Minor histocompatibility antigens are normal proteins that are themselves polymorphic in a given population. Even when a transplant donor and recipient are identical with regard to MHC genes, amino acid differences in these minor proteins can lead to rejection.
Minor antigens are responsible for the need for immunosuppression after donation between HLA-matched nonidentical twin siblings. The minor histocompatibility antigen HY is associated with acute rejection.Male grafts in female recipients have reduced graft survival .
Examples;
1-The male or H-Y antigen, is derived from a group of proteins encoded on the Y chromosome. Alloresponses to this antigen may explain reduced long-term graft survival observed in male-to-female donations.
2- MHC I–related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity. Exposure to allogeneic MICA during transplantation can elicit antibody formation.
3- ABO blood group glycolipids expressed on endothelial and red blood cells are other notable non-MHC antigens.
Minor histocompatibility antigens are small peptides occupying antigen binding sites of MHC molecules of he donor. They are recognized by CD8+ cytotoxic T cells leading to allograft rejection.
Examples are MHC class I -related chain A and MHC class I-related chain B .They are expressed on endothelial cells. Antibodies against them cause ABMR.2 haplotype matched siblings (fraternal twins or non-twin siblings )require small dose IS due to difference in minor histocompatibility antigens. They do no not engage T cell receptors.
Hamdy Hegazy
3 years ago
Minor histocompatibility antigens are non-HLA antigens or any non-MHC encoded polymorphic proteins that can induce immune response via indirect recognition by T cells when transplanted to a recipient with absent or altered gene expression.
If transplant donor and recipient are identical with regard to HLA, amino acid differences in these minor proteins can lead to antibody mediated rejection. It was found that 38% of graft loss could be due to non-HLA antigens which are responsible for chronic graft loss in other studies.
Examples for Non-HLA antigens of clinical significance:
1- HY antigen: is derived from a group of proteins encoded on the Y chromosome. Alloresponses to this antigen may explain reduced long-term graft survival observed in male-to-female donations.
2- Angiotensine II type I receptor: associated with high graft failure risk, Hypertension, and arterial inflammation. 3- Endothelin type A receptor: associated with hypertension, cardiovascular disease and preeclampsia. 4- Heat shock protein. 5- Endothelial cell antigen: leads to complement mediated cell injury and endothelial cell activation, antibodies against this receptor are associated with higher rejection rate. 6- Major histocompatibility complex class I chain related gene A(MICA): are surface glycoproteins with functions related to innate immunity. Exposure to allogeneic MICA during transplantation can elicit antibody formation.
References:
Reindl-Schwaighofer R., Heinzel A., Gualdoni G.A., Mesnard L., et al. Novel insights into non-HLA alloimmunity in kidney transplantation. Transplant International 2020; 33: 5–17.
Zhang X., Reinsmoen N.L. Impact of Non-Human Leukocyte Antigen Specific Antibodies in Kidney and Heart Transplantation. Frontiers in Immunology, 2017, April,Vol. 8, article 434.
Wael Hassan
3 years ago
Minor histocompitability AG are normal proteins that are themselves polymorphic in a given population
we can say it is a sub types of MHC major histocompitability,may donor &recipient have identical MHC genes but amino acids differences in these minor proteins can lead to rejection.
For example, the sex-specific antigen H-Y in males may cause rejection of male organs or bone marrow grafts by MHC-identical female recipients. The epitope of the H-Y antigen has been mapped to an 11-residue peptide located near one end of the protein encoded by the conserved Y-chromosome gene SMCY, which is homologous to the SMCX gene on the X chromosome. Identical results have been reported for the mouse H-Y antigen.
Balaji Kirushnan
3 years ago
mHA (minor histocomaptibility antgens) include alloantigens which have various expression and are polymorphic. They account for the rejection in HLA identical transplants. They are peptides on the cell surface which develop immune response by indirect allorecognition by T cells. They are different from the non HLA antigens like MICA, AT1R antigen, ETR antigen. 2 such antigens are reported.
HY antigen – encoded on the Y chromosome. Female recipients receiving a male kidney have been reported to cause this kind of antigen antibody rejection. Studies show decrease in graft survival in female to male transplants due to mHA HY antigen. In a study of retrospective cohort of renal transplant patients published in Lancet in 2008, inferior graft survival was reported in female to male transplant patients due anti HY antibody
HA1, HA3 and HA 8 are the other mHA reported, but they do have effect on death censored graft survival
Other studies also mention non HLA antigens as also included in the Minor Histocomaptibility antigens.
References:
Gratwohl A, Dohler B, Stern M, Opelz G. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 2008; 372:49–53.
Ben Lomatayo
3 years ago
Minor histocompatibility complex are those genes that encodes antigens other than that of the major histocompatibility antigens. It is less important but still relevant to transplantation and can adversely affect graft survival. This could be one of the reasons we still use immunosuppression in non identical twins. The common example is H-Y antigen
Ahmed Abdalla
3 years ago
Minor histocompatibility antigens are normal polymorphic proteins encoded by a large number of chromosomes presented only as peptides which can lead to rejection Even in identical HLA matching groups causing (indirect allorecognition).
Minor antigens are responsible for the need for immunosuppression in HLA –matched non identical twins after donation.
Types of minor histocompatibility antigens:,
1- the male or H-Y antigen, is derived from Y chromosome. Alloresponses to this antigen may explain reduced long-term graft survival between male-to-female donations. It showed that H-Y antigen responsible for third of graft rejections in male donor to female recipient
2- MHC I–related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity causing allograft damage.. Exposure to allogeneic MICA during transplantation can elicit antibody formation.20 ABO blood groupglycolipids expressed on endothelial and red blood cells are other notable non-MHC antigens.
Minor histocompatibility complex showed some relationship ABMR in negative DSA.
References:
Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Org Transpl 2009;14:419-425.
Pfeffer PF, Thorsby E. HLA-restricted cytotoxicity against male-
specific (H-Y) antigen after acute rejection of an HLA-identical sib-
ling kidney: Clonal distribution of the cytotoxic cells. Transplanta-
tion 1982; 33: 52–56.
Ahmed mehlis
3 years ago
●Definition
Minor histocompatibility ..they are receptors on the cellular surface of donated organs that are known to give an immunological response in some organ transplants.They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides . These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene
deletions, frameshift mutations, or insertions.About a third of the characterized MiHAs come from the Y chromosome.[4] The proteins are composed of a single immunogenic HLA allele . Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules’s antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities’ proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.
●H Y antigens?
antigens are encoded by genes on the Y chromosome. Both HLA class I and II alleles have been found to present these antigens. Some of these antigens are expressed in nucleated male cells, and the presence of these antigens has been associated with a greater risk of developing GVHD allogeneic stem cell transplantation for a HLA matched gene when there’s a male recipient and female donor. To clarify our point here , in pregnancy H-Y MiHA play a role in pregnancy with a male fetus because fetal cells can cross from the placenta into the maternal blood stream where the maternal T cells respond to the foreign antigen presented on both MHC class I and II. Therefore, H-Y specific CD8+ T cells develop in the maternal blood and can target the fetal cells with nucleus expressing the antigen on a MHC class I molecule. The response to these fetal H-Y antigens are involved with women experiencing secondary recurrent miscarriage who were previously pregnant with a male fetus.Women with an earlier male pregnancy have T cells which were previously exposed to these H-Y antigens, and consequently recognize them quicker. It has been found that women with recurrent miscarriage also contain MHC II with ability to present these antigens to T helper cells (CD4+) which is significant for CD8+ activation.
To sum up Minor histocompatibility has a role in acute rejection in positive cross matching .
●references
1. Robertson NJ, Chai JG, Millrain M, Scott D, Hashim F, Manktelow E, Lemonnier F, Simpson E, Dyson J (March 2007). “Natural regulation of immunity to minor histocompatibility antigens”. Journal of Immunology.
2.Hirayama M, Azuma E, Komada Y (2012). Major and Minor Histocompatibility Antigens to Non-Inherited Maternal Antigens (NIMA), Histocompatibility.
Last edited 3 years ago by Ahmed mehlis
Nasrin Esfandiar
3 years ago
Even HLA- identical siblings have 10 year graft survival rate of 82.5% and it was hypothesized that minor histocompability antigens(mHags) could induce rejection. The mHags are polymorphic self-peptides which are presented at the surface of cells by HLA molecules and are recognized by T cells. Their mismatches are not as potent as HLA-mismatches but can have a cumulative response in case of many mHA mismatches.
H-Y antigene is one of them that received attention in kidney transplantations from male donors to female recipient and causes adverse effects on these transplants. Another one are polymorphic mitochondrial proteins.
Other examples are: HA-1, HA-2, HA-3, HA-8, HB-1 and ACC-1.
References: 1. Heinold A, Opelz G, Scherer S, Ruhenstroth A, Laux G, Doehler B, Tran TH. Role of minor histocompatibility antigens in renal transplantation. Am J Transplant. 2008 Jan;8(1):95-102. 2. Locke, J. E. (2018). Handbook of Kidney Transplantation. Sixth Edition. G. M. Danovitch (Editor) Wolters Kluwar, 2017.
Theepa Nesam
3 years ago
Minor Histocompatibility Antigens
Rejection still can occur even organs transplanted between HLA-matched individuals.
Although the highest degree of genetic polymorphism within a species lies within MHC, many other loci encode proteins with a lower degree variability that can act as transplantation antigen -miH antigen
Single miHA mismatch is not potent enough to stimulate alloimmunity but cumulative anti-miHA ( as many disparities might happen in between donor and recipient) respond can cause significant harm
This probably explains the occurrence of rejection but not significant graft loss in HLA identical siblings
H-Y antigen has been suggested possibly compromises the survival of male renal allograft
Polymorphic mitochondrial proteins – another example of MiHA after H-Y antigen that can trigger alloimmunity in which its relevant proven in transplanting -induced pluripotent stem (iPS)cells
Examples of other miHA
HA-1,LRH-1,LB-EBI3-1,HB-1,ACC-2,ACC-1,ACC-6,HA-2,HA-1/B60,LB-ITGB2-1
References
hand book of kidney transplantation -gabriel danovich
kidney transplantation: principles and practice – Stuart j Knechtle
Jamila Elamouri
3 years ago
Minor histocompatibility (H) antigens are T-cell epitopes, acquired from polymorphic proteins. These peptides are presented by various histocompatibility complex (MHC) class I and II molecules. Minor histocompatibility antigens are expressed on a wide variety of cell types and tissues>
The MHC/minor H peptide complexes can be a barrier to transplantation.
They are encoded by polymorphic genes on autosomal chromosomes, their transcription produces proteins with different amino-acid sequences in recipient and donor. These polymorphic peptides end up in the groove of HLA molecules, minor H antigen-specific cells (T-cell receptors) can recognize these differences after transplantation and evoke alloimmune reactivity. 54 minor H antigens have been identified.
