outcome.(phenotype 1 ABMR).
Mechanism of injury:complement-dependent cytotoxicity.
Respond well to treatment IgG2 & IgG4
1- non complement binding antibodies.
2-occurs late in post-transplant period .
3-associated with anti-HLA class II antibodies. 4-IgG4 associated with subclinical AMR ( diagnosed by protocol biopsy) & chronic transplant glomerulopathy and interstitial fibrosis .(phenotype 2 ABMR).
Mechanism of injury: antibody -mediated cellular toxicity.
Less response to treatment. REFERENCES: 1-Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. CJASN January 2018, 13 (1) 182-192
kumar avijeet
3 years ago
There are 4 classes of IgG DSA-
IgG1,IgG2,IgG3,IgG4.There is two type of phenotypes-
1.TYPE 1-
IgG 1 and IgG 3 Ab
against HLA class 1(preformed)
Complement C1q fixing
Capillaritis with C4d positive
Hyper acute and acute rejection with graft loss
2.TYPE 2-
IgG 2 and IgG 4 Ab
Against HLA class 2(denovo)
Noncomplement fixing
Transplant glomerulopathy with IFTA
sub acute and chronic rejection with ultimately graft loss
Amit Sharma
3 years ago
2. What are the classes of IgG DSA? What is the mechanism of the injury they cause?
Immunoglobulin G (IgG), comprising 10-20% of plasma protein, is one of the most abundant proteins in serum. It can be divided into 4 subclasses, namely IgG1, IgG2, IgG3, IgG4 , according to their decreasing abundance.
IgG1: Most common IgG, causes complement dependent injury.
IgG2: Weak complement fixing, causes complement independent injury.
IgG3: Has high complement binding capacity, leading to complement dependent injury, with shorter time to rejection, C4d positive and increased microvascular injury.
IgG4: Non complement fixing, is a marker of matured alloresponse and associated with later graft injury presenting with advanced stage of rejection (transplant glomerulopathy, interstitial fibrosis/ tubular atrophy).
Over the course of immune response, there is subclass switching from IgG3 to IgG2 to IgG2 to IgG4.
de novo class I DSA are of subclass IgG1 and IgG3, presenting with strong complement binding, and acute, early and aggressive C4d positive AMR which can lead to early graft loss, although more responsive to treatment. The graft injury is due to classical complement activation and the resultant complement mediated tissue injury.
de novo class II DSA are of subclass IgG2 and IgG4, presenting with weak or no complement binding, chronic or subclinical, late C4d negative AMR, which is less responsive to treatment leading to late graft loss. The graft injury is due to antibody dependent cytotoxicity or due to direct lytic action on the endothelial cell.
Reference:
1) Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014 Oct 20;5:520. doi: 10.3389/fimmu.2014.00520. PMID: 25368619; PMCID: PMC4202688.
2) Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
Hinda Hassan
3 years ago
Do you think that sensitisation against HLA A36 will affect only this HLA antigen only or other HLA antigens as well? Please justify your answer.
yes. HLA-A36 is found in the Black (Afro-Caribbean) population. It is rare in other ethnic groups(1). A36 had epitopes that were also present on HLA-A1and so reactivity with A36 was seen only in sera that also reacted with A1. However a murine monoclonal antibody was produced that reacted with A36 but not A1 whichindicate the presence of a xenogeneic epitope. However, the epitope was not necessarily allogeneic. To date there have been no reports of polyclonal antibodies that react with A36 but not A1. Sequence alignments show that an epitope shared between A36, A28, A33, and A34, but not found on A1, is formed by substitutions at residues 163 and 166–167 (2) 1- Rees L, Kim JJ. HLA sensitisation: can it be prevented?. Pediatr Nephrol. 2015;30(4):577-587. doi:10.1007/s00467-014-2868-6 2- Paul Sikorski; Dessislava Kopchaliiska; Donna P. Lucas; Mary S. Leffell; Andrea A. Zachary (2011). Characterization of an antibody specific for HLA-A36 and not reactive with HLA-A1. , 72(1), 0–90. doi:10.1016/j.humimm.2010.10.008
mai shawky
3 years ago
actually IgG subclass determines the phenotype of AMR and its characteristics as shown in table below.
Excellent table ! Hope it helps you diagnose and manage
The reflection on the cross match is very informative!
The work up should also include the MFI or MCS to help you decide the management.
Tahani Hadi
3 years ago
The effects of DSA on the graft survival differ according to its strength and subclasses leading to ABMR with its different phenotypes.
There are 4 subclasses of IgG DSA 1,2,3and 4.
IgG 3 has stronge effect on graft survival within short period of time by C4d deposition and inflammatory changes within micro circulation and it has with IgG1 complement binding ability while IgG2 can activate complement but weakly.
IgG4 also affect on graft survival but after longer period of time causing graft injury, interstitial fibrosis and tubular injury and it has no complement activation ability.
Reference
Zhang R. at al, Donor Specific Antibodies in kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018;13(1):182_192.
The classes of IgG DSA are IgG1, IgG2, IgG23 and IgG4. They differ according to 1- The cause of sensitization. Patients sensitized by only transfusion or pregnancies had anti-HLA antibodies of IgG1 and/or IgG3 subclasses, whereas patients with both transfusion and pregnancies and previous transplant showed a broader range of IgG subclasses. (1) 2- Whether preformed DSA or de novo DSA, in which de novo DSA were primarily made up of IgG1 and IgG3 alone. A positive T cell cross match secondary to cytotoxic IgG antibody, is usually complement binding IgG1 or IgG3 subclass. De novo DSAs after kidney transplant are usually class 2 antibodies, especially DQ. They appear later and persist. De novo DSAs are commonly non-complement binding IgG2 or IgG4 subclass and are associated with chronic AMR and transplant glomerulopathy. Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses. They are associated with acute AMR and early graft loss. 3- Early antigen clearance. It has been suggested that subclass switching occurs first from IgM to IgG3 and then to IgG1, IgG2, and IgG4. In many responses early antigen clearance would prevent the appearance of IgG2 and IgG4. (1) IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade. Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor. IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection . IgG3 DSA was associated with cute AMR ,a shorter time to rejection , increased microcirculation injury and C4d capillary deposition . IgG4 DSA was associated with sub-clinical AMR later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions. (2) 1-Ponsirenas, R., Cazarote, H. B., Araújo, S. A., Wanderley, D. C., Shimakura, S., Valdameri, J. S., Contieri, F., von Glehn, C., Susin, M. F., & Sotomaior, V. S. (2018). Anti-HLA Donor-Specific IgG Subclasses and C1q-binding Evolution in Posttransplant Monitoring. Transplantation direct, 4(9), e385. https://doi.org/10.1097/TXD.0000000000000823 2-Rubin Zhang, Donor-Specific Antibodies in Kidney Transplant Recipients,CJASN Jan 2018, 13 (1) 182-192; DOI: 10.2215/CJN.00700117
Mentioning causes of sensitization can you comment on transplanting a lady from her child!,
Do you perform a Tx with a + T cell cross math?
Nandita Sugumar
3 years ago
IgG has various subclasses ranging from 1 to 4. They activate complement and recruit effector cells through the Fc receptor.
IgG 1 and 3 are complement binding.
IgG1 is the most abundant. It mirrors the total level of IgG.
G3 binds to complement strongly and activates the complement cascade.They have a shorter time to rejection, increased microcirculation injury and positive C4d deposits, indicating complement dependent cytotoxicity.
G2 activates complement weakly.
G4 cannot activate complement
Both G2 and G4 can recruit effector cells through Fc receptor.
IgG4 is associated with late graft injury and increased transplant glomerulopathy and interstitial fibrosis or tubular atrophy. They are associated with complement independent AMR.
References :
Professor Ahmed Halawa. Applied Transplant Immunology, Case based discussion (part 2).
Good but refer to the table above as it covers all the aspects.
amiri elaf
3 years ago
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
# There are four subclasses of IgG, and there may be progressive subclass switching from IgG3 to IgG1 to IgG2 and, finally, after prolonged immunization, to IgG4
* IgG subclasses exhibit functional differences such as complement activation and Fc receptor binding. IgG1 and IgG3 are the most effective at complement activation, IgG3 has the greater binding efficiency to complement component C1q
IgG1 is the subclass most effective at complement‐dependent cell lysis IgG2 can fix complement weakly, but IgG4 not at all.
* In pretransplant and posttransplant sera, IgG1 was the most common IgG subclass.
* Presensitized patients showed different compositions of IgG subclasses according to the cause of sensitization. Patients sensitized by only transfusion or pregnancies had anti-HLA antibodies of IgG1 and/or IgG3 subclasses, whereas patients with both transfusion and pregnancies and previous transplant showed a broader range of IgG subclasses.
* IgG3 more frequently than IgG2 in posttransplant sera rather than the expected order of the IgG subclass concentration IgG1, IgG2, IgG3, and IgG4.
* There were differences between patients with preformed DSA and de novo DSA, in which de novo DSA were primarily made up of IgG1 and IgG3 alone.
* The first IgG detected was a class II DSA of IgG3 subclass
* Subclass switching occurs first from IgM to IgG3 and then to IgG1, IgG2, and IgG4.
* In many responses early antigen clearance would prevent the appearance of IgG2 and IgG4, and there presance was shown in elutes of rejected renal allografts confirming sequential subclass switching.
* There is correlation between the occurrence of AMR and the expansion of complement-fixing to noncomplement fixing DSA.