The nonsynonymous single nucleotide polymorphism (SNP) is the most common form of genetic polymorphism leading to minor H antigen. Ex; minor antigen HA-1 and HA-2.
SNPs can lead to the introduction of a stop codon instead of an altered amino acid or to changes in intron splicing.
H-antigen polymorphisms may also produce from the absence of a complete gene, or copy-number variation (CNV).
Deletion-insertion polymorphism (DIPs) may also lead to minor H antigens ex; LRH-1
v The T-cell response to minor H-Ag is based on the absence of the immunogenic allele in the donor T-cell and the presence of the immunogenic allele in the targeted individual. (In the target individual, HLA restriction molecule that presents the minor H peptide, should be present, as well, in the T-cell donor in order for the response to occur). Example: HA-3 responses are only generated against the HA-3T minor H peptide when presented in HLA-A1. This means; this minor H antigen can only play a role in one immunogenic HA-3T allele on its chromosome 15 and the donor is homozygous for the HA-3M allele.
Minor H-Ag-specific T-cell response is related to CD8+cytotoxic T- lymphocytes (CTL) and CD4+ T-helper cells. In addition, minor H antigen disparity can lead to induction of Treg which is observed after kidney transplantation.
There is disagreement and limited information about the role of minor H antigen mismatch in graft survival. Some show no effect, while others show the correlation between HY mismatch and the outcome of kidney transplantation, that explained by antibodies mediated response rather than CTL response in graft rejection.
Female recipients of male kidneys more frequently show HY antibody development after transplantation than other gender combinations.
RPS4Y1 is the most commonly known antigen, which is an HY antigen against which CD4 positive, HLA class II-restricted. In summary: when addressing the role of minor H antigens in organ transplantation, a focus on antibodies and HLA class ii-restricted T-helper epitopes might be preferred to the analysis of HLA class I-restricted CTL epitopes. (1)
Reference:
1. Spierings E. Minor histocompatibility antigens : past , present , and future. :13–7.
saja Mohammed
3 years ago
What is the effect of minor histocompatibility complex on graft survival? Minor histocompatibility complex antigens are non-HLA polymorphic cellular proteins bound to MHC class1 of the recipient, can trigger rejection in HLA matched non identical twin sibling, therefore they need to continue on IS therapy, by principle any change in amino acid sequence in these minor proteins can trigger rejection. with the improvement of our understanding of the molecular DNA -genetic testing for MHC antigens over years with the identification of more number of such minor MHC antigens which encoded by the Y chromosome in male which may cause rejection in male -female donation or bone marrow grafts by MHC-identical female recipients, another possibility that the peptide may be autosomal derived and represents polymorphisms among autosomal proteins or enzymes .we don’t have systematic studies in human to address their contribution to the human kidney transplant . the mechanism of the allogenic response to this type of minor MHC antigens is similar to the response to microbial antigens in that host, like the minor -MHC -class1 related chain A (MICA) antigen which structurally similar to MHC Class1 antigen it can be expressed on different cells including monocytes epithelial and endothelial cell and can trigger the antibodies production and worsening graft survival. these peptides recognized by cytotoxic T-cells, at the level of CD8, based on the animal studies in mouse model slight modification of such minor antigen result in the production of regulatory T Cells receptor (RTC) that can induce tolerance,Recently, Ca-et al, found coexisting CD8+memory regulatory and effector T-cells, both specific for the same HA-1 antigen, in renal transplant recipients who had apparently developed graft tolerance (4), In contrast, Kr-ishnan et al. (5) found a significant association between
HA-1 mismatch and chronic kidney rejection, we need more studies to elaborate more about the definite roles of the Minor MHC petites in human kidney transplant and its possible therapeutic impact by inducing tolerance
Reference 1-Comprehensive Clinical Nephrology (Fourth Edition), 2010 2-handbook of kidney transplant, fifth edition, Gabril M.Danovitch 3- up to date, transplant immunology, minor MHC antigens in kidney transplant . 4-Role of Minor Histocompatibility Antigens in Renal Transplantation A. Heinold,G. Opelz,S. Scherer,A. Ruhenstroth,G. Laux,B. Doehler,T. H. Tran 5-Krishnan NS, Higgins RM, Lam FT et al. HA-1 mismatch has significant effect in chronic allograft nephropathy in clinical renal transplantation. Transplant Proc 2007; 39: 1439– 1445.
Mohamed Fouad
3 years ago
The minor histocompatibility antigens (mHags) are polymorphic cell-derived self-peptides, encoded by sex-linked (Y-chromosomally encoded) or diallelic autosomal genes, which are presented at the cell surface by HLA molecules and recognized by alloreactive HLA class I-restricted CD8+ or HLA class II-restricted CD4+ T cells.
In the context of kidney graft rejection, mHag can only display its immunogenicity if an HLA molecule that is able to bind this mHag is present in the recipient (direct allorecognition, the mHag is presented by recipient antigen-presenting cells [APCs]) or donor (indirect allorecognition, the mHag is presented by donor passenger APCs within the graft).
In hematopoietic stem cell transplantation (HSCT), HLA-matched but mHag-mismatched transplants show increased rates of graft-versus-host disease (GVHD) and graft rejection.
In retrospective study, they selected HLA-A, -B and -DRB1 (two-digit) matched recipient/donor pairs of Caucasian origin in order to reduce the effect of HLA mismatches which may mask an impact of mHags. In addition, this selection criterion assures that recipient and donor both express the mHag-presenting HLA molecule; this allows the evaluation of a potential effect of both antigen recognition pathways (indirect and direct). They analysed only first transplants to reduce effects of sensitization. Out of 33 785 kidney transplants on which DNA and clinical data was available, only 702 transplants fulfilled the criteria: sufficient DNA available for mHag typing, first transplant, Caucasian origin, matched for HLA-A, -B and -DRB1
In summary, they found no significant effect of incompatibility for the mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1 or UGT2B17 on allograft survival in HLA-A, -B and -DRB1 matched first kidney transplants. Results indicate that typing of mHags provides no useful information for predicting 5-year graft outcome in kidney transplantation.
Encoded by a large number of chromosomes and are presented only as peptides in the context of recipient MHC (indirect allorecognition).These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins.
MiHA antigens are either: (i)ubiquitously expressed in most tissue like skin and intestines ; or (ii) restrictively expressed in the immune cells.
MiHAs are Autosomally and Y chromosome encoded.A third of the characterized MiHAs encoded by the Y chromosome.
Likely to cause or lead to rejection and explaining the need for immunosuppression between HLA-matched nonidentical twin siblings.
Minor histocompatibility antigens(MiHA):
The MiHAs bound to a MHC presented on a cell surface may be recognized as a self peptide or not recognized by either CD8+ or CD4+ T cells.
There is death by apoptosis of thymocytes that (i) do not interact with MHC molecules or (ii) have high-affinity receptors for self MHC plus self antigen a process referred to as negativeselection.
The process of positive and negative selection means fewer self-reactive mature T cells will leave the thymus and lead to autoimmune problems.
Some MiHAs can be used as therapeutic T cell targets to augment the graft-vs.-leukemia (GVL) effect in order to prevent or manage leukemia relapse after HCT.
It is assumed that the selective infusion of T-cells reactive with MiHA exclusively expressed on recipient hematopoietic cells would help to separate the beneficial GVL effect from GVHD, and identification of MiHA with a hematopoietic expression pattern is therefore of interest.
Effect of minor histocompatibility Ag (MiHA)on graft survival :
The first hypothesis concerning potential impact of MiHA on the outcome of BMT (bone marrow transplantation) was based on a case of a female recipient (with severe aplastic anemia) who received a transplant from her brother. Graft rejection after BMT was diagnosed and reactivity of cytotoxic T cells isolated from peripheral blood of recipient was directed to antigens present on donor’s cells which were not associated with HLA. {E. Goulmy, “Minor histocompatibility antigens: from transplantation problems to therapy of cancer,”Human Immunology, vol. 67, no. 6, pp. 433–438, 2006.}
Disparities of immunogenic MiHA alleles between the donor and the recipient may trigger GVHD and HVG reactions, which may lead to graft rejection or to GVH/GVL reaction.Female recipients after transplantation from male donors may experience graft failure due to HVG reaction against HY antigens resulting in a worse survival.{ B. E. Shaw and A. Madrigal, “Immunogenetics of allogeneic HSCT,” in Haematopoietic Stem Cell Transplantation, ESH-EBMT Handbook, J. Apperley, E. Carreras, E. Gluckman, and T. Masszi, Eds., pp. 74–89, 2012.}
Knowledge of MiHA alleles and genotypes enables to detect their disparities, which could be helpful not only in optimal matching of a donor/recipient pair and in understanding transplant results, but also it may create a chance to the use of MiHA in immunotherapy aiming to improve patients’ survival. {A. Dickinson, “Biomarkers in acute and chronic GVHD,” in Graft -Versus-Host Disease, H. T. Greinix, Ed., pp. 17–31, Unimed Verlag AG, 2008}.
Graft loss was more common with kidneys from female donors than with those from male donors (p<0.001) after both 1 and 10 years. Female recipients had a lower rate of graft failure between the end of the first year and the end of the tenth year (p<0.001). Compared with all other combinations of sex, transplantation of male donor kidneys into female recipients was associated with an increased risk of graft failure during the first year(hazard ratio [HR] 1.08, 95% CI 1.03-1.14, p=0.003; death censored HR 1.11, 1.04-1.19, p=0.003)and between 2 and 10 years(HR 1.06, 1.01-1.10, p=0.008; death censored HR 1.10, 1.05-1.16, p<0.001).
Lancet. 2008 Jul 5;372(9632):49-53. doi:10.1016/S01406736(08)60992-7. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study Alois Gratwohl1, Bernd Döhler, Martin Stern, Gerhard Opelz
H-Y antigen in undifferentiated embryonic stem cells (ESCs), as well as ESC-derived endothelial cells, provokes T- and B cell responses in female recipients.
(Stem Cells Dev. 2020 Sep 15;29(18):11791189.doi:10.1089/scd.2019.0299. Epub 2020 Aug 25.The H-Y Antigen in Embryonic Stem Cells Causes Rejection in Syngeneic Female Recipients)
Cross-sex-KTX alters gene expression levels and induces inflammatory responses, which might play an important role in long-term graft function.
Comparative Study Am J Physiol Renal Physiol. 2017 Aug 1;313(2):F326-F338. doi: 10.1152/ajprenal.00039.2017. Epub 2017 May 17 Cross-sex transplantation alters gene expression and enhances inflammatory response in the transplanted kidneys
?????? FOR OPINIONS: None of the minor histocompatibility antigens (mHag) disparities showed a statistically significant effect on death-censored 5-year graft survival. This report represents the first large-scale study on the relevance of mHags in kidney transplantation.