# The presence of different subclasses indicate distinct phenotypes of AMR. IgG4-containing DSA was associated with features of subclinical AMR, whereas IgG3-containing DSA was associated with an acute form of AMR and represented a greater risk for allograft loss.
Starzl TE, Marchioro TL, Hermann G, Brittain RS, Waddell WR. Renal homografts in patients with major donor‐recipient blood group incompatibilities. Surg Forum 1963; 14: 214. [PMC free article] [PubMed] [Google Scholar]
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Transplant Immunology Laboratory, Hospital Universitário Cajuru, Curitiba, PR, Brazil.
School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil.
Nephropathology Institute, Hospital das Clinícas da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Department of Statistics, Universidade Federal do Paraná, Curitiba, PR, Brazil.
They differs with regard to their ability in complement activation and effector cell activation
IgG 1 & IgG3: Complement Binding
IgG1: Most abundant /
IgG3: Greater binding to c1q/ Acute antibody-mediated rejection was mainly driven by IgG3 DSA / Shorter time to rejection / C4d deposits / IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
IgG2 : Least complement binding /
IgG4 : Does not bind to complement / A marker of matured all response & is associated with late rejection/ Subclinical antibody-mediated rejection was driven by IgG4 DSA/Increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy
Ref: Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018;13(1):182-192. doi:10.2215/CJN.00700117
Very good but refer to table presented by Dr. Mai Shawky
Weam Elnazer
3 years ago
What are the different types of IgG DSA? What is the process through which they inflict the harm they do?
It is possible to divide IgG into numerous subclasses (IgG1, 2, 3, and 4), each of which has a unique ability to activate complement and attract effector cells via the Fc receptor.
• IgG1 and IgG3 are subclasses of antibodies that bind to complement. IgG1 is the most prevalent subclass and reflects the overall IgG level; nevertheless, IgG3 has a higher binding efficiency to C1q and is more effective at activating the complement cascade than IgG1.
• Despite the fact that IgG2 can only weakly activate complement, IgG4 can not activate complement at all, both IgG2 and IgG4 can attract effector cells via the Fc receptor.
As a biomarker of developed allo response, IgG4 is also related to an advanced degree of rejection, according to some researchers.
DSAs derived from human IgG3 were shown to be related to quicker time to rejection, greater microcirculation damage, and positive C4d deposits, all of which suggests that the immune system is causing cytotoxicity.
A higher IgG4 level was related to graft harm later in the process, as seen by greater transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
• DSAs with IgG3 and C1q binding were shown to be significantly and independently linked with graft loss.
• IgG4 DSAs were shown to be related to both subacute and chronic forms of AMR, indicating that they are connected with complement-independent pathogens.
Reference: – Schaub S, Hönger G, Amico P: The complexity of the humoral immune response against HLA antigens. Transpl Int 27: 249–250.
☆Subclasses of IgG DSA:
____________________________
▪︎There are four Subclasses of IgG DSA IgG1- IgG4.
▪︎Anti-HLA DSA may have different pathogenicities according to IgG subclass. and they cause a wide spectrum of effects on the allograft, ranging from the absence of injury and no recognizable damage to indolent subclinical ABMR to full-blown acute ABMR [1].
▪︎IgG 1 and IgG 3 are complement fixing antibodies and IgG2 and IgG4 DSA are non complement fixing Abs [2].
▪︎Noncomplement-fixing DSA was considered potentially beneficial by “blocking” the binding of complement-fixing DSA, which are consideredmore harmful [3].
☆Mechanisms of injury of different IgG DSA subclassess:
_______________
▪︎IgG3- DSA cause intense microvascular inflammation and higher C4d deposition in allografts and had greater ability to bind Fc receptor on monocytes, macrophages, and natural killer cells, which are the main effector cells involved in ABMR.
▪︎IgG3 DSA subclass is associated with a greater risk of graft loss, independently of the DSA capacity to bind complement, suggesting the contribution of multiple effector mechanisms leading to graft loss [2].
▪︎ IgG4-DSA cause subclinical ABMR that is characterized by the predominance of chronic features ( it is associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions.
______________________________
Ref:
[1] Papadimitriou JC, et al “Antibody-mediated allograft rejection: morphologic spectrum and serologic correlations in surveillance and for cause biopsies. Transplantation 95: 128–136, 2013
[2] Carmen Lefaucheur, Denis Viglietti, […], and Adriana Zeevi “IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury”. https://dx.doi.org/10.1681/ASN.2014111120
[3] lSchaub S, Hönger G, Amico P: The complexity of the humoral immune response against HLA antigens. Transpl Int 27: 249–250, 2014
The distribution of IgG1–4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively.
All have different potentials to activate complement and recruit the effector cells through Fc receptors to produce tissue injury.
IgG3 & IgG1 usually strong complement binding antibodies, occur early in post-transplant period, associated with anti-HLA class I antibodies. IgG3 associated with high incidence of ABMR, C4d positive & worse graft outcome.
IgG2 & IgG4 -non complement binding antibodies, occurs late in post-transplant period & associated with anti-HLA class II antibodies. IgG4 associated with subclinical AMR ( diagnosed by protocol biopsy) & chronic transplant glomerulopathy and interstitial fibrosis . REFERENCES:
1-Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. CJASN January 2018, 13 (1) 182-192
IgG DSA sub-classes ; are IgG1, IgG2, IgG3, & IgG4
IgG1 & IgG3 strongly fix complement
IgG2 & IgG4 both weak for complement fixations
Mechanism of injury ; 3 main mechanisms
Direct injury to the graft
Complement activation through FC receptor
Recruitment of the inflammatory cells e.g. neutrophils,macrophages, monocytes, & NK cells
Zahid Nabi
3 years ago
IgG3 & IgG1 usually strong complement binding antibodies, occur early in post transplant period, associated with anti-HLA class I antibodies. IgG3 associated with high incidence of ABMR, severity & poor graft outcome.
IgG2 & IgG4 weak or non complement binding antibodies, occurs late in post transplant period & associated with anti-HLA class II antibodies. IgG4 associated with subclinical AMR and chronic transplant glomerulopathy.
IgG subclasses are switched after programmed sequence( signal received from germinal center) leading to production of IgM at first followed by IgG3, IgG1, IgG2 & at last IgG4.
IgG1 is the most frequent subclass (62.2%) in pre- & post transplant sera. Usually sensitized patient by only transfusion or pregnancy had IgG1 &/or IgG3, but patients sensitized by transfusion & pregnancy & previous transplant had a broad range of IgG subclass.
Frequency of IgG subclasses: IgG1 62.2%, IgG2 23.1%, IgG3 7.8% & IgG4 4.7%. IgG3 & IgG1 usually strong complement binding antibodies, occur early in post transplant period, associated with anti-HLA class I antibodies. IgG3 associated with high incidence of ABMR, severity & poor graft outcome. IgG2 & IgG4 weak or non complement binding antibodies, occurs late in post transplant period & associated with anti-HLA class II antibodies. IgG4 associated with subclinical AMR ( diagnosed by protocol biopsy) & chronic transplant glomerulopathy.
References:
Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol, 2018; 13:182-192.
Ponsirenas R., Cazarote H., Araujo S., Wanderley D., Shimakura S., etal. Anti-HLA Donor-Specific IgG Subclasses and C1q-binding Evolution in Posttransplant Monitoring. Transplant Direct, 2018;4.
Pemin V., Beyze A., Szwarc I., Bec N., Salsac C., et al. Distribution of de novo Donor-Specific Antibody Subclasses Quantified by Mass Spectrometry: High IgG3 Proportion Is Associated With Antibody-Mediated Rejection Occurrence and Severity. Frontiers in Immunology, 2020;11.
Lefaucheur C., Biglietti D. and Zeevi A. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury. Am J Soc Nephrol, 2016; 27(1): 293-304.
4 classes of IgG are related to AMR.
classes IgG 1 and IgG 3 are complement fixing causes acute AMR with MVI glomerular and PTC capilaritis.they are usually preformed , interacting with class I HLA.
Classes 2 and 4 IgG are usually De novo antibodies , non complement fixing , causes Chronic AMR in the form of TG and PTC multilayering. usually associated with poor adherance to medications.
reference:
Dr. Ahmad Halawa Lecture.
Abdulrahman Ishag
3 years ago
The distribution of iDSA IgG1–4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively.
Antibodies may have different pathogenicities according to IgG subclass.
IgG 1 and IgG3 are complement fixing DSA
IgG2 and IgG4 complement non fixing DSA
IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy .
Reference ;
1. Schaub S, Hönger G, Amico P: The complexity of the humoral immune response against HLA antigens. Transpl Int 27: 249–250, 2014 [PubMed] [Google Scholar
Mohamed Saad
3 years ago
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
=IgG has several subclasses (IgG1, 2, 3, and 4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
• IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade.
• Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor.
IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection.
• IgG3 DSAs were associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
• IgG4 was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
• IgG3 and C1q binding DSAs were strongly and independently associated with graft loss.
• IgG4 DSAs were associated subacute and chronic phenotypes of AMR consistent with complement- independent pathogeneses.
References:
1-Applied Transplant Immunology; Case-based Discussion (Part 2) By professor Ahmed Halawa. 2-Zhang, Rubin. “Donor-Specific Antibodies in Kidney Transplant Recipients.” Clinical journal of the American Society of Nephrology : CJASN vol. 13,1 (2018): 182-192. doi:10.2215/CJN.00700117
IgG immunodominant DSA subclasses carrying distinct phenotypes of kidney allograft and associated with AMR. It’s detected by IMF high level of anti HLA antibodies.
iDSA igG1
iDSA igG2
iDSA igG3
iDSA igG4
iDSA igG3 associated with acute ABMR and short time of rejection. If it’s associated with C1q binding are strongly associated with inferior allograft survival and graft loss.