Comparative Study Am J Transplant. 2008 Jan;8(1):95-102. doi: 10.1111/j.1600-6143.2007.02042.x. Epub 2007 Dec 18. Role of minor histocompatibility antigens in renal transplantation A Heinold1, G Opelz, S Scherer, A Ruhenstroth, G Laux, B Doehler, T H Tran
Mujtaba Zuhair
3 years ago
The occurance of rejection in recipient of HLA matched grafts had lead to the discovery of antigens , they call it minor HLA or non HLA antigens. These antigens had lower effect on graft survival when compared with major HLA but can induce graft rejection.
MICA antigens ( MHC I related A) : MICA antigen is present on the surface of endothelium , monocytes and keratinocytes , it’s not present on the lymphocytes , so flow cross match will not be positive even if the recipient had anti MICA antibodies.
Different studies assessed the effect of presence of anti MICA antibodies on graft survival with different results .
Anti Angiotensin II Type I Receptor antibodies (AT1R ):
Many studies showed that the presence of aanti AT1R antibodies is associated increased rate of ABMR and transplant glomerulopathy and anti major HLA antibodies and poor graft survival.
Anti Perlecan (LG3) antibodies:
The heparin sulfate proteoglycan (perlecan) had C terminal domain called LG3, and antibodies to this protien had been opserved as a cause of ABMR and poor graft survival by many studies.
H-Y antibodies :
H-Y antigen genes are genes located on chromosome Y . these antigens explains the slightly lower graft survival in female recipient of male donor kidneys.
There are many other antigen implicated in the ABMR like Vimentin Ag, Collagen 4 Ag, fibronectin .
Reference:
María Gutiérrez-Larrañaga, Marcos López-Hoyos , André Renaldo and David San Segundo Non-HLA Abs in Solid Organ Transplantation
Transplantology 2020, 1, 24–41; doi:10.3390/transplantology1010003
Shereen Yousef
3 years ago
Minor Transplantation Antigens
A minor histocompatibility antigen is molecularly defined as a donor-derived peptide presented on a donor cell by an MHC molecule shared by a donor and a recipient.
Studies involving MHC identical grafts in mice indicate that minor histocompatibility antigens can also mediate rejection.
Minor antigens are responsible for the need for immunosuppression after donation between HLA-matched nonidentical twin siblings.
Minor histocompatibility antigens are polymorphic peptides consisting of 9–12 amino acids. After binding to the antigen recognition site of either class I or class II HLA molecules present on a cell surface MiHAs can be recognized by T-lymphocytes. Thus the occurrence of MiHA depends on the presence of specific HLA antigens, which is called the MHC restriction. MiHAs are encoded by either autosomal chromosomes or by Y-chromosome (1).
Recipient T cells can be directly primed to minor histocompatibility antigens.
Donor dendritic cells (DCs) directly prime CD8+ T cells to become effector cells without the need for further antigen processing by recipient APCs.
research of the human genome revealed that polymorphism of nucleotides in genes that are non-HLA related (e.g., NOD2/CARD15 or genes encoding cytokines: TNF-alpha, IL-10, IL-6, interferon gamma, IL-1, and TGF-beta) may also determine the individual immunological phenotype of donor-recipient pairs, thus influencing GVHD, infections, and overall survival (2).
In humans, it has been recognized for several years that minor histocompatibility antigens can be immunogenic from observations based on organ graft rejections and bone marrow graft-versus-host reactions in cases of genetically matched HLA antigens.
Two general families of such antigens have been identified:
1.H-Y antigens are proteins encoded on the Y chromosome. Females of the species may mount an immune response against these proteins.
2.T cells recognize peptidic antigens corresponding to polymorphisms among autosomal proteins expressed by individuals of the species. Examples include mitochondrial proteins and enzymes. In the presence of both major and minor incompatibilities, it is clear that the alloimmune response targeted against the MHC molecules predominates.
Several studies reported a detrimental role for minor H antigen-specific T cells in graft survival. However, some data indicate that minor H antigens might also be clinically involved in preventing rejection of solid organ grafts, possibly by induction of regulatory T cells.
Knowledge of MiHA alleles and genotypes enables to detect their disparities, which could be helpful not only in optimal matching of a donor/recipient pair and in understanding transplant results, but also it may create a chance to the use of MiHA in immunotherapy aiming to improve patients’ survival (3).
REFERENCE
1 E. Spierings, B. Wieles, and E. Goulmy, “Minor histocompatibility antigens—big in tumour therapy,” Trends in Immunology, vol. 25, no. 2, pp. 56–60, 2004.
2 B. E. Shaw and A. Madrigal, “Immunogenetics of allogeneic HSCT,” in Haematopoietic Stem Cell Transplantation, ESH-EBMT Handbook, J. Apperley, E. Carreras, E. Gluckman, and T. Masszi, Eds., pp. 74–89, 2012.
3 A. Dickinson, “Biomarkers in acute and chronic GVHD,” in Graft -Versus-Host Disease, H. T. Greinix, Ed., pp. 17–31, Unimed Verlag AG, 2008.
Amer Hussein
3 years ago
Minor histocompatibility antigen (also known as MiHA) are receptors on the cellular surface of donated organs that are known to give an immunological response in some organ transplants.They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides . These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins.Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. The proteins are composed of a single immunogenic HLA allele . Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules’s antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities’ proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells. Minor histocompatibility antigens are due to normal proteins that are in themselves polymorphic in a given population. Even when a transplant donor and recipient are identical with respect to their major histocompatibility complex genes, the amino acid differences in minor proteins can cause the grafted tissue to be slowly rejected. Several of the identified Autosomally and Y chromosome encoded MiHAs
Abdullah Raoof
3 years ago
Minor histocompatibility antigens are normal proteins that are poly-
morphic within a given species. Even when a transplant donor and
recipient are identical with regard to MHC genes, amino acid differ-
ences in these minor proteins can lead to rejection. Minor antigens are
encoded by a large number of chromosomes and are presented only as
peptides in the context of recipient MHC (indirect allorecognition).
Minor antigens are responsible for the need for immunosuppression
after donation between HLA matched but nonidentical twin siblings.
The prototypic minor histocompatibility antigen, the male or H-Y
antigen, is derived from a group of proteins encoded on the Y chro-
mosome. Alloresponses to this antigen are responsible for rejection of
male mouse skin grafts by otherwise identical female recipients and
may explain observations of reduced long-term graft survival in human
male-to-female donations.
MHC I–related chain A (MICA) antigens are surface glycoproteins
with functions related to innate immunity. Exposure to allogeneic MICA
during transplantation can elicit antibody formation.19 ABO blood group
glycolipids expressed on endothelial and red blood cells are other notable
non-MHC antigens. Finally, immune responses to autoantigens have
been associated with allograft damage
Reff= Bates RL, Frampton G, Rose ML, et al. High diversity of non-human
leukocyte antigens in transplant-associated coronary artery disease.
Transplantation. 2003;75:1347–1350.
You need to elaborate more and to use more updated references
Tahani Hadi
3 years ago
Minor histocompatibility antigens are polymorphic normal proteins that are encoded by large numbers of chromosomes.
Slow graft rejection may be related to a large number of these antigens once it’s detected by T cells even when both donor and recipient are identical, the differences in amino acid are responsible for this rejection making the needs of immunosuppression is mandatory.
Mahmoud Hamada
3 years ago
minor HC complex is a structure of polypeptide on top of cell surface. they are the cause of graft dysfunction in kidney transplantation even if the MHC matching is good.
AMAL Anan
3 years ago
•••The Minor histocompatability antigens are polymorphic cell-derived self-peptides, encoded by sex-linked (Y-chromosomally encoded) or diallelic autosomal genes, which are presented at the cell surface by HLA molecules and recognized by alloreactive HLA class I-restricted CD8+ or HLA class II-restricted CD4+ T cells .Most autosomally encoded mHags arise from nonsynonymous single nucleotide polymorphisms (SNPs) which result in an amino acid exchange within an HLA-binding peptide. This could either alter the affinity of the peptide to the transporter protein (TAP, transporter associated with antigen processing) or to the presenting HLA molecule or, alternatively, lead to cleavage of the peptide by the proteasome.
•••It can be reasonably hypothesized that an alloimmune response evoked by minor histocompatibility antigens (mHags) might lead to graft rejection.
•••Even organs transplanted between HLA-matched individuals (for example, between two-haplotype matched siblings) are not safe from rejection. This is because any protein that is present in the graft but not the recipient, or that is sufficiently dis-similar (polymorphic) between the graft and the recipient, will behave as a foreign, transplantation antigen. Such non-HLA transplantation antigens are called minor histocompatibility antigens (mHA). A single mHA disparity is not as potent at inducing alloimmunity as a single HLA disparity (thus, the designation “minor”), but since many mHA mismatches exist between donors and recipients, the cumulative anti-mHA response is significant. A particular mHA that has garnered attention in transplantation is the H-Y antigen present only in males of the species. Clinical data suggest that it possibly compromises the survival of male renal allografts transplanted to female
recipients. The role of mHA in graft-versus-host disease is well established as the vast majority of hematopoietic stem cell transplants are performed between HLA-matched individuals, making the contribution of mHA more noticeable. Polymorphic mitochondrial proteins are another type of mHA that can trigger alloimmunity. This is
particularly relevant to transplanting-induced pluripotent stem (iPS) cells generated by nuclear transfer, wherein the nucleus is “self” but the mitochondria are foreign.
References:
~Hu M, Wang YM, Wang Y, et al. Regulatory T cells in kidney disease and transplantation. Kidney Int 2016;90:502-514.
~Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274-293.
~Liu Z, Fan H, Jiang S. CD4+ T-cell subsets in transplantation. Immunol Rev 2013;252:183-191.
Mori DN, Kreisel D, Fullerton JN, et al. ~Inflammatory triggers of acute rejection of organ allografts. Immunol Rev 2014;258:132-144.
~Murphy K, Weaver C. Janeways Immunobiology. 9th ed. New York: Garland Science; 2016.
~Oberbarnscheidt MH, Lakkis FG. Innate allorecognition. Immunol Rev 2014;258:145-149
~Opelz G for the Collaborative Transplant Study. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 2005; 365: 1570– 1576.
~Terasaki PI. Deduction of the fraction of immunologic and non-immunologic failure in cadaver donor transplants. In: JM Cecka, PI Terasaki, eds. Clinical transplants. Los Angeles , CA : UCLA Tissue Typing Laboratory, 2003: 449– 452.