Histomorphological manifested by glomerlitis and tubulitis and presence of C4d deposition along peritubular capillarities.
iDSA igG4 is associated with sub clinical ABMR and late allograft rejection with increase allograft glomerulopathy manifested by interstitial fibrosis and tubular atrophy.
References:
Carmen Lefaucheur, et al, IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury: jAm Soc Nephrol. 2016 Jan; 27(1): 293–304.
Published online 2015 Aug 20.
Thank you all.
Does the phenotype of the rejection differ between the 4 types of IgG classes?
This what really matter
does the phenotype of the rejection differ between the 4 types of IgG classes?
ABMR was mainly driven by IgG3 iDSA (91%).
whereas subclinical antibody-mediated rejection was driven by IgG4 iDSA (76%).
IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation
injury, and positive C4d deposits.
IgG4 iDSA associated with later graft injury with increased transplant glomerulopathy
and IF/TA. i.e. subacute and chronic phenotypes of antibody-mediated rejection.
Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients.
CJASN January 2018, 13 (1) 182-192.
As to the first part of the question which is the (mechanism of non complement fixing antibody injury ).those are IGg 2 ,4
Two routes:
1.Innate immunity where the following cells bind to the Fc fragment of the DSA ab causing degranulation of the cells ,release of lytic enzymes that cause endothelial injury ending in sub clinical rejection or cABMR.These cells are NK, neutrophils ,macrophages.
2.DSAs directly act on endothelial cells leading to proliferation and growth factors production as VEGF ,fibroblast GF ending in vascular intimacy proliferation and TG.
As for the phenotypes:
Most of you have the correct information you can please refer to my comment for Dr .Lomatayo,
A very informative ,simple and clear table is presented by Dr. Mai Shawky look at it.
Lefaucheur et al. explored the association of DSA IgG subclasses with various phenotypes of AMR:
1. iDSAs (iDSAs= immunodominant DSA; the single DSA with the highest MFI) of
the IgG3 subclass had the strongest association with acute AMR (P= 0.002).
======================================================
2. iDSAs of the IgG4 subclass were strongly associated with subclinical ABMR
(P= 0.001) & showed features of chronic AMR, including TG & IF/TA.
======================================================
3. IgG3 iDSAs & C1q1 iDSAs were strongly associated with allograft failure.
Reference
Stanley C. Jordan Donor-Specific HLA Antibody IgG Subclasses Are Associated
with Phenotypes of Antibody-Mediated Rejection in Sensitized Renal Allograft
Recipients
J Am Soc Nephrol 27: 6–8, 2016.doi: 10.1681/ASN.2015060608
IgG3 DSAs were associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
• IgG4 was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
• IgG3 and C1q binding DSAs were strongly and independently associated with graft loss.
• IgG4 DSAs were associated subacute and chronic phenotypes of AMR consistent with complement- independent pathogeneses.
References:
1-Applied Transplant Immunology; Case-based Discussion (Part 1) By Professr Ahmed Halawa.
To differentiate between complement fixing and non complement fixing DSAs address the following points systematically:
1.class of HLA
2.class of IGg
3.time of appearance
4.circumstances of their appearance eg.non compliance ,etc
5.along with the subclass are there predisposing factor as IRI, infection,TCMR all these cause ischemia predisposing to their injurious effect.
Alongside with the rest of the battery for work up try to make your report or answer analytical as a clinician to help in decision taking for each patient.
Again there are many tables to demonstrate the different phenotypes but the one presented by Dr.Mai Shawky is fine.
yes
IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy .
Reference ;
1. Schaub S, Hönger G, Amico P: The complexity of the humoral immune response against HLA antigens. Transpl Int 27: 249–250, 2014 [PubMed] [Google Scholar
Good
absolutely,
with class 1 and 3 IgG causes acute and accelerated Acute rejection presented with abrupt deterioration of allograft function, histologically MVI {acute active cappilaritis [glomerulitis and peri tubular capillaritis} with C4d staining in PTC as its complement fixing antibodies.
Meanwhile IgG2 and IgG4 [non complement fixing] related to Chronic AMR presented with subtle deterioration of allograft function and proteinuria. Histologically, presented as Transplant Glomerulopathy TG with double contouring of glomerular basement membrane membrano proliferaive pattern of glomerulopathy, and PTC multilayring.
reference:
Dr.Ahmad halawa Lecture.
No Ben the phenotype is different:
Type1
DSA 1,3 class1HLA IGg 1,3
Effector cells are memory B cells ,Plasma cells.
Complement fixing C1q.
Pathology:microvasculitis,ptc
Timing. Early aggressive ABMR with C4d+.
Type 2.
Class2.HLA eg.DQ
IGg 2;4
Not complement fixing
Effector cells NK ,neutrophils, macrophage
Direct lytic action on endothelial cells.
Timing. Late.
Need ischemia as IRI, infections ,TCMR
Effects sub clinical rejection, chronic rejection TG
So as you see there are major differences!,
Thanks prof, this is very informative
Ben
Read my lecture (week 1)
Sure prof
Yes, usually IgG 1,3 are associated with acute ABMR,
while IgG 2,4 are seen in cases of subacute or chronic ABMR.
Yes,
▪︎ Acute ABMR is mainly driven by IgG3 DSA, whereas subacute ABMR is driven by IgG4 DSA.
▪︎IgG3 DSA is associated with a shorter time to rejection, increased microcirculation injury , and C4d capillary deposition
▪︎IgG4 iDSA is associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions
Good
A quicker time to rejection, greater microcirculation damage, and positive C4d deposits were seen in patients with IgG3 DSAs, indicating that the DSAs were causing cytotoxicity that was reliant on the complement system.
• DSAs with IgG3 and C1q binding were shown to be significantly and independently linked with graft loss.
• IgG4 DSAs were shown to be related to both subacute and chronic forms of AMR, indicating that they are connected with complement-independent pathogens.
Very good
Only IgG3,IgG4 subclasses correlated with the ABMR phenotyping
1-IgG 3 subclass associated with early aggressive type of AMR ( phenotype 1)with lower GFR at time of rejection with C1q complement binding activity and positive C4D staining. Histologically shows microvascular inflammation with typical g, PTCS its independent risk of early graft loss.
2- IgG4 class correlated with phenotype 2 less aggressive subclinical AMR non-complement binding activity and occur late with better GFR at time of presentation but associated with more chronic damage characterized by histological finding of chronic Tg and IFTA, ,less responsive to treatment and associated with progressive late graft loss.
References:
1-Lefaucheur C, Viglietti D, Bentlejewski C, et al. IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury. J Am Soc Nephrol. 2016;27(1):293-304. doi:10.1681/ASN.2014111120
Yes there is a difference in the rejection phenotype between the different IgG classes.
Time of occurrence.?
Circumstances around their occurance?
IgG class 1, 3 usually involved in type 1 AMR, which is usually mediated by complement fixing antibodies , with memory B cells and plasma cells are main effector cells, it if formed due to preformed DSA (directed against HLA class I) and presented as hyper-acute , acute rejection with rapid progression of graft loss. it is characterized histologically by positive c4d in ptc, plus presence of c1q which indicated complement activation. it respond well to anti rejection therapy as PEX, IVIG and rituximab.
however, IgG class 2, 4 are involved in type 2 ABM, which mediated by non complement fixing antibodies, formed denovo after transplantation against HLA class II and cause graft damage through antibody mediated cellular toxicity or direct endothelial activation. it is usually presented later or as as chronic AMR, with slow progressive course and less response to anti-rejection therapy , but eventually TG and graft loss.
Very well explained
Thanks dear professor
Yes
There are 2 phenotypes of AMR (1&2)
Phenotype 1 AMR usually caused by sensitization events.caused by DSA class 1 IgG 1&3 subclasses.
It is Complement fixing
The effector cells are memory B cells and plasma cells
Crossmatching result usually positive T cells
Occurs early with C4d positive in ptc
It is complement- dependent cytotoxicity
Lead to acute ABMR with rapid graft dysfunction and rapid graft loss
Phenotype 2 AMR
Caused by ischemia-reperffusion injury
No adherence to IS or viral infection
Caused by DSA class ll IgG 2 &4
It is non-complement fixing with effector cells NK, neutrophils and macrophages
Cause positive B cells crossmatching
With negative C4d in ptc
Late in presentation lead to late AMR or chronic active ABMR
Mechanism of action antibody -mediated cellular cytotoxicity or direct endothelial injury and swelling.
It slowly progress but lead eventually to graft loss.
Excellent
Does the phenotype of the rejection differ between the 4 types of IgG classes?
Yes phenotype of rejection differs according to the IgG subclass
Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury.
*IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
*IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
*whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy.
Very good
Yes, The phenotype of rejection difference with sub class of IgG :
Acute ABMR was mainly driven by IgG3 DSA, whereas subclinical ABMR was driven by IgG4 DSA.
IgG3 DSA was associated with a shorter time to rejection , increased microcirculation injury , and C4d capillary deposition .
IgG4 DSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions .
Integrating DSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses revealed IgG3 DSA and C1q-binding DSA were strongly and independently associated with allograft failure.
-Lecture of Professor Ahmed Halawa.
-https://jasn.asnjournals.org/
Very good
IgG3 subclass DSA has associted with ABMR and characterized by intense micro vascular inflammation and higher C4d deposition in allograft and has great risk of graft loss,
IgG4 subclass DSA exhibit specific phenotype of antibody mediated injury as represent by transplant glommularpathy , interstitial fibrosis and tubular atrophy.
References1. Sellarés J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, Hidalgo LG, Famulski K, Matas A, Halloran PF: Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 12: 388–399, 2012 [PubMed] [Google Scholar]
2. Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B: Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 4: 378–383, 2004 [PubMed.
What are the classes of IgG DSA?what is the mechanism of the injury they cause?IgG has several subclasses IgG1,2,3 and 4 and thy have various ability to activates complement and recruit effector cells through the FC receptor.
IgG1 and IgG 3 usullaly complement binding subclasses
IgG3 binding to C1q and activate complement cascade
also increased microcirculation and postive C4d deposit indicate complement depented cytotoxcity .
IgG2 can activate complement weakly
IgG4 does not activate complement at all but both can recruit effector cells through the FC receptors and associttted with advanced stage of rjection such as TG , IF and TA
associtted with subacute and chronic ABMR.
Referenc
PROF.Ahmed H alawa
Better than above!
Several phenotypes of ABMR are determşned by the timing and extent of humoral response and various characteristics of DSAs. they differ in terms of strength and complement-fixing capacity.
For example, Denovo DSAs are usually related to late Acute AMR.
Preformed DSAs can lead to hyperacute, accelerated acute and early acute rejection.
IgG subclasses have different affinities and capabilities to activate complement and recruit effector cells. For instance, IgG3 are frequently associated with acute rejection, while IgG4 subclass is mostly associated with chronic or subclinical rejection
yes,
IgG3 C1q binding DSA is commonly associated with acute AMR, more severe graft injury and early graft loss while IgG4 C1q non binding DSA is more related to subclinical, chronic AMR and transplant glomerulopathy.
Zhang R. Donor-specific antibodies in kidney transplant recipients. Clinical Journal of the American Society of Nephrology. 2018 Jan 6;13(1):182-92.
IgG 1 , IgG3 ( mainy IgG 3 ) : involved in Acute ABMR , early graft loss
IgG2 , IgG4 : more associated with chronic ABMR ( TG , IFTA ) , later graft loss
There is IgG 1,3 which is usually secreted in response to HLA class 1 mismatch and usually causes early post-transplant graft acute ABMR by Complement fixing C1q. causing severe microvascular inflammation and C4D +ve in immunohistochemistry microscopy.
There is IgG 2;4 which is usually secreted in response to HLA class2 mismatch and usually causes late post-transplant graft subacute and chronic TG by not complement-fixing by direct lytic action on endothelial cells.
this is usually precipitated by ischemia as IRI, infections,TCMR as class II not usually expressed on the surface except after stress conditions.
yes sir
in one study
After analysis of iDSAs and their subclasses, there was an interested association.
1. iDSAs of the IgG3 subclass had the strongest association with acute ABMR.
2. iDSAs of the IgG4 subclass were strongly associated with subclinical ABMR and showed features of CABMR, including TGand interstitial fibrosis/tubular atrophy.
This study found that IgG3iDSAs and C1q1 iDSAs were strongly associated with allograft failure.
This finding is of paramount importance as it is show that iDSA characteristics
can predict risk for developing different phenotypes of ABMR.
These data help to characterize the specific phenotype of ABMR and may help to specify specific treatment for each phenotype .
phenotype of rejection is different between IgG subclasses.
IgG3 and IgG4 were the most discriminating IgG subclasses for identifying ABMR phenotypes.Studies revealed that IgG immunodominant DSA(iDSA) subclasses identify phenotypes of kidney allograft ABMR. IgG3 iDSA was associated with a shorter time to rejection, increased microvascular injury and C4d capillary deposition. IgG4 iDSA was associated with later graft injury, increased transplant glomerulopathy and IFTA
Ig G DSA can be divided into Ig G 1 , Ig G 2, Ig G 3, Ig G 4.
IgG1 comprises 60 to 70 percent of total IgG
IgG2 comprises 20 to 30 percent of total IgG
IgG3 comprises 5 to 8 percent of total IgG
IgG4 comprises 1 to 4 percent of total IgG
IgG1 and IgG3 fix C1q most effectively, while IgG2 does so weakly. IgG4 does not bind complement at all.
Reference.
There are 4 types of IgG classes:
IgG 1 and 3 which leads to acute antibody mediated rejection
Where IgG 2 and 4 lead to chronic antibody mediated rejection
IgG has several subclasses (IgG1, -2, -3, and -4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor. IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade.
Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor.
Phenotype 1 AMR related to IgG class 1 and 3
Phenotype 2 related to IgG class 2 and 4
IgG classes:
There are four sub-classes of IgG: IgG1, IgG2, IgG3, and IgG4.
What is the mechanism of the injury they cause?
IgG1: in response to anaphylaxis or allergic reaction along with IgE.It is also involved in opsonization and activation of the complement cascade and strong association was found between the C1q-binding ability and the IgG1 strength. It has been observed in cardio-pulmonary responses to anaphylaxis. These responses being mediated by the Fc portion of the IgG1.
IgG2: found in relation with the host reaction to bacterial capsular polysaccharide antigens.
IgG3: found to be associated with effector responses to foreign antigens. It’s a complement-binding subclass. It has been hypothesized that it might play a role in the acquirement of protective immunity.
IgG4: has been associated with chronic exposure to an antigen and also auto-immune disease.
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
o There are 4 IgG classes that differ in their ability to activate complement and recruiting effector cells through their Fc receptor.
IgG1 and IgG3:
o IgG1 and IgG3 are the complement binding subclasses.IgG1 is the most common subclass. Whereas, IgG3 has the greatest ability to activate the complement cascade.
o IgG1 and IgG3 results in type 1 ABMR directed against HLA class 1
o Clinically presents with hyper acute or acute graft loss and increased microcirculation injury
o Histologically, C4d in the PTC and C1q can be detected indicating complement activation.
o Shows better response to treatment that includes PP,IVIG +/- Rituximab
IgG2 and IgG4:
o IgG2 can weakly activate complement. On the other side,IgG4 does not activate complement completely. Graft injury results from Antibody-dependent cellular cytotoxicity or direct endothelial activation.
o IgG2 and IgG4 results in type 2 ABMR directed against HLA class 2
o Clinically presents with more chronic, sub-acute forms of graft loss and TG
o Histologically, it results in C4d negative rejection or direct endothelial activation.
o Shows poor response to anti-rejection treatment
References:
1. Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. CJASN January 2018, 13 (1) 182-192
2. Update June 2020
The donor specific IgG antibodies belong to various classes namely IgG1,IgG2, IgG3 and IgG4….They have variable expression and belong to different classes and have different complement binding capacity…..
IgG1 – It is the most common IgG which causes complement dependent damage and they belong to de-novo class 1 DSA…They have a strong complement affinity potential…They cause ABMR very early after transplant and respond to the usual treatment..They are responsible for the classical C4d positive ABMR
IgG2 – They are responsible for complement independent injury and are weekly bound to complement…They are usually de novo class II DSA and bind to the endothelium and cause chronic ABMR which is resistant to treatment and occurs late in the course of the treatment…They cause C4d negative ABMR
IgG3 – It has high complement binding capacity and they are similar to IgG1 in the features of ABMR..
IgG4 – It is similar to IgG2 and it causes late onset ABMR…It is associated with similar features to IgG2 and causes long term graft damage due to complement dependent cell cytotoxicity and direct endothelial cell damage..
There are 4 classess of IgG : IgG1,IgG2, IgG3 and IgG4.
IgG4 was associated with delayed allograft injury, high risk of allograft glomerulopathy, and interstitial fibrosis/tubular atrophy IFTA.
on the other hand, early rejection, higher microvascular injury, more C4d capillary deposition, and graft failure.
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
DSA IgG 1, 2, 3, 4.
IgG 1, 3 are usually against class I HLA, usually are performed antibodies that leads to early acute ABMR via complement fixation, are usually associated with C4d positive staining in IF and IHC microscopy, usually associated with poor graft outcome, however it responds to treatment.
IgG 2, 4 are usually directed against class II HLA, usually denovo antibodies, non-complement fixing but direct lytic effect that leads to late (after first year post TX) subacute graft dysfunction.
Serum IgG can be divided into 4 subclasses (IgG1, IgG2, IgG3, IgG4).
These sub classes has different ability to activate complement system with (IgG1 & IgG3) has higher ability than (IgG2 & IgG4).
A study done by Lefaucheur et al. report that diferent DSA IgG subclasses associated with various phenotypes of ABMR.
In this study there was , 125 patients with positive DSAs .
40.8% of patients had acute ABMR.
28.8% had subclinical ABMR.
30.4% remained free of ABMR.
Immunodominant DSA (iDSAs) the single DSA with the highest mean fluorescence intensity [MFI]) were 6724 , and 41.6%of patients had C1q1DSAs.
After analysis of iDSAs and their subclasses, there was an interested association.
1. iDSAs of the IgG3 subclass had the strongest association with acute ABMR.
2. iDSAs of the IgG4 subclass were strongly associated with subclinical ABMR and showed features of CABMR, including TGand interstitial fibrosis/tubular atrophy.