Minor histocompatibility antigens ( non -MHC polymorphic molecules) which are small peptides presented on MHC class l and MHC class ll with inter individual difference due to heterogenecity they are recognised by the recepient T cells by indirect pathway where donor-derived peptides loaded onto self-MHC molecules expressed by self-APCs, which lead to immune response Mechanism is poorly understood, but some studies showed its ability to induce rejection in HLA identical donor and recipient not identical twins . they mediate acute graft versus host disease in setting of HLA-matched allogeneic hemopoietic stem cell transplantation (HSCT). Sánchez‐Fueyo, Alberto, and Francesco Dazzi. “On minor histocompatibility antigens, mixed chimerism, and transplantation tolerance.” (2021): 919-920. Giesler S, Zeiser R. Deciphering the role of Minor histocompatibility antigens for acute graft-versus-host disease. Transplant Cell Ther. 2021 Jul;27(7):523-524. Heinold A, Opelz G, Scherer S, Ruhenstroth A, Laux G, Doehler B, Tran TH. Role of minor histocompatibility antigens in renal transplantation. Am J Transplant. 2008 Jan;8(1):95-102.
minor histocompatibility antigens are many. It was found to adversely affect renal graft survival. one of the prototypes H-Y may be the reason for less survival of grafts donated to women from men as this is found in the Y chromosome. minor HLA antigens are more in number and more polymorphic but still less immunogenic. they are known to cause graft versus host disease as graft versus leukemia in bone marrow transplantation.
Ramy Elshahat
3 years ago
Major HLA are antigens encoded on short arm of chromosome 6 and get identified by immune system by direct,indirect and semidirect pathways
Minor HLA antigens are other proteins and receptors presented on the surface of the graft and usually not strongly stimulate immune system
It’s role still not clear but still play important role in rejection in dizygotic twins with zero major HLA mismatch and so they still need to receive immune suppression medications
One example of minor HLA is HY antigens which are encoded on Y chromosome and several studies showed that it was responsible for 30% rejection of graft from male donor to female recipient
Our center experience in screening for these circulating antibodies just if we have biopsy proven ABMR and we have negative DSA.
Always appear to be positive….and respond well to usual protocol of treatment of ABMR which usually consist of IVIG and plasma exchange(only if happened in first year post transplant)+rutiximab
But multiple questions here still not answered like
Do we need to respect it in matching?
Do we need to screen antibodies against it before and after transplant
Antibodies against it are they denovo or they already preformed pre-transplant?
Are they really the cause of rejection or there are other factors like epitopic mismatch , hormonal effect, or noncompliance
This topic need randomized control trials to be clinical applied in better way
But it should be kept in mind when we see a crime(ABMR) and we can’t find the criminal (DSA)
References:
1)Danovitch G.M handbook of kidney transplantation sixth edition
Karl Womer, Hamid Rabb, in Comprehensive Clinical Nephrology (Fourth Edition), 2010
Tan JC, Wadia PP, Coram M, et al.H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation 2008; 86: 75
2) Reindl-Schwaighofer R, Heinzel A, Gualdino GA, et al. Novel insights into non-HLA alloimmunity in kidney transplantation. Transplant Int 2020;33:5-17.
3) Terasaki PI. Deduction of the fraction of immunologic and nonimmunologic failure in cadaver donor transplants. Clin Transpl 2003:449-452.
4) Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Org Transpl 2009;14:419-425.
5) Heinold A, Opelz G, Scherer S, et al. Role of minor histocompatibilty antigens in renal transplantation. Am J Transpl 2008;8:95-102.
Mahmoud Rabie
3 years ago
Minor HLA antigens are peptides composed of amino acids and bound to both class I and class ll major histocompatibility complex on the cell surface.
Even if the donor and recipient are identical regarding major histocompatibility complex, they will be different in minor HLA antigens, and this explain why we use immunosuppressive drugs in case of non identical twins.
Minor HLA antigens play a role in chronic allograft rejection.
Minor histocompatibilty complex antigens (mHA) are peptides present over cell surface which develop immune response by indirect allorecognition by a T cell post transplant. (1) So even if someone gets a transplant with HLA matched organ, these minor histocompatibility antigens can cause immune mediated reactions leading to graft injury.
A number of mHA have been evaluated in organ transplants, especially in HLA matched transplants. The most important mHA is HY encoded antigen, which is encoded on the Y chromosome. In a study comparing HLA identical siblings for graft failure, 38% graft failure was due to non-HLA factors like mHA mismatch, MICA, ABO incompatibility etc. (2)
mHA impacting graft function include autosomally encoded as well as Y chromosome encoded antigens. Studies have shown that mHA A2/HY has been associated with decreased graft survival of male renal graft in female HLA-A2 recipients. HY based cytotoxicity was seen in HLA identical sibling renal transplants. Denovo HY antibody formation was associated with acute rejection. A2/HA-1 mismatch has been shown to be associated with chronic allograft nephropathy (but not with acute rejection). (3)
Another study by Heinold et al demonstrated that certain mHA mismatches (HA-1, HA-1, HA-3, HA-8, HB-1, ACC-1, UGT2B17) had no significant effect on death censored graft survival at 5 years. (4)
The importance of all these studies lie in the search for criteria to choose patients in whom immunosuppression can be stopped.
References:
1) Reindl-Schwaighofer R, Heinzel A, Gualdino GA, et al. Novel insights into non-HLA alloimmunity in kidney transplantation. Transplant Int 2020;33:5-17.
2) Terasaki PI. Deduction of the fraction of immunologic and nonimmunologic failure in cadaver donor transplants. Clin Transpl 2003:449-452.
3) Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Org Transpl 2009;14:419-425.
4) Heinold A, Opelz G, Scherer S, et al. Role of minor histocompatibilty antigens in renal transplantation. Am J Transpl 2008;8:95-102.
Ahmed Fouad Omar
3 years ago
Minor histocompatibility antigens are normal proteins that are themselves polymorphic in a given population. During transplantation of a donor and a recipient with identical MHC genes, amino acid differences in these minor proteins can lead to rejection and are responsible for the need of immunosuppression after donation between HLA-matched non identical twin siblings.
In HLA-matched transplants, minor histocompatibility antigens (mHAs) are important targets for alloimmunity.
H-Y antigens provide an important model for alloimmunity because they serve as significant immunogenic targets with clinical consequences in either the donor graft or the recipient in sex-mismatched transplantation.
H-Y antigens are expressed only on tissues from male donors, and are therefore at risk of being recognized as foreign by female-but not male-recipients
Allo-responses to this antigen may explain reduced long-term survival of the graft observed in male-to-female donations
kidney grafts from male donors to female recipients experience increased rates of graft rejection. The rationale behind this increase in graft rejection is that the recipient’s lymphocytes develop an allo-immune response against the H-Y antigens present on the donor graft
miHA is “any non-MHC gene product which, when transplanted, is sufficiently antigenic to induce CD4and CD8T cells to trigger an immune response.” These peptides are derived from intracellular proteins and show polymorphisms among related and unrelated individuals. Thus even people with identical HLA phenotypes can experience immune rejection.
The role of non-HLA histocompatibility systems, such as minor histocompatibility antigens (miHA), albeit known many years ago, is still a mystery. miHA are polymorphic proteins that vary even in monozygotic twins. The best known is the H-Y antigen, but there are also other autosomal miHA and MICA (MHC class I chain-related gene A). miHA have been well studied in transplantation of hematopoietic precursors, but not in solid organ transplantation. The most important studies in this field relate to the incompatibility of H-Y antigen as a risk factor in kidney transplantation, although the findings are still inconclusive.
The minor histocompatibility antigen HY encoded in the Y chromosome is associated with acute rejection episodes and decreased transplant survival, specifically when a donor is a man and the recipient a woman.
References:
1. Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Organ Transplant. 2009 Aug;14(4):419-25.
2. Pabón MA, Navarro CE, Martin R, Rodríguez M, Martin I, Gaitán L, Gómez A, Lozano E. Minor histocompatibility antigens as risk factor for poor prognosis in kidney transplantation. Transplant Proc. 2011 Nov;43(9):3319-23.
3. Kumbala D, Zhang R. Essential concept of transplant immunology for clinical practice. World J Transplant. 2013 Dec 24;3(4):113-8.
Dalia Ali
3 years ago
Minor antigens
minor antigens are peptides protein recognized by CD8 positive T-cell (cytotoxic cell)and do not induce allo antibody responce and derived from polymorphic celular protein which is bound to MHC class I of recipient.
minor antigen are encoded by Y chromosome in male (H-Y)So This will induce an allo immune responce when male Kidney Transplanted to female recipient.so these antigens lead to decreased long term graft survival in male to female donation
minor antigens have important role in graft- versus-host disease and can cause allograft rejection even when transplant donner and recipient have identical MHC antigens and it’s responsible for using immune suppression drugs in HLA matched non identical twin transplantation
Reference
1-Transplantation immunobiology ,up to date 2021.
2- Womer K, Rabb H. Immunologic Principles in Kidney Transplantation
in Comprehensive Clinical Nephrology (Fourth Edition), 2010
Ala Ali
Admin
3 years ago
We are looking for more replies.
Ban Mezher
3 years ago
The transplant between 2 haplotype matched are not protected from rejection because any protein can be present in the graft but not in the recipient can considered as transplant antigens which called minor histocompatible (mHA).
if just one mHA is incompatible it can not induce strong immune response, but if there are numerous antigens are mismatched the immunological response will be insignificant. mHA has important role in graft-versus-host disease. H-Y antigen is one of mHA that present only in male so a male donor carry this antigen & the recipient is female it will affect the graft survival. Another types of mHA :
HA-1
LHR-1
LB-EBI3-1.
HB-1
ACC-1
ACC-2
ACC-6
HA-2
HA-1/B60
LB-ITGB2-1
REFERENCES:
Danovithch G. Hand book of Kidney Transplantation , 6th ed.
Summers C., Sheth V. and Bleakley M. Minor Histocompatibility Antigen-Specific T cells.Front.Pediatr, 2020; 8:284.
Numerous mHA mismatch can cause significant immune response
Professor Ahmed Halawa
Admin
3 years ago
Dear All
I was watching and reading your entries. There is a confusion between minor HLA and non-HLA. The good thing, many of you recently realised the difference. For example MICA and MICB are non-HLA, while H-Y is minor HLA.
Dear All What is the effect of H-Y antigen on the outcome of transplant? Does transplanting a kidney from a male donor into a female recipient makes a difference on the outcome of transplantation compared to transplanting between same sex?
On an epidemiological level, transplantation of male donor kidneys into female recipients was associated with a negative impact on long-term graft function in a retrospective cohort study in 200 000 kidney transplant recipients
Reference:
Reindl-Schwaighofer, R., Heinzel, A., Gualdoni, G.A., Mesnard, L., Claas, F.H. and Oberbauer, R. (2020), Novel insights into non-HLA alloimmunity in kidney transplantation. Transpl Int, 33: 5-17. https://doi.org/10.1111/tri.13546
————–
There is increased rate of graft failure in female recipients transplanted with male kidneys. This is consistent with the results of Gratwohl et al. [1] and Tan et al. [2]. This may be owing to the effect of histocompatibility H-Y antibodies [1].