This study found that IgG3iDSAs and C1q1 iDSAs were strongly associated with allograft failure.
This finding is of paramount importance as it is show that iDSA characteristics
can predict risk for developing different phenotypes of ABMR.
These data help to characterize the specific phenotype of ABMR and may help to specify specific treatment for each phenotype .
Kamisawa et al in his study shows that
· patients withIgG4related disease present with a spectrum of autoimmune
·disorders characterized by storiform fibrosis, phlebitis, levels. These patient are known to respond well to rituximab.
· Patients with predominant IgG3 iDSAs and C1q1 iDSAs will likely require a combination of antibody reduction therapies and complement inhibitors to control the ABMR process.
REFRENCESS
Stanley C. Jordan Donor-Specific HLA Antibody IgG Subclasses Are Associated
with Phenotypes of Antibody-Mediated Rejection in Sensitized Renal Allograft
RecipientsJ Am Soc Nephrol 27: 6–8, 2016.doi: 10.1681/ASN.2015060608
What are the classes of IgG DSA? What is the mechanism of the injury they cause?there is IgG 1,3 which is usually secreted in response to HLA class 1 mismatch and usually causes early post-transplant graft acute ABMR by Complement fixing C1q. causing severe microvascular inflammation and C4D +ve in immunohistochemistry microscopy.
There is IgG 2;4 which is usually secreted in response to HLA class2 mismatch and usually causes late post-transplant graft subacute and chronic TG by not complement-fixing by direct lytic action on endothelial cells.
this is usually precipitated by ischemia as IRI, infections,TCMR as class II not usually expressed on the surface except after stress conditions.
IgG has four subclasses: IgG1-4.IgG 1&3 are complement fixing. They work against class I HLA through complement binding leading to more rapid rejection ,more microcirculation damage in addition to C4d deposition.
DSAs with IgG3 & C1q binding are significantly and independently linked with graft loss.
• IgG4 DSAs were shown to be associated with both subacute and chronic AMR, indicating that they are connected with complement-independent pathogens and they are HLA class II antibodies .
IgG is composed of four subclasses: IgG1, IgG2, IgG3, and IgG4
IgG 1 and 3 are complement-fixing subclasses. They are class I HLA antibodies, strong complement binding, associated with quicker time to rejection, greater microcirculation damage, and positive C4d deposits • DSAs with IgG3 and C1q binding were shown to be significantly and independently linked with graft loss.
• IgG4 DSAs were shown to be related to both subacute and chronic forms of AMR, indicating that they are connected with complement-independent pathogens and they are HLA class II antibodies .
There are several phenotypes of antibody-mediated rejection that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity.
de novo class I DSA are of subclass IgG1 and IgG3 while class II are IgG2 and IgG4
▪︎DSA IgG Subclasses:
*IgG has 4 subclasses (IgG1, -2, -3, and -4), with different abilities to activate complement and recruit effector cells through the Fc receptor.
▪︎IgG1 and IgG3
*IgG1 and IgG3 are usually complement binding subclasses.
* IgG1 is the most abundant subclass and mirrors the total IgG level.
* IgG3 has the greater binding efficiency to C1q and activate complement cascade.
*acute antibody-mediated rejection is mainly caused IgG3 iDSA.
*IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
*IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
▪︎IgG2 and IgG4
* IgG2 can activate complement weakly, IgG4 does not activate complement at all.
*both can recruit effector cells through the Fc receptor.
*IgG4 is a biomarker of matured alloresponse and associated with advanced stage of rejection.
* IgG4 iDSA usually associated with subclinical AMR.
* IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
*IgG4 iDSA–associated subacute and chronic of antibody-mediated rejection with complement-independent pathogeneses.
Rubin Zhang.Donor-Specific Antibodies in Kidney Transplant Recipients.CJASN January 2018, 13 (1) 182-192
Dear Dr Farag
This is a copy and paste from a colleague’s reply. This is very unethical; therefore, you have been referred to the Academic Integrity officer for investigation. Please see below:
Shereen Yousef
15 days ago
■What are the classes of IgG DSA? What is the mechanism of the injury they cause?
There are several phenotypes of antibody-mediated rejection that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity.
de novo class I DSA are of subclass IgG1 and IgG3 while class II are IgG2 and IgG4
▪︎DSA IgG Subclasses:
*IgG has 4 subclasses (IgG1, -2, -3, and -4), with different abilities to activate complement and recruit effector cells through the Fc receptor.
▪︎IgG1 and IgG3
*IgG1 and IgG3 are usually complement binding subclasses.
* IgG1 is the most abundant subclass and mirrors the total IgG level.
* IgG3 has the greater binding efficiency to C1q and activate complement cascade.
*acute antibody-mediated rejection is mainly caused IgG3 iDSA.
*IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
*IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
▪︎IgG2 and IgG4
* IgG2 can activate complement weakly, IgG4 does not activate complement at all.
*both can recruit effector cells through the Fc receptor.
*IgG4 is a biomarker of matured alloresponse and associated with advanced stage of rejection.
* IgG4 iDSA usually associated with subclinical AMR.
* IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
*IgG4 iDSA–associated subacute and chronic of antibody-mediated rejection with complement-independent pathogeneses.
Rubin Zhang.Donor-Specific Antibodies in Kidney Transplant Recipients.CJASN January 2018, 13 (1) 182-192
IgG1 is the most prevalent subclass in the pre- & post transplant sera.
IgG1 & IgG3( associated with high incidence of ABMR , and poor graft outcome) are strong complement binding antibodies which occur early in post transplant period and are associated with anti-HLA class I antibodies.
IgG2 & IgG4 ( Chronic transplant glomerulopathy ) are non complement binding antibodies which take part late in post transplant period & associated with anti-HLA class II antibodies.
IgG DSA classes : IgG 1 ,2,3,4
IgG1, IgG3 : complement binding Abs , activate the classical complement pathway by binding to c1q , resulting in cell damage
these are directed against class 1 HLA , leading to acute ABMR and early graft loss
IgG2 , IgG4 : Complement non-fixing DSA ,they are commonly targeting class 2 HLA on graft endothelium and can induce cell damage by the following mechanisms :
1- Ab dependant cellular cytotoxicity , by recuitinmg immune cells namely neutrophils , macrophages & NK cells that by degranulation and release of their lytic enzymes cause cell damage
2- direct endothelial cell activation and proliferation resulting in vasculopathy
in general it tends to occur later than the complement binding type , more associated with chronic changes and subclinical presentation and thereby slower graft loss
Subclasses of IgG DSA : 4 subclasses IgG 1 , 2,3,4
IgG1 & IgG3 : these are complement binding Abs ( after binding to their target Ag , they activate the classical complement pathway by binding to C1q ) resulting in cell damage .
they are directed to class 1 HLA , associated with Acute ABMR , early presentation , rapid graft dyysfunction & graft loss , C4d +ve in graft biopsy
IgG 2 , IgG4 : they are commonly targeting class 2 HLA on graft endothelium and can induce cell damage by the following mechanisms :
1- Ab dependant cellular cytotoxicity , by recuitinmg immune cells namely neutrophils , macrophages & NK cells that by degranulation and release of their lytic enzymes cause cell damage
2- direct endothelial cell activation and proliferation resulting in vasculopathy
in general it tends to occur later than the complement binding type , more associated with chronic ABMR and subclinical presentation and thereby slower graft loss . C4d is negative in graft biopsy
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
IgG subclasses are IgG1, 2, 3, and 4.
IgG1 and 3 are complement-fixing subclasses. They are class I HLA antibodies, strong complement binding, associated with early (acute) AMR, and rapid graft dysfunction. C4d positivity.
IgG1 is a more abundant subclass and it mirrors the total IgG level. While IgG3 has a greater binding affinity to C1q and complement activation.
IgG2 and 4 are weak or non-complement fixing. They are class ii HLA antibodies. Associated with late (chronic) AMR and late graft loss. C4d negative biopsy. Both make injury through the recruitment of the effector cells through the Fc receptor.
Yes
Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas non complement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy.
Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses. They are associated with acute antibody-mediated rejection and early graft loss.
Class 2 de novo DSAs appear later and are commonly non complement binding IgG2 or IgG4 subclass. They tend to be persistent and are associated with chronic antibody-mediated rejection and transplant glomerulopathy.
What are the classes of IgG DSA?
IgG has several subclasses (IgG1, -2, -3, and-4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor
what is the mechanism of the injury they cause
The major three mechanism of graft injury are
complement-dependent mechanisms
1.Binding of DSA to antigen expressed on allograft endothelial cells can activate classic complement pathway, a key pathologic process of acute antibody-mediated rejection phenotypes.
complement-independent mechanism
2. DSAs can cause graft damage through antibody-dependent cellular cytotoxicity. The innate immune cells, including neutrophils, macrophages, and natural killer cells, can bind to Fc fragments of DSAs, trigger degranulation, and release lytic enzymes, which cause tissue injury and cell death. This process can mediate smoldering damages to the endothelial cells and is proposed as an important pathogenesis in subclinical and chronic antibody-mediated rejection phenotypes.
3. DSAs can cause graft injury by direct activation of endothelial proliferation through increasing vascular endothelial growth factor production, upregulating fibroblast growth factor receptor, and increasing its ligand binding as well as other signaling pathways for cellular recruitment. This pathogenesis may contribute to transplant glomerulopathy and vasculopathy that feature vascular intima thickness with smooth muscle cell invasion. The latter two complement-independent mechanisms can explain the clinical phenotypes of antibody-mediated rejection with negative C4d staining in peritubular capillaries.