Reference :
I. Elmenyawia AA, Donia A, Ahmed TT. The impact of Recipient and Donor Characteristics on Kidney Transplant Graft Survival. J Med Sci Res 2021;4:11-25
[1]Gratwohl A, Dohler B, Stern M, Opelz G. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 2008; 372:49–53.
[2]Tan JC, Kim JP, Chertow GM, Grumet FC, Desai M. Donor-recipient sex mismatch in kidney transplantation. Gend Med 2012; 9:335–347.
The male H-Y antigen is derived from a group of proteins encoded on the Y chromosome and associated with reduced long-term graft survival observed in male to female donations.
The pattern of sex differences in graft outcomes is likely due to a complex interplay of several factors,
including age-related differences in immune potency,
the effects of sex hormones on immune activation,
sex differences in adherence to immunosuppressive medications,
differing metabolic demands on the basis of sex-related differences in body size,
donor sex-related differences in nephron mass,
and immune reactivity to sexually determined minor histocompatibility antigens (H-Y effect).
Changes in the potency of the immune response with increasing age may also modify the effects of other factors affecting graft survival.
Among the youngest recipients,
poorer graft outcomes in females are likely driven primarily by the H-Y effect—present only in the setting of a male donor; any effect of sex hormones is likely small in a group that is largely prepubertal.
Fanny Lepeytre, Mourad Dahhou, Xun Zhang, Julie Boucquemont, Ruth Sapir-Pichhadze, Heloise Cardinal and Bethany J. Foster
JASN October 2017, 28 (10) 3014-3023; DOI: https://doi.org/10.1681/ASN.2016121380
The minor histocompatibility antigen HY encoded in the Y chromosome is associated with acute rejection episodes and decreased transplant survival, specifically when a donor is a man and the recipient a woman. Studies in solid organ transplantation, have suggested that women receiving grafts from men are at higher risk of acute rejection episodes. Nonetheless, the Y chromosome is not the only one with a minor antigen generating a gender mismatch. Wang et al found a new peptide closely related to the H-Y antigen that is present in the MHC class I HLA-B7 and encoded by the Smcx gene in the X chromosome.
H-Y antigens are expressed only on tissues from male donors, and are therefore at risk of being recognized as foreign by female-but not male-recipients.
kidney grafts from male donors to female recipients experience increased rates of graft rejection and reduced graft survival. The rationale behind this increase in graft rejection is that the recipient’s lymphocytes develop an allo-immune response against the H-Y antigens present on the donor graft
H-Y antigens are minor histocompatibility antigens encoded on chromosome Y …it is sex linked antigen …it affects graft outcome as antibodies formed against this antigen will induce graft versus host disease.
transplantation from male donor to female will initiate antibody formation in the female against male H-Y antigen and this will lead to graft rejection
also, there is antibody formation against H-Y antigen in the pregnant female in boy baby.
HY antigen has been shown to be associated with reduced graft survival of male organs in female HLA-A2 recipients. De-novo HY antibody formation has been shown to be associated with acute rejection. (1,2)
1) Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Org Transpl 2009;14:419-425. 2) Tan JC, Wadia PP, Coram M, et al. H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation 2008;86:75-81.
Clinical data suggest that H-Y antigen compromises the survival of male allograft transplanted to a female recipient. As H-Y antigen encoded in Y chromosome and is expressed in male donors and being recognized by female recipient as a foreign.
In general females produce more severe cellular and humoral immune reaction than male, this is partly due to:
1.Immune enhancing effect of estrogen and the suppressive effect of androgen. this hormonal effect vary with age particularly in post-menopausal woman when sex hormone levels drop sharply.
2.Medication adherence differ by sex.
3.The difference in body size and the resultant difference in the metabolic demand.
4. The effect of H-Y antigen among female recipient for male donor.
The relationship between sex and graft survival is complex and likely to be affected by age and donor sex.
Reference:
Lepeytre F., Dahhou M., Zhang X., Boucquemont J. Association of Sex with Risk of Kidney Graft Failure Differs by Age. J Am Soc Nephrol. 2017, 28: 3014–3023.
the outcomes in other solid organs transplants are mixed, but regarding KIDNEY some studies showed a negative impact though I think may not be proved. as in Immunol Res. Author manuscript; available in (Immunol Res. 2014 May; 58(0): 249–258.doi: 10.1007/s12026-014-8514-3 Clinical impact of H-Y alloimmunity) a study of 26 transplants found 54% more deposition of H_Y antibodies)
***A particular mHA that has garnered attention in transplantation is the H-Y antigen present only in males of the species. Clinical data suggest that it possibly compromises the survival of male renal allografts transplanted to female recipients.
*** The most successful transplants, based on donor-recipient gender, were seen in male donors to male recipients, and then male donors to female recipients. Contradictory, the most unsuccessful transplant was observed when the donor was female and the recipient was male. In female transplant recipients, the level of serum cratinine, and eGFR, positive dialysis history before transplant, and low donor hemoglobin levels can be good prognostic factors in kidney transplant survival. By Judging these results based on hemoglobin yields, if we take Gender into account, we get inconsistent results. Therefore, further studies are needed to complete this section.
References:
••Auglienė R, Dalinkevičienė E, Kuzminskis V, Jievaltas M, Peleckaitė L, Gryguc A, et al. Factors influencing renal graft survival: 7-year experience of a single center. Med. 2017;53(4):224–32.
••Muhammad AS, Naicker S. HLA matching and kidney allograft function, experience from a south African transplant Centre. Trop J Nephrol. 2018;13(1):17–20.
••Danovithch G. Hand book of Kidney Transplantation , 6th ed.
the most successful transplants, based on donor-recipient gender, were seen in male donors to male recipients, and then male donors to female recipients. Contradictory, the most unsuccessful transplant was observed when the donor was female and the recipient was male. In female transplant recipients, the level of serum cratinine, and eGFR, positive dialysis history before transplant, and low donor hemoglobin levels can be good prognostic factors in kidney transplant survival.
studies on renal transplantation observed that male donor to female recipient combination is an independent risk factor for poor graft survival [19, 20] and the significantly higher percentage of H-Y antibody production in the male donor-female recipient population could play a role in this phenomenon (2)
There are many other factors determine the outcome also such as age of doner ,
HB level, cardiac condition of recipient, difference in body size , all these factors may also play a role
1 Gholamhossein Naderi, Amin Azadfar, Seyed Reza Yahyazadeh, Fatemeh Khatami & Seyed Mohammad Kazem Aghamir -Show fewer authors BMC Nephrology volume 21, Article number: 5 (2020).
2 Scott DM, Ehrmann IE, Ellis PS, Chandler PR, Simpson E. Why do some females reject males? The molecular basis for male-specific graft rejection. J Mol Med. 1997;75:103–14.
In patients who are HLA matched transplantation, microhistocompatibility antigens are targeted for alloimmunity .
What is mHA
-peptides – represented in HLA Class 1 and 2
-to elicit an adaptive response
-encode in Y chromosome
-H-Y – highly expressed in whole body and show a great similarity to homologous H-X located on X chromosomes
-important – significant immunologic targets with clinical consequences in donor graft or the recipient sex-mismatched
H-Y alloimmunity in KT
-Even in HLA matched KT, significant levels of graft rejection occurs
-Terasaki found that 38% of kidney failure due to non-HLA immunologenic factors
Sex-mismatched KT and graft rejection
-Female host lymphocytes recognise mHA such as H-Y proteins in the male graft as foreign
-this mechanism leads to decreased engraftment and increased in graft rejection
-Male to Female (M -> F) KT involves transfer of an immune system target (kidney graft) from the male host to female recipient but opposed to F-> M in which functional immune system from female(donor) to male (recipient)- so higher rate of graft rejection in M->F
-alloimmunity against mHA ( H-Y) may be major cause of rejection
Reference
Rakesh Popli et al 2014-Clinical impact of H-Y alloimmunity
–H-Y antigens are a group of minor histocompatibility antigens on the Y chromosome with homologous H-X antigens on the X chromosome they are highly immunogenic with affection on graft survival on whom sex mismatched transplantation kidney grafts from male donors to female recipients have increased rates of graft rejection because female recipient*s lymphocytes develop an alloimmune response against H-Y on the donor graft.
Although H-Y is minor, it can still adversely affect the graft outcome. Theoretically , Yes because the female may develop antibodies against H-y antigen and this can lead poor outcome, but transplantation is not all about H-Y antigen. Females specially wives, they are usually sensitised during conception and receiving kidney from the the husband is increase chances of poor outcomes.
Even when a transplant donor and recipient are identical with regard to MHC genes, amino acid differences in these minor proteins can lead to rejection.
Minor antigens are encoded by a large number of chromosomes and are presented only as peptides in the context of recipient MHC (indirect allorecognition).
Minor antigens are responsible for the need for immunosuppression after donation between HLA-matched nonidentical twin siblings.
The prototypic minor histocompatibility antigen, the male or H-Y antigen, is derived from a group of proteins encoded on the Y chromosome.
Alloresponses to this antigen may explain reduced long-term graft survival observed in male-to-female donations. MHC I–related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity.
Exposure to allogeneic MICA during transplantation can elicit antibody formation.20 ABO blood groupglycolipids expressed on endothelial and red blood cells are other notable non-MHC antigens. immune responses to autoantigens have been associated with allograft damage.
The role of minor histocompatibility complex was 1st introduced in the context of bone marrow transplantation, when they noticed significant failure rates even among HLA matched Siblings, so they started searching human genom , of another polymorphic genes that could induce immune responses .
Minor antigens are responsible for the need immunosuppression after donation between HLA-matched nonidentical twin siblings
Because only amino acid differences in these minor histocompatibility antigens , can lead to immune responses .
differences in these peptides may arise from single nucleotide polymorphism in the coding region of genes, gene deletions, frameshift mutations, or insertions
The minor histocompatibility complex are
polymorphic self-peptides, which are presented at the cell surface of HLA molecule .
They are encoded either by Y chromosome or autosomal chromosomes .
The H-Y antigen which is encoded by the Y chromosome , is responsible for the reduced long term survival of graft donated from males to females .
They are recognized by CD8+ and CD4+ T cells ( after binding to antigen recognition sites of either class I or II major histocompatibility molecules ) .
Thus, minor histocompatibility antigens are capable of causing cell-mediated graft rejection.
MHC I–related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity.
Exposure to allogeneic MICA during transplantation can elicit antibody formation.
Examples of minor histocompatibility antigens include:-
HA-1/A2
HA-2
HA-8
HA-3
BCL2A1/ACC-1 and ACC-2
P2X5/P2RX5/LRH-1
1) Wallny HJ, Rammensee HG. Identification of classical minor histocompatibility antigen as cell-derived peptide. Nature 1990; 343: 275–278.