REF:1. Donor-Specific Antibodies in Kidney Transplant Recipients
Rubin Zhang
CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
IgG is divided into 4 subclasses IgG 1,2,3 and 4 and can initiate different effector functions based on their structure
IgG1 and IgG3 are usually complement binding, IgG1 is the most abundant while IgG3 has higher binding affinity to C1q
IgG1 and 3 are are likely to be class I DSA, detected sooner post transplant and are associated with acute AMR and early graft loss
IgG2 can weakly activate complement but IgG4 is unable to activate it, they can recruit effector cells through Fc receptor
IgG4 is considered a biomarker of advanced stage of rejection.
IgG2 and 4 subclasses are likely to be class II DSA that appear late post transplant and are commonly persistent and associated with chronic AMR
Zhang R. Donor-specific antibodies in kidney transplant recipients. Clinical Journal of the American Society of Nephrology. 2018 Jan 6;13(1):182-92.
DSA IgG class
IgG has subclasses IgG1,2,3,4
Have various abilities to activate complement and recruit effector cells through Fc receptor
IgG1 and 3 – usually complement binding subclasses
IgG1- most abundant subclass and mirrors total IgG1 level
IgG3
IgG2- weakly activate complement pathway, but can recruit effector cells thru Fc receptors
IgG4
Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients.
CJASN January 2018, 13 (1) 182-192.
In addition to MFI strength and complement binding ability, another important characteristic of DSAs that influences their effects on graft damage is IgG subclasses.
IgG has several subclasses (IgG1, -2, -3, and -4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
There is a sequential IgG subclass switching, typically from IgG3 to IgG1 to IgG2 to IgG4 in the process of the immune response and antibody production. The pathogenicities of DSAs are a dynamic course and vary based on different IgG subclass profile.
IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and reflects the total IgG level, but IgG3 has the greater binding capability to C1q and activate complement cascade. Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor. IgG4 is also considered as a biomarker of matured alloresponse and is associated with an advanced stage of rejection.
Cytotoxic IgG antibodies are usually complement-binding IgG1 or IgG3 subclasses and can lead to a positive T cell crossmatch.
Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses and are associated with acute AMR and early graft loss. Class 2 de novo DSAs appear later and are commonly non-complement binding IgG2 or IgG4 subclasses, which tend to be persistent and are related to chronic AMR and transplant glomerulopathy.
IgG3 immune-dominant DSA (iDSA) is associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
IgG4 iDSA is associated with subacute and chronic phenotypes of antibody-mediated rejection, later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy that is consistent with complement independent pathogeneses including recruitment of innate immune cells (NK cells, macrophages, and neutrophils) through Fc receptors that lead to antibody-dependent cellular toxicity, and direct stimulation and pleotrophic effects on endothelial cells that cause tissue injury, cellular recruitment, and endothelial proliferation.
IgG has several subclasses (IgG1, -2, -3, and -4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
There is a sequential IgG subclass switching, typically from IgG3 to IgG1 to IgG2 to IgG4
IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade
Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor. IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection
It was found that acute antibody-mediated rejection was mainly driven by IgG3 iDSA, whereas subclinical antibody-mediated rejection was driven by IgG4 iDSA.
IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss.
IgG subclasses are IgG 1, 2, 3, 4. IgG subclass switching from IgG3 to IgG1, to IgG2 or IgG4 occurs during antibody production.
IgG1 and IgG3 are complement binding subclass with IgG3 more binding affinity To C19.
IgG2 weakly activates complement but IG4 can’t activate complement. They are effective in recruitment of immune cells.
IgG3 DSA is associated with early rejection, ↑ MVI and C4d+ or complement dependent cytotoxicity but IgG4 DSA is associated with later rejection and TG and IF/TA.
IgG3 and C19 binding DSAs are associated with graft loss but IgG4 DSAs are associated with subacute & chronic AMR with complement independent way. Immunological risk assessment a is improved with determining DSA strength,
IgG3 subclass or C1q binding capacity and harmful DSAs could be recognized.
So, mechanism of injury in IgG3 subclasses is complement dependent and in IgG4 is through cellular cytotoxicity or endothelial proliferation by complement independent pathways.
What are the classes of IgG DSA?what is the mechanism of the injury they cause?IgG has several subclasses IgG1,2,3 and 4 and thy have various ability to activates complement and recruit effector cells through the FC receptor.
IgG1 and IgG 3 usullaly complement binding subclasses
IgG3 binding to C1q and activate complement cascade
also increased microcirculation and postive C4d deposit indicate complement depented cytotoxcity .
IgG2 can activate complement weakly
IgG4 does not activate complement at all but both can recruit effector cells through the FC receptors and associttted with advanced stage of rjection such as TG , IF and TA
associtted with subacute and chronic ABMR.
Referenc
PROF.Ahmed H alawa
There are 4 subclass of IgG switching from IgG3 to IGg1 to IgG2 and finally after prolong immunization IgG4 .
they are exhibit functional difference such as complement activation and FC binding
IgG1 and 3 are the most effective at complement activation .
interesting IgG 3 the has the greater binding efficiency to complement C1q .
IgG 1 effective in complement dependent cell lysis .
IgG 2 can fix complement weakly but IgG 4 not at all .
Transplant International ISSN 0934-0874
Need more information
.-IgG has several subclasses (IgG1, -2, -3, and -4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
-Over the course of immune response and antibody production, there is a sequential IgG subclass switching, typically from IgG3 to IgG1 to IgG2 to IgG4 .
-IgG1 and IgG3 are usually complement binding subclasses.
– IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activates the complement cascade.
-IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor.
-IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection .
– Studies showed :
-IgG3 -DSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
– IgG4 -DSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
– IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss .
-IgG4 -DSA–associated subacute and chronic phenotypes of antibody-mediated rejection were consistent with complement-independent pathogeneses .
-The advances in complement binding DSA assay and IgG subclass analysis have improved the ability to assess a patient’s immunologic risk and can help clinicians to identify more harmful DSAs, predict the distinct phenotypes of antibody-mediated rejection, and guide the clinical decision for kidney biopsy as well as immunosuppressive management.
Reference:
-Rubin Zhang .Donor-Specific Antibodies in Kidney Transplant Recipients
CJASN January 2018, 13 (1) 182-192; DOI: https://doi.org/10.2215/CJN.00700117
Last paragraph is very good
■What are the classes of IgG DSA? What is the mechanism of the injury they cause?
There are several phenotypes of antibody-mediated rejection that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity.
de novo class I DSA are of subclass IgG1 and IgG3 while class II are IgG2 and IgG4
▪︎DSA IgG Subclasses:
*IgG has 4 subclasses (IgG1, -2, -3, and -4), with different abilities to activate complement and recruit effector cells through the Fc receptor.
▪︎IgG1 and IgG3
*IgG1 and IgG3 are usually complement binding subclasses.
* IgG1 is the most abundant subclass and mirrors the total IgG level.
* IgG3 has the greater binding efficiency to C1q and activate complement cascade.
*acute antibody-mediated rejection is mainly caused IgG3 iDSA.
*IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
*IgG3 and C1q binding iDSAs were strongly and independently associated with graft loss
▪︎IgG2 and IgG4
* IgG2 can activate complement weakly, IgG4 does not activate complement at all.
*both can recruit effector cells through the Fc receptor.
*IgG4 is a biomarker of matured alloresponse and associated with advanced stage of rejection.
* IgG4 iDSA usually associated with subclinical AMR.
* IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
*IgG4 iDSA–associated subacute and chronic of antibody-mediated rejection with complement-independent pathogeneses.
Rubin Zhang.Donor-Specific Antibodies in Kidney Transplant Recipients.CJASN January 2018, 13 (1) 182-192
This is excellent.
IgG has several subclasses (IgG1,-2,-3, and-4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
IgG1 and IgG3 are usually complement binding subclasses.
IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade
IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor. IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection
acute antibody-mediated rejection was mainly driven by IgG3 iDSA (91%), whereas subclinical antibodymediated rejection was driven by IgG4 iDSA (76%).
IgG3 iDSA was associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
IgG4 iDSA was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy
IgG subclass analysis have improved our ability to assess patient’s immunologic risk.
They can help clinicians to identify more harmful DSAs, predict the distinct phenotypes of antibody-mediated rejection, and guide our clinical decision for kidney biopsy as well as immunosuppressive management.
Reference
Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol 13: 182–192, 2018. doi: https://doi.org/10.2215/CJN.00700117
There are 4 subclasses of IgG DSA 1,2,3and 4.
All have different potentials to activate complement and recruit the effector cells through Fc receptors to produce tissue injury with different spectrum ranging from no damage to severe damage .
IgG3 & IgG1
1-usually strong complement binding antibodies 2-occur early in post-transplant period .
3-associated with anti-HLA class I antibodies. 4-IgG3 associated with high incidence of ABMR, C4d positive & worse graft outcome.(phenotype 1 ABMR).
Mechanism of injury:complement-dependent cytotoxicity.
Respond well to treatment IgG2 & IgG4
1- non complement binding antibodies.
2-occurs late in post-transplant period .
3-associated with anti-HLA class II antibodies. 4-IgG4 associated with subclinical AMR ( diagnosed by protocol biopsy) & chronic transplant glomerulopathy and interstitial fibrosis .(phenotype 2 ABMR).
Mechanism of injury: antibody -mediated cellular toxicity.
Less response to treatment. REFERENCES: 1-Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. CJASN January 2018, 13 (1) 182-192
There are 4 classes of IgG DSA-
IgG1,IgG2,IgG3,IgG4.There is two type of phenotypes-
1.TYPE 1-
IgG 1 and IgG 3 Ab
against HLA class 1(preformed)
Complement C1q fixing
Capillaritis with C4d positive
Hyper acute and acute rejection with graft loss
2.TYPE 2-
IgG 2 and IgG 4 Ab
Against HLA class 2(denovo)
Noncomplement fixing
Transplant glomerulopathy with IFTA
sub acute and chronic rejection with ultimately graft loss
2. What are the classes of IgG DSA? What is the mechanism of the injury they cause?
Immunoglobulin G (IgG), comprising 10-20% of plasma protein, is one of the most abundant proteins in serum. It can be divided into 4 subclasses, namely IgG1, IgG2, IgG3, IgG4 , according to their decreasing abundance.
IgG1: Most common IgG, causes complement dependent injury.
IgG2: Weak complement fixing, causes complement independent injury.
IgG3: Has high complement binding capacity, leading to complement dependent injury, with shorter time to rejection, C4d positive and increased microvascular injury.
IgG4: Non complement fixing, is a marker of matured alloresponse and associated with later graft injury presenting with advanced stage of rejection (transplant glomerulopathy, interstitial fibrosis/ tubular atrophy).
Over the course of immune response, there is subclass switching from IgG3 to IgG2 to IgG2 to IgG4.
de novo class I DSA are of subclass IgG1 and IgG3, presenting with strong complement binding, and acute, early and aggressive C4d positive AMR which can lead to early graft loss, although more responsive to treatment. The graft injury is due to classical complement activation and the resultant complement mediated tissue injury.
de novo class II DSA are of subclass IgG2 and IgG4, presenting with weak or no complement binding, chronic or subclinical, late C4d negative AMR, which is less responsive to treatment leading to late graft loss. The graft injury is due to antibody dependent cytotoxicity or due to direct lytic action on the endothelial cell.
Reference:
1) Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014 Oct 20;5:520. doi: 10.3389/fimmu.2014.00520. PMID: 25368619; PMCID: PMC4202688.
2) Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018 Jan 6;13(1):182-192. doi: 10.2215/CJN.00700117. Epub 2017 Apr 26. PMID: 28446536; PMCID: PMC5753302.
Do you think that sensitisation against HLA A36 will affect only this HLA antigen only or other HLA antigens as well? Please justify your answer.
yes.
HLA-A36 is found in the Black (Afro-Caribbean) population. It is rare in other ethnic groups(1). A36 had epitopes that were also present on HLA-A1and so reactivity with A36 was seen only in sera that also reacted with A1. However a murine monoclonal antibody was produced that reacted with A36 but not A1 which indicate the presence of a xenogeneic epitope. However, the epitope was not necessarily allogeneic. To date there have been no reports of polyclonal antibodies that react with A36 but not A1. Sequence alignments show that an epitope shared between A36, A28, A33, and A34, but not found on A1, is formed by substitutions at residues 163 and 166–167 (2)
1- Rees L, Kim JJ. HLA sensitisation: can it be prevented?. Pediatr Nephrol. 2015;30(4):577-587. doi:10.1007/s00467-014-2868-6
2- Paul Sikorski; Dessislava Kopchaliiska; Donna P. Lucas; Mary S. Leffell; Andrea A. Zachary (2011). Characterization of an antibody specific for HLA-A36 and not reactive with HLA-A1. , 72(1), 0–90. doi:10.1016/j.humimm.2010.10.008
actually IgG subclass determines the phenotype of AMR and its characteristics as shown in table below.
Excellent table ! Hope it helps you diagnose and manage
The reflection on the cross match is very informative!
The work up should also include the MFI or MCS to help you decide the management.
The effects of DSA on the graft survival differ according to its strength and subclasses leading to ABMR with its different phenotypes.
There are 4 subclasses of IgG DSA 1,2,3and 4.
IgG 3 has stronge effect on graft survival within short period of time by C4d deposition and inflammatory changes within micro circulation and it has with IgG1 complement binding ability while IgG2 can activate complement but weakly.
IgG4 also affect on graft survival but after longer period of time causing graft injury, interstitial fibrosis and tubular injury and it has no complement activation ability.
Reference
Zhang R. at al, Donor Specific Antibodies in kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018;13(1):182_192.
Very good refer to the above table
The classes of IgG DSA are IgG1, IgG2, IgG23 and IgG4. They differ according to
1- The cause of sensitization. Patients sensitized by only transfusion or pregnancies had anti-HLA antibodies of IgG1 and/or IgG3 subclasses, whereas patients with both transfusion and pregnancies and previous transplant showed a broader range of IgG subclasses. (1)
2- Whether preformed DSA or de novo DSA, in which de novo DSA were primarily made up of IgG1 and IgG3 alone. A positive T cell cross match secondary to cytotoxic IgG antibody, is usually complement binding IgG1 or IgG3 subclass. De novo DSAs after kidney transplant are usually class 2 antibodies, especially DQ. They appear later and persist. De novo DSAs are commonly non-complement binding IgG2 or IgG4 subclass and are associated with chronic AMR and transplant glomerulopathy. Class 1 de novo DSAs are usually detected sooner after transplant and more likely IgG1 and IgG3 subclasses. They are associated with acute AMR and early graft loss.
3- Early antigen clearance. It has been suggested that subclass switching occurs first from IgM to IgG3 and then to IgG1, IgG2, and IgG4. In many responses early antigen clearance would prevent the appearance of IgG2 and IgG4. (1)
IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade. Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor. IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection .
IgG3 DSA was associated with cute AMR ,a shorter time to rejection , increased microcirculation injury and C4d capillary deposition . IgG4 DSA was associated with sub-clinical AMR later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions. (2)
1-Ponsirenas, R., Cazarote, H. B., Araújo, S. A., Wanderley, D. C., Shimakura, S., Valdameri, J. S., Contieri, F., von Glehn, C., Susin, M. F., & Sotomaior, V. S. (2018). Anti-HLA Donor-Specific IgG Subclasses and C1q-binding Evolution in Posttransplant Monitoring. Transplantation direct, 4(9), e385. https://doi.org/10.1097/TXD.0000000000000823
2-Rubin Zhang, Donor-Specific Antibodies in Kidney Transplant Recipients,CJASN Jan 2018, 13 (1) 182-192; DOI: 10.2215/CJN.00700117
Mentioning causes of sensitization can you comment on transplanting a lady from her child!,
Do you perform a Tx with a + T cell cross math?
IgG has various subclasses ranging from 1 to 4. They activate complement and recruit effector cells through the Fc receptor.
IgG 1 and 3 are complement binding.
References :
Good but refer to the table above as it covers all the aspects.
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
# There are four subclasses of IgG, and there may be progressive subclass switching from IgG3 to IgG1 to IgG2 and, finally, after prolonged immunization, to IgG4
* IgG subclasses exhibit functional differences such as complement activation and Fc receptor binding. IgG1 and IgG3 are the most effective at complement activation, IgG3 has the greater binding efficiency to complement component C1q
IgG1 is the subclass most effective at complement‐dependent cell lysis IgG2 can fix complement weakly, but IgG4 not at all.
* In pretransplant and posttransplant sera, IgG1 was the most common IgG subclass.
* Presensitized patients showed different compositions of IgG subclasses according to the cause of sensitization. Patients sensitized by only transfusion or pregnancies had anti-HLA antibodies of IgG1 and/or IgG3 subclasses, whereas patients with both transfusion and pregnancies and previous transplant showed a broader range of IgG subclasses.
* IgG3 more frequently than IgG2 in posttransplant sera rather than the expected order of the IgG subclass concentration IgG1, IgG2, IgG3, and IgG4.
* There were differences between patients with preformed DSA and de novo DSA, in which de novo DSA were primarily made up of IgG1 and IgG3 alone.
* The first IgG detected was a class II DSA of IgG3 subclass
* Subclass switching occurs first from IgM to IgG3 and then to IgG1, IgG2, and IgG4.
* In many responses early antigen clearance would prevent the appearance of IgG2 and IgG4, and there presance was shown in elutes of rejected renal allografts confirming sequential subclass switching.
* There is correlation between the occurrence of AMR and the expansion of complement-fixing to noncomplement fixing DSA.
# The presence of different subclasses indicate distinct phenotypes of AMR. IgG4-containing DSA was associated with features of subclinical AMR, whereas IgG3-containing DSA was associated with an acute form of AMR and represented a greater risk for allograft loss.
Starzl TE, Marchioro TL, Hermann G, Brittain RS, Waddell WR. Renal homografts in patients with major donor‐recipient blood group incompatibilities. Surg Forum 1963; 14: 214. [PMC free article] [PubMed] [Google Scholar]
Zachary AA, Montgomery RA, Ratner LE, et al Specific and durable elimination of antibody to donor HLA antigens in renal‐transplant patients.
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Transplant Immunology Laboratory, Hospital Universitário Cajuru, Curitiba, PR, Brazil.
School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, PR, Brazil.
Nephropathology Institute, Hospital das Clinícas da Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Department of Statistics, Universidade Federal do Paraná, Curitiba, PR, Brazil.