2) Linscheid C, Petroff MG (April 2013). “Minor histocompatibility antigens and the maternal immune response to the fetus during pregnancy”. American Journal of Reproductive Immunology. 69 (4): 304–14.
Ala Ali
Admin
3 years ago
Dear All, excellent start Please consider not mentioning these minor MHC only; the critical issue is how they are affecting transplant outcomes? This is the core question. Best Luck
Mohammed Sobair
3 years ago
Minor histocompatibility antigens are small peptides that are found on the cell surface in
association with class I or class II major histocompatibility complex (MHC) molecules. (1, 2).
The origin mHC antigen is not known but any single or multiple amino acid polymorphism
in protein can present as foreign antigen.
Minor histocompatibility antigen are weaker antigen but still can cause rejection in 30%
of patient with HSC transplantation
More than 100 mHC is found, 10 minor antigen located in autosomal chromosomes
being identified among the 100 mihc.(3)
Examples of minor HA Chromosome
HA -1 19
HA- 2 6
HA -8 9
HB- 1 5
HY- A 1 Y
HY- A 2 Y
HY -B 7 Y
HY –B8 Y
HY –B60 Y
HY-DQ5 Y
Others minor histocompatibility antigen antigen:
Anti-MICA Abs:
MHC I-related chain gene A (MICA) ,present in 7 % of transplant cases and associated
with delayed graft function and acute rejection(4).
.
Anti-Angiotensin II Type 1 Receptor (AT1R) Abs and Anti-Endothelin Receptor (ETAR) Abs:
I has being associated with acute rejection of kidney transplant.it augment AntiHLA in
reduce graft survival.
Anti-Perlecan (LG3) Abs:
Is associated with increased risk of vascular rejection in kidney transplant.
Anti-Collagen Abs and Anti-K-Alpha-Tubulin Abs:
The development of post-transplant Abs against Col-IV and fibronectin as well as anti-
HLA DSA were associated with Transplant glomerulopathy.
Anti-Vimentin Abs:
Anti-vimentin IgG Abs could play a role in patients developing IFTA and delayed graft
function.
HY antigen is known to cause rejection in male to female transplantation, due to
absence of Y chromosomes in female.
HA-2:
Cause GVHD mHC antigen.
Best approach to minor histocompatibility antigen identification relies on proteomic analysis using mass spectrometry.
Genome sequencing can help identification of coding single nucleotide polymorphisms
(SNPs) provide a reasonable estimation of minor histocompatibility antigens.
Reference:
1-Denis Claude Roy,Claude Perreault . Major vs minor histocompatibility antigens.
Blood (2017) 129 (6): 664–666.
3-Faculte de medecine de Genève, Minor histocompatibility Antigen, Jan. Transplant
immunology. Review, 21 Jan.201.
4-María Gutiérrez-Marcos López-Hoyos . Non-HLA Abs in Solid Organ Transplantation.
Crossmatching by Lymphocytotoxicity and Flow Cytometry .
Detection of soluble Ab.
DNA-Based Histocompatibilitytesting: ByPCR.
Mohamed Essmat
3 years ago
Minor histocompatibility antigens are the non-HLA antigens which are Non MHC antigens capable if inducing an immunological reaction. They can result in ABMR in absence of DSAs and chronic renal allograft nephropathy as well hence studying and understanding them was crucial. Many of these non-HLA antibodies are direted against endothelial or epithelial cells .
Examples include :
Angiotensin II type 1-receptor antibodies (anti-AT1R) Major Histocompatibility Complex class I chain-related molecule A (MICA) H-Y antigen Endothelin receptor type A (ETAR) Anti-endothelial cell antibodies (AECA)
Danovitch G.M handbook of kidney transplantation sixth edition Karl Womer, Hamid Rabb, in Comprehensive Clinical Nephrology (Fourth Edition), 2010 Tan JC, Wadia PP, Coram M, et al.H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation 2008; 86: 75
Mohamad Habli
3 years ago
Minor histocompatibility antigens (mHA) are diverse proteins from non-HLA antigen origin. m-HA are peptides/receptors on the cellular surface of kidney allograft that could be implicated in the development of immunological response in some organ transplants. This is because this receptor or protein is not found in the recipient and consequently will induce the immune response of the recipient to be activated. Although the mismatch will not induce potent reaction as with HLA mismatch but cumulative response could occur in the setting of multiple m-HA mismatches. Examples: H-Y antigen which is present only in males account for arounf 30 % of m-HA. This m-HA could induce immune response when transplanted into female recipients leading to shortening of the graft survival. Histocompatibility antigen 1(HA1) HA1 results from conversion of a nonimmunogenic allele into an immunogenic allele. This conversion results in better peptide binding ability to the groove of a particular MHC class I molecules found on antigen presenting cells. As a result, T cells can recognize the modified allele as foreign, leading to activation of immune response. Graft versus host immune response between HLA matched individuals is also an example to the role of m-HA in inducing rejection
Heba Wagdy
3 years ago
Minor histocompatibility antigens (mHA):
It refers to non-HLA antigens defined as “any non-MHC antigens encoded polymorphic proteins that is sufficiently antigenic to induce an immune response through indirect allorecognition by a T cell when transplanted into an individual with absent or altered gene expression” (1)
It is well studied in hematopoietic stem cell transplantation and has an effect on graft versus host disease & graft versus leukemia effect in HLA identical matches. (2)
mHA antibodies are classified into
alloantibodies (directed against polymorphic antigens different between recipient & donor)
autoantibodies (represent an immune response to self antigen) (3)
H-Y antigen:
polymorphic Y-chromosomal encoded proteins that act as mHA in gender mismatched transplantation,
humoral allograft immunity can target H-Y antigen (4)
Major Histocompatibility Complex class I chain-related molecule A (MICA)
highly polymorphic, alloantigen
not well determined as the pre transplant cross match is not sensitive enough to detect MICA DSA (5)
Anti endothelial cell antibodies (AECA)
most endothelial antigens are unknown
endothelial cell injury include complement mediated cell injury & endothelial cell activation. (6)
cell based cross match using endothelial cells showed that AECA was associated with higher rates of rejection (7)
Angiotensin II type 1-receptor antibodies (anti-AT1R):
associated with high risk of graft failure irrespective of HLA system with high prevalence of HTN & more vascular rejection with arterial inflamation (8)
anti-AT1R were associated with antibody mediated rejection in absence of DSA (9)
Endothelin receptor type A (ETAR)
G protien coupled receptor, also considered endothelial antigen
AT1r & ETAR are considered autoantibodies as they were detected in patients without transplant& associated with HTN, cardiovascular disease and preeclampsia (10)
(1) Reindl‐Schwaighofer, Roman, Andreas Heinzel, Guido A. Gualdoni, Laurent Mesnard, Frans HJ Claas, and Rainer Oberbauer. “Novel insights into non‐HLA alloimmunity in kidney transplantation.” Transplant International 33, no. 1 (2020): 5-17.
(2) Bertinetto FE, Dall’Omo AM, MazzolaGA, et al. Role of non-HLA geneticpolymorphisms in graft-versus-hostdisease after haematopoietic stem celltransplantation. Int J Immunogenet2006; 33: 375
(3) Danovitch G.M handbook of kidney transplantation sixth edition (4) Tan JC, Wadia PP, Coram M, et al.H-Y antibody development associateswith acute rejection in female patientswith male kidney transplants.Transplantation 2008; 86: 75
(5) Baranwal AK, Mehra NK. Majorhistocompatibility complex class Ichain-related A (MICA) molecules:relevance in solid organtransplantation. Front Immunol 2017;8: 182 (6) Dragun D, Catar R, Philippe A. Non-HLA antibodies against endothelialtargets bridging allo- andautoimmunity. Kidney Int 2016; 90:280 (7) Breimer ME, Rydberg L, Jackson AM,et al. Multicenter evaluation of a novelendothelial cell crossmatch test inkidney transplantation. Transplantation2009; 87: 549.
(8) Lefaucheur C, Viglietti D, Bouatou Y,et al. Non-HLA agonistic anti-angiotensin II type 1 receptorantibodies induce a distinctivephenotype of antibody-mediatedrejection in kidney transplantrecipients. Kidney Int 2019; 96: 189.
(9) Reinsmoen NL, Lai CH, Heidecke H, et al. Anti-angiotensin type 1receptor antibodies associated with antibody mediated rejection indonor HLA antibody negative patients. Transplantation 2010; 90:1473–1477.
(10) Philogene MC, Johnson T, Vaught AJ,Zakaria S, Fedarko N. Antibodiesagainst angiotensin II type 1 andendothelin A receptors: relevance andpathogenicity. Hum Immunol 2019; 80 :561.
Doaa Elwasly
3 years ago
Alloimmune response caused by Minor histocompatibility antigens (mHags) can cause graft rejection.
The mHags are polymorphic self-peptides, encoded by sex-linked or diallelic autosomal genes, presented by HLA molecules and recognized by HLA class I-restricted CD8+ or HLA class II-restricted CD4+ T cells.Different HLA alleles bind different repertoires of peptides. In renal graft rejection, mHag can be immunogenic if an HLA molecule that can bind to that specific mHag is present in the recipient (direct allorecognition)or donor (indirect allorecognition) serum (1)
MiHA vary even in monozygotic twins. The best known is the H-Y antigen, but there are also other autosomal miHA and MICA. Incompatibility of H-Y antigen as a risk factor in kidney transplantation is the most significant finding in the studies done(2)
Two articles opposing each others on the role of mHags in renal transplantation were published. Cai et al. identified the association of CD8+ memory regulatory and effector T cells specific for HA-1 in renal transplant recipients who had developed graft tolerance and on the other hand , Krishnan et al. detected an important corelation between HA-1 mismatch and chronic kidney rejection. (1)
1-Heinold A.etal , Role of Minor Histocompatibility Antigens in Renal Transplantaion, American journal of transplantation,2008 .8,92-102.
2-M A Pabón MA et al. Minor histocompatibility antigens as risk factor for poor prognosis in kidney transplantation.Transplant Pro2011 Nov;43(9):3319-23.
Thank you Doaa I’ll quit your sentence ” Two articles opposing each others on the role of mHags in renal transplantation were published. Cai et al. identified the association of CD8+ memory regulatory and effector T cells specific for HA-1 in renal transplant recipients who had developed graft tolerance and on the other hand , Krishnan et al. detected an important corelation between HA-1 mismatch and chronic kidney rejection. (1)”
This needs to be rephrased in a more clear way. Both the references dated more than 10 years. Please check
Last edited 3 years ago by Ala Ali
Ahmed Faisal
3 years ago
The donor specific antibodies (DSAs), which are anti-HLA antibodies, are the major cause of most case of antibody-mediated rejection (ABMR) —–> (ABMR h DSA pos)
However, many cases of ABMR are diagnosed without presence of DSAs, which explained by identification of non-HLA antibodies ——> (ABMR h DSA neg).
And this also gives explanation for graft rejection and failure from HLA- matched identical donors and among HLA-matched monozygotic twin siblings.
Therefore, many recent researches and evidences that confirm that minor histocompatibility complex, which may be refered as non-HLA antigens, is an important player in immunology of kidney transplantation.
Examples
• H-Y antigen (male to female donations).
• MHC Class I Polypeptide-Related Sequence A (MICA)
• Antibodies against autoantigens like angiotensin II type 1 receptor (AT1R-Ab), endothelin-1 type A receptor (ETAR-Ab),
☆ Reference
• Crespo M, Llinàs-Mallol L, Redondo-Pachón D, Butler C, Gimeno J, Pérez-Sáez MJ, Burballa C, Buxeda A, Arias-Cabrales C, Folgueiras M, Sanz-Ureña S, Valenzuela NM, Reed EF and Pascual J (2021) Non-HLA Antibodies and Epitope Mismatches in Kidney Transplant Recipients With Histological Antibody-Mediated Rejection. Front. Immunol. 12:703457. doi: 10.3389/fimmu.2021.703457
• Etta PK, Madhavi T, Parikh N. Pathobiology of non‑HLA immunity in renal transplantation. Indian J Transplant 2021;15:147‑56.
Last edited 3 years ago by Ahmed Faisal
MOHAMMED GAFAR medi913911@gmail.com
3 years ago
acute and chronic allograft rejection can occur in HLA identical silblings, transplantion implicating the importnance of immune responce aganist non HLA targets
Many of these non-HLA antibodies are directed against endothelial or epithelial cells and represent a heterogeneous group of antibodies comprising both IgM and IgG subclasses. These non-HLA antibodies are classified as either alloantibodies such as MICA or tissue-specific autoantibodies depending on whether they are directed against polymorphic antigens that differ between the host and donor, or if they represent an immune response to a self-antigen.
Antibodies specific for alloantigens such as MICA and autoantigens such as agrin, angiotensin II type I receptor (AT1R) have been implicated in acute and/or chronic renal allograft injury.
Known non-HLA targets such as AT1R antibody can be measured using ELISA assays, while cell-based crossmatch assays using endothelial cells can be used to identify non-HLA antibodies in the sera of transplant recipients.
Advantages include the ability to detect antibodies specific for novel antigens, in particular, polymorphic antigens, which may differ between cell donors.
However, incomplete knowledge of the non-HLA targets make it diifucult understanding of the clinical significance of the assay
Organs transplanted between HLA-matched individuals are not safe from rejection because any protein that is present in the graft but not in the recipient will behave as a foreign transplantation antigen. Non-HLA transplantation antigens are called Minor histocompatibility antigens(mHA). They are normal proteins that are themselves polymorphic in a given population and it bound to MHC class I and class II protein. mHA is encoded by a large number of chromosomes.
The male H-Y antigen is derived from a group of proteins encoded on the Y chromosome and associated with reduced long-term graft survival observed in male to female donations. MHC I-related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity. During transplantation MICA, can lead to antibodies formation. ABO blood group glycolipids are mHA.
The single mHA is not potent to induce immune response but commonly many mHA mismatches exist between donor and recipient, the cumulative Anti-mHA is significant that can lead to graft damage. References
1.Karl Womer, Hamid Rabb, in Comprehensive Clinical Nephrology (Fourth Edition), 2010
2.Danovitch G.M handbook of kidney transplantation sixth edition.
Esmat MD
3 years ago
Even organ transplantation between HLA-matched individuals such as two haplotype siblings is not sufficiently safe from rejection because any proteins expressed by allograft and not the recipient, behave as foreign antigen and induce alloreactivity those called minor histocompatibility antigens.
Although these minor histocompatibility antigens (mHA) don’t induce an alloreactive response as much as HLA disparity, since many mHA antigens exist, cumulate response to these antigens can be significant and important.
These minor antigens are recognized by T cells (most often by CD8-positive cytotoxic T cells) in the context of self MHC (such as indirect allorecognition)
Minor antigens are derived from polymorphic cellular proteins that are bound to MHC class I of recipient. Possibly these antigens are derived autosomally and represent polymorphism among autosomal proteins and enzymes.
One of the specific and important mHA is H-Y antigen that is presented only in males, so in donation of males’ kidney allografts to female recipients it may have a negative influence on graft survival. Another noticeable mHA antigens are polymorphic mitochondrial proteins.
MICHAEL Farag
3 years ago
Minor histocompatibility antigens (mHAs) can be any polymorphic gene product encoded outside the MHC that differs between donor and recipient and that can stimulate a T-cell response
Minor histocompatibility antigens are normal proteins that are polymorphic within a given species. Even when a transplant donor and recipient are identical with regard to MHC genes, amino acid differences in these minor proteins can lead to rejection. Minor antigens are encoded by a large number of chromosomes and are presented only as peptides in the context of recipient MHC (indirect allorecognition). Minor antigens are responsible for the need for immunosuppression after donation between HLA matched but nonidentical twin siblings. The prototypic minor histocompatibility antigen, the male or H-Y antigen, is derived from a group of proteins encoded on the Y chromosome. Alloresponses to this antigen are responsible for rejection of male mouse skin grafts by otherwise identical female recipients and may explain observations of reduced long-term graft survival in human male-to-female donations.
Dear All Thank you for your replies. Well done. I will wait for more colleagues to participate. This topic has a very important clinical significance which will be addressed later
Sherif Yusuf
3 years ago
Major histocompatibility antigens are antigens encoded by MHC genes, they have antigen binding sites on its surface that enable binding to forgin peptide protein (either endogenous intracelluller in class I or exogenous extracellular in class II) that is to present it either to CD8- cytotoxic T cells (HLA class I) or to CD4 hellper Tcells (HLA class II)
It was found that these antigen binding sites are occupied by small sized endogenous peptides these are known as minor histocompatibility antigens (MiHA).
Evidence
1- Rejection can occur between HLA matched non identical twins without immunosuppression
2- Male has H-Y antigens derived from gene on Y chromosome which constitute MiHA present in male, thus it was found that graft survival is lower when donor is male and recipient is female.
REFERANCES
1- Zou Y, Stastny P, Süsal C, et al. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med 2007; 357:1293.
MiHA are related to HLA class I so when recognized as a foreign immune response develop (CD8 T cell- mediated), but chronic low level stimulation of TCR may lead to tolerance by production of regulatory T cells.
Riham Marzouk
3 years ago
Minor histocompatibility is still in early phase of recognition in the research.
Major histocompatibility is critical in organ transplantation, but minor histocompatibility system also affects graft outcome and survival, as graft of HLA identical siblings can be rejected and lost, this denotes that there is other histocompatibility antigens sensitization.
Minor histocompatibility antigens are responsible of delayed or chronic or slow rejection of the graft.
J. Michael Cecka. Significance of histocompatibility in organ transplantation. Current Opinion in Organ Transplantation 2007, 12:402–408.
Karl Womer, Hamid Rabb, Immunologic Principles in Kidney Transplantation. Comprehensive Clinical Nephrology 2010 4th ed.
Huda Al-Taee
3 years ago
The term minor histocompatibility antigen is used to refer to non-HLA antigens. They are defined as any non-MHC encoded polymorphic protein that is sufficiently antigenic to induce immune response through indirect allorecognition by T cells when transplanted to an individual with absent or altered gene expression.1
The occurrence of ABMR in HLA identical kidney transplantation highlights the importance of non-HLA antigens in allorecognition. Studies showed that around 38% of graft loss could be due to non-HLA antigens while only 18% were due to HLA antigens. Other studies concluded that non-HLA alloimmunity associated with chronic allograft loss.1
Antibodies to the following non-HLA antigens have been associated with graft dysfunction or rejection (Even though the detection of many non-HLA antigens remains elusive):2
Major histocompatibility complex class I chain related gene A( MICA)
HY antigen
Angiotensine II type I receptor
Endothelin type A receptor
Heat shock protein
Phospholipid
K-α- tubulin
Vimentin
Endothelial cell antigen
References:
Reindl-Schwaighofer R., Heinzel A., Gualdoni G.A., Mesnard L., et al. Novel insights into non-HLA alloimmunity in kidney transplantation. Transplant International 2020; 33: 5–17.
Zhang X., Reinsmoen N.L. Impact of Non-Human Leukocyte Antigen specific Antibodies in Kidney and Heart Transplantation. Frontiers in Immunology, 2017, April,Vol. 8, article 434.
Thank you, Huda, for mentioning the effect on graft loss after ABMR.
The idea is not to know the presence or absence of Non-HLA antibodies BUT how they affect the transplant outcome. Excellent citation for reference 1 Transplant International 2020; 33: 5–17.
Even transplants between HLA-identical siblings result in progressive graft loss, characterized by a 10-year death-censored graft survival rate of 82.5% according to the data of the Collaborative Transplant Study (CTS) . Terasaki deduced that 38% of graft failures are due to non-HLA factors, 18% to HLA factors and 43% to nonimmunologic factors .
Incompatibilities for the mHags HA-1 , HA-2 , HA-3 , HA-8 , HB-1 , ACC-1 and UGT2B17 had no statistically significant effect on graft survival.
Disparities for the mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1 or UGT2B17 did not significantly influence graft survival in deceased donor transplants.
Role of Minor Histocompatibility Antigens in Renal Transplantation
A. Heinold et al
H-Y antigens are encoded by genes on the Y chromosome. Both HLA class I and II alleles have been found to present these antigens. Some of these antigens are ubiquitously expressed in nucleated male cells, and the presence of these antigens has been associated with a greater risk of developing GVHD allogeneic stem cell transplantation for a HLA matched gene when there’s a male recipient and female donor.
Compared with all other combinations of sex, transplantation of male donor kidneys into female recipients was associated with an increased risk of graft failure during the first year and between 2 and 10 years.
H-Y minor histocompatibility affects human kidney transplantation.
H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study
Alois Gratwohl et al
The minor histocompatibility complex are polymorphic and are presented at the cell surface association with class I or class II major histocompatibility complex (MHC) molecules
It may be encoded either by Y chromosome or autosomal chromosomes and are recognized by CD8+ and CD4+ T cells.
An example of mHC : HY antigen is responsible for the reduced graft survival especially graft donated from males to females , and it is encoded by the Y chromosome .
Thus, minor histocompatibility antigens are capable of causing cell-mediated graft rejection.
in dizygotic twins with zero major HLA mismatch and so they still need to receive immune suppression medications
Other examples of minor histocompatibility antigens include:-
HA-1/A2
HA-2
HA-8
HA-3
BCL2A1/ACC-1 and ACC-2
P2X5/P2RX5/LRH-
Minor histocompatibility antigens are normal proteins that are themselves polymorphic in a given population. Even when a transplant donor and recipient are identical with regard to MHC genes, amino acid differences in these minor proteins can lead to rejection.