Very good
Various Classes of IgG DSA:
Ref:
Zhang R. Donor-Specific Antibodies in Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2018;13(1):182-192. doi:10.2215/CJN.00700117
Very good but refer to table presented by Dr. Mai Shawky
What are the different types of IgG DSA? What is the process through which they inflict the harm they do?
It is possible to divide IgG into numerous subclasses (IgG1, 2, 3, and 4), each of which has a unique ability to activate complement and attract effector cells via the Fc receptor.
• IgG1 and IgG3 are subclasses of antibodies that bind to complement. IgG1 is the most prevalent subclass and reflects the overall IgG level; nevertheless, IgG3 has a higher binding efficiency to C1q and is more effective at activating the complement cascade than IgG1.
• Despite the fact that IgG2 can only weakly activate complement, IgG4 can not activate complement at all, both IgG2 and IgG4 can attract effector cells via the Fc receptor.
As a biomarker of developed allo response, IgG4 is also related to an advanced degree of rejection, according to some researchers.
DSAs derived from human IgG3 were shown to be related to quicker time to rejection, greater microcirculation damage, and positive C4d deposits, all of which suggests that the immune system is causing cytotoxicity.
A higher IgG4 level was related to graft harm later in the process, as seen by greater transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
• DSAs with IgG3 and C1q binding were shown to be significantly and independently linked with graft loss.
• IgG4 DSAs were shown to be related to both subacute and chronic forms of AMR, indicating that they are connected with complement-independent pathogens.
Reference:
– Schaub S, Hönger G, Amico P: The complexity of the humoral immune response against HLA antigens. Transpl Int 27: 249–250.
Very good but refer to the above table by Dr. Mai
☆Subclasses of IgG DSA:
____________________________
▪︎There are four Subclasses of IgG DSA IgG1- IgG4.
▪︎Anti-HLA DSA may have different pathogenicities according to IgG subclass. and they cause a wide spectrum of effects on the allograft, ranging from the absence of injury and no recognizable damage to indolent subclinical ABMR to full-blown acute ABMR [1].
▪︎IgG 1 and IgG 3 are complement fixing antibodies and IgG2 and IgG4 DSA are non complement fixing Abs [2].
▪︎Noncomplement-fixing DSA was considered potentially beneficial by “blocking” the binding of complement-fixing DSA, which are consideredmore harmful [3].
☆Mechanisms of injury of different IgG DSA subclassess:
_______________
▪︎IgG3- DSA cause intense microvascular inflammation and higher C4d deposition in allografts and had greater ability to bind Fc receptor on monocytes, macrophages, and natural killer cells, which are the main effector cells involved in ABMR.
▪︎IgG3 DSA subclass is associated with a greater risk of graft loss, independently of the DSA capacity to bind complement, suggesting the contribution of multiple effector mechanisms leading to graft loss [2].
▪︎ IgG4-DSA cause subclinical ABMR that is characterized by the predominance of chronic features ( it is associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions.
______________________________
Ref:
[1] Papadimitriou JC, et al “Antibody-mediated allograft rejection: morphologic spectrum and serologic correlations in surveillance and for cause biopsies. Transplantation 95: 128–136, 2013
[2] Carmen Lefaucheur, Denis Viglietti, […], and Adriana Zeevi “IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury”.
https://dx.doi.org/10.1681/ASN.2014111120
[3] lSchaub S, Hönger G, Amico P: The complexity of the humoral immune response against HLA antigens. Transpl Int 27: 249–250, 2014
Now this is quite serious
No DSA can be beneficial!,,
Non fixing ones are harmful on a long and slower course
Please revise
I will do . Thanks
The distribution of IgG1–4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively.
All have different potentials to activate complement and recruit the effector cells through Fc receptors to produce tissue injury.
IgG3 & IgG1 usually strong complement binding antibodies, occur early in post-transplant period, associated with anti-HLA class I antibodies. IgG3 associated with high incidence of ABMR, C4d positive & worse graft outcome.
IgG2 & IgG4 -non complement binding antibodies, occurs late in post-transplant period & associated with anti-HLA class II antibodies. IgG4 associated with subclinical AMR ( diagnosed by protocol biopsy) & chronic transplant glomerulopathy and interstitial fibrosis .
REFERENCES:
1-Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients. CJASN January 2018, 13 (1) 182-192
Very good
IgG DSA sub-classes ; are IgG1, IgG2, IgG3, & IgG4
Mechanism of injury ; 3 main mechanisms
IgG3 & IgG1 usually strong complement binding antibodies, occur early in post transplant period, associated with anti-HLA class I antibodies. IgG3 associated with high incidence of ABMR, severity & poor graft outcome.
IgG2 & IgG4 weak or non complement binding antibodies, occurs late in post transplant period & associated with anti-HLA class II antibodies. IgG4 associated with subclinical AMR and chronic transplant glomerulopathy.
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IgG subclasses are switched after programmed sequence( signal received from germinal center) leading to production of IgM at first followed by IgG3, IgG1, IgG2 & at last IgG4.
IgG1 is the most frequent subclass (62.2%) in pre- & post transplant sera. Usually sensitized patient by only transfusion or pregnancy had IgG1 &/or IgG3, but patients sensitized by transfusion & pregnancy & previous transplant had a broad range of IgG subclass.
Frequency of IgG subclasses: IgG1 62.2%, IgG2 23.1%, IgG3 7.8% & IgG4 4.7%.
IgG3 & IgG1 usually strong complement binding antibodies, occur early in post transplant period, associated with anti-HLA class I antibodies. IgG3 associated with high incidence of ABMR, severity & poor graft outcome.
IgG2 & IgG4 weak or non complement binding antibodies, occurs late in post transplant period & associated with anti-HLA class II antibodies. IgG4 associated with subclinical AMR ( diagnosed by protocol biopsy) & chronic transplant glomerulopathy.
References:
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4 classes of IgG are related to AMR.
classes IgG 1 and IgG 3 are complement fixing causes acute AMR with MVI glomerular and PTC capilaritis.they are usually preformed , interacting with class I HLA.
Classes 2 and 4 IgG are usually De novo antibodies , non complement fixing , causes Chronic AMR in the form of TG and PTC multilayering. usually associated with poor adherance to medications.
reference:
Dr. Ahmad Halawa Lecture.
The distribution of iDSA IgG1–4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively.
Antibodies may have different pathogenicities according to IgG subclass.
IgG 1 and IgG3 are complement fixing DSA
IgG2 and IgG4 complement non fixing DSA
IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury. aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy .
Reference ;
1. Schaub S, Hönger G, Amico P: The complexity of the humoral immune response against HLA antigens. Transpl Int 27: 249–250, 2014 [PubMed] [Google Scholar
What are the classes of IgG DSA? What is the mechanism of the injury they cause?
=IgG has several subclasses (IgG1, 2, 3, and 4), and they have various abilities to activate complement and recruit effector cells through the Fc receptor.
• IgG1 and IgG3 are usually complement binding subclasses. IgG1 is the most abundant subclass and mirrors the total IgG level, but IgG3 has the greater binding efficiency to C1q and activate complement cascade.
• Although IgG2 can activate complement weakly, IgG4 does not activate complement at all, but both can recruit effector cells through the Fc receptor.
IgG4 is also considered as a biomarker of matured alloresponse and associated with advanced stage of rejection.
• IgG3 DSAs were associated with a shorter time to rejection, increased microcirculation injury, and positive C4d deposits, which indicate the complement-dependent cytotoxicity.
• IgG4 was associated with later graft injury with increased transplant glomerulopathy and interstitial fibrosis/tubular atrophy.
• IgG3 and C1q binding DSAs were strongly and independently associated with graft loss.
• IgG4 DSAs were associated subacute and chronic phenotypes of AMR consistent with complement- independent pathogeneses.
References:
1-Applied Transplant Immunology; Case-based Discussion (Part 2) By professor Ahmed Halawa.
2-Zhang, Rubin. “Donor-Specific Antibodies in Kidney Transplant Recipients.” Clinical journal of the American Society of Nephrology : CJASN vol. 13,1 (2018): 182-192. doi:10.2215/CJN.00700117
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IgG immunodominant DSA subclasses carrying distinct phenotypes of kidney allograft and associated with AMR. It’s detected by IMF high level of anti HLA antibodies.
iDSA igG1
iDSA igG2
iDSA igG3
iDSA igG4
iDSA igG3 associated with acute ABMR and short time of rejection. If it’s associated with C1q binding are strongly associated with inferior allograft survival and graft loss.
Histomorphological manifested by glomerlitis and tubulitis and presence of C4d deposition along peritubular capillarities.
iDSA igG4 is associated with sub clinical ABMR and late allograft rejection with increase allograft glomerulopathy manifested by interstitial fibrosis and tubular atrophy.
References:
Carmen Lefaucheur, et al, IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury: jAm Soc Nephrol. 2016 Jan; 27(1): 293–304.
Published online 2015 Aug 20.
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What are the classes of IgG DSA? What is the mechanism of the injury they cause?
IgG has several subclasses:
IgG1, -2, -3, and -4.
mechanism of the injury they cause?
activate complement and recruit effector cells through the Fc receptor.
gG1 and IgG3 are usually complement binding .IgG3 has the greater binding efficiency
to C1q and activate complement cascade.
IG2 can activate complement weakly, IgG4 does not activate complement at all, but both
can recruit effector cells through the Fc receptor.
IgG4 IS associated with advanced stage of rejection .
References:
Rubin Zhang. Donor-Specific Antibodies in Kidney Transplant Recipients.
CJASN January 2018, 13 (1) 182-192.