Minor antigens are responsible for the need for immunosuppression after donation between HLA-matched nonidentical twin siblings. The minor histocompatibility antigen HY is associated with acute rejection.Male grafts in female recipients have reduced graft survival .
Examples;
1-The male or H-Y antigen, is derived from a group of proteins encoded on the Y chromosome. Alloresponses to this antigen may explain reduced long-term graft survival observed in male-to-female donations.
2- MHC I–related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity. Exposure to allogeneic MICA during transplantation can elicit antibody formation.
3- ABO blood group glycolipids expressed on endothelial and red blood cells are other notable non-MHC antigens.
Reference ;
Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer .
-Karl Womer, Hamid Rabb, in Comprehensive Clinical Nephrology (Fourth Edition), 2010
Minor histocompatibility antigens are small peptides occupying antigen binding sites of MHC molecules of he donor. They are recognized by CD8+ cytotoxic T cells leading to allograft rejection.
Examples are MHC class I -related chain A and MHC class I-related chain B .They are expressed on endothelial cells. Antibodies against them cause ABMR.2 haplotype matched siblings (fraternal twins or non-twin siblings )require small dose IS due to difference in minor histocompatibility antigens. They do no not engage T cell receptors.
Minor histocompatibility antigens are non-HLA antigens or any non-MHC encoded polymorphic proteins that can induce immune response via indirect recognition by T cells when transplanted to a recipient with absent or altered gene expression.
If transplant donor and recipient are identical with regard to HLA, amino acid differences in these minor proteins can lead to antibody mediated rejection.
It was found that 38% of graft loss could be due to non-HLA antigens which are responsible for chronic graft loss in other studies.
Examples for Non-HLA antigens of clinical significance:
1- HY antigen: is derived from a group of proteins encoded on the Y chromosome. Alloresponses to this antigen may explain reduced long-term graft survival observed in male-to-female donations.
2- Angiotensine II type I receptor: associated with high graft failure risk, Hypertension, and arterial inflammation.
3- Endothelin type A receptor: associated with hypertension, cardiovascular disease and preeclampsia.
4- Heat shock protein.
5- Endothelial cell antigen: leads to complement mediated cell injury and endothelial cell activation, antibodies against this receptor are associated with higher rejection rate.
6- Major histocompatibility complex class I chain related gene A(MICA): are surface glycoproteins with functions related to innate immunity. Exposure to allogeneic MICA during transplantation can elicit antibody formation.
References:
Reindl-Schwaighofer R., Heinzel A., Gualdoni G.A., Mesnard L., et al. Novel insights into non-HLA alloimmunity in kidney transplantation. Transplant International 2020; 33: 5–17.
Zhang X., Reinsmoen N.L. Impact of Non-Human Leukocyte Antigen Specific Antibodies in Kidney and Heart Transplantation. Frontiers in Immunology, 2017, April,Vol. 8, article 434.
Minor histocompitability AG are normal proteins that are themselves polymorphic in a given population
we can say it is a sub types of MHC major histocompitability,may donor &recipient have identical MHC genes but amino acids differences in these minor proteins can lead to rejection.
For example, the sex-specific antigen H-Y in males may cause rejection of male organs or bone marrow grafts by MHC-identical female recipients. The epitope of the H-Y antigen has been mapped to an 11-residue peptide located near one end of the protein encoded by the conserved Y-chromosome gene SMCY, which is homologous to the SMCX gene on the X chromosome. Identical results have been reported for the mouse H-Y antigen.
mHA (minor histocomaptibility antgens) include alloantigens which have various expression and are polymorphic. They account for the rejection in HLA identical transplants. They are peptides on the cell surface which develop immune response by indirect allorecognition by T cells. They are different from the non HLA antigens like MICA, AT1R antigen, ETR antigen. 2 such antigens are reported.
Other studies also mention non HLA antigens as also included in the Minor Histocomaptibility antigens.
References:
Minor histocompatibility complex are those genes that encodes antigens other than that of the major histocompatibility antigens. It is less important but still relevant to transplantation and can adversely affect graft survival. This could be one of the reasons we still use immunosuppression in non identical twins. The common example is H-Y antigen
Minor histocompatibility antigens are normal polymorphic proteins encoded by a large number of chromosomes presented only as peptides which can lead to rejection Even in identical HLA matching groups causing (indirect allorecognition).
Minor antigens are responsible for the need for immunosuppression in HLA –matched non identical twins after donation.
Types of minor histocompatibility antigens:,
1- the male or H-Y antigen, is derived from Y chromosome. Alloresponses to this antigen may explain reduced long-term graft survival between male-to-female donations. It showed that H-Y antigen responsible for third of graft rejections in male donor to female recipient
2- MHC I–related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity causing allograft damage.. Exposure to allogeneic MICA during transplantation can elicit antibody formation.20 ABO blood group glycolipids expressed on endothelial and red blood cells are other notable non-MHC antigens.
Minor histocompatibility complex showed some relationship ABMR in negative DSA.
References:
Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Org Transpl 2009;14:419-425.
Pfeffer PF, Thorsby E. HLA-restricted cytotoxicity against male-
specific (H-Y) antigen after acute rejection of an HLA-identical sib-
ling kidney: Clonal distribution of the cytotoxic cells. Transplanta-
tion 1982; 33: 52–56.
●Definition
Minor histocompatibility ..they are receptors on the cellular surface of donated organs that are known to give an immunological response in some organ transplants.They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides . These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene
deletions, frameshift mutations, or insertions.About a third of the characterized MiHAs come from the Y chromosome.[4] The proteins are composed of a single immunogenic HLA allele . Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules’s antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities’ proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.
●H Y antigens?
antigens are encoded by genes on the Y chromosome. Both HLA class I and II alleles have been found to present these antigens. Some of these antigens are expressed in nucleated male cells, and the presence of these antigens has been associated with a greater risk of developing GVHD allogeneic stem cell transplantation for a HLA matched gene when there’s a male recipient and female donor. To clarify our point here , in pregnancy H-Y MiHA play a role in pregnancy with a male fetus because fetal cells can cross from the placenta into the maternal blood stream where the maternal T cells respond to the foreign antigen presented on both MHC class I and II. Therefore, H-Y specific CD8+ T cells develop in the maternal blood and can target the fetal cells with nucleus expressing the antigen on a MHC class I molecule. The response to these fetal H-Y antigens are involved with women experiencing secondary recurrent miscarriage who were previously pregnant with a male fetus.Women with an earlier male pregnancy have T cells which were previously exposed to these H-Y antigens, and consequently recognize them quicker. It has been found that women with recurrent miscarriage also contain MHC II with ability to present these antigens to T helper cells (CD4+) which is significant for CD8+ activation.
To sum up Minor histocompatibility has a role in acute rejection in positive cross matching .
●references
1. Robertson NJ, Chai JG, Millrain M, Scott D, Hashim F, Manktelow E, Lemonnier F, Simpson E, Dyson J (March 2007). “Natural regulation of immunity to minor histocompatibility antigens”. Journal of Immunology.
2.Hirayama M, Azuma E, Komada Y (2012). Major and Minor Histocompatibility Antigens to Non-Inherited Maternal Antigens (NIMA), Histocompatibility.
Even HLA- identical siblings have 10 year graft survival rate of 82.5% and it was hypothesized that minor histocompability antigens(mHags) could induce rejection. The mHags are polymorphic self-peptides which are presented at the surface of cells by HLA molecules and are recognized by T cells. Their mismatches are not as potent as HLA-mismatches but can have a cumulative response in case of many mHA mismatches.
H-Y antigene is one of them that received attention in kidney transplantations from male donors to female recipient and causes adverse effects on these transplants. Another one are polymorphic mitochondrial proteins.
Other examples are: HA-1, HA-2, HA-3, HA-8, HB-1 and ACC-1.
References:
1. Heinold A, Opelz G, Scherer S, Ruhenstroth A, Laux G, Doehler B, Tran TH. Role of minor histocompatibility antigens in renal transplantation. Am J Transplant. 2008 Jan;8(1):95-102.
2. Locke, J. E. (2018). Handbook of Kidney Transplantation. Sixth Edition. G. M. Danovitch (Editor) Wolters Kluwar, 2017.
Minor Histocompatibility Antigens
Rejection still can occur even organs transplanted between HLA-matched individuals.
Although the highest degree of genetic polymorphism within a species lies within MHC, many other loci encode proteins with a lower degree variability that can act as transplantation antigen -miH antigen
Single miHA mismatch is not potent enough to stimulate alloimmunity but cumulative anti-miHA ( as many disparities might happen in between donor and recipient) respond can cause significant harm
This probably explains the occurrence of rejection but not significant graft loss in HLA identical siblings
H-Y antigen has been suggested possibly compromises the survival of male renal allograft
Polymorphic mitochondrial proteins – another example of MiHA after H-Y antigen that can trigger alloimmunity in which its relevant proven in transplanting -induced pluripotent stem (iPS)cells
Examples of other miHA
HA-1,LRH-1,LB-EBI3-1,HB-1,ACC-2,ACC-1,ACC-6,HA-2,HA-1/B60,LB-ITGB2-1
References
hand book of kidney transplantation -gabriel danovich
kidney transplantation: principles and practice – Stuart j Knechtle
Minor histocompatibility (H) antigens are T-cell epitopes, acquired from polymorphic proteins. These peptides are presented by various histocompatibility complex (MHC) class I and II molecules. Minor histocompatibility antigens are expressed on a wide variety of cell types and tissues>
The MHC/minor H peptide complexes can be a barrier to transplantation.
They are encoded by polymorphic genes on autosomal chromosomes, their transcription produces proteins with different amino-acid sequences in recipient and donor. These polymorphic peptides end up in the groove of HLA molecules, minor H antigen-specific cells (T-cell receptors) can recognize these differences after transplantation and evoke alloimmune reactivity. 54 minor H antigens have been identified.
The nonsynonymous single nucleotide polymorphism (SNP) is the most common form of genetic polymorphism leading to minor H antigen. Ex; minor antigen HA-1 and HA-2.
SNPs can lead to the introduction of a stop codon instead of an altered amino acid or to changes in intron splicing.
H-antigen polymorphisms may also produce from the absence of a complete gene, or copy-number variation (CNV).
Deletion-insertion polymorphism (DIPs) may also lead to minor H antigens ex; LRH-1
v The T-cell response to minor H-Ag is based on the absence of the immunogenic allele in the donor T-cell and the presence of the immunogenic allele in the targeted individual. (In the target individual, HLA restriction molecule that presents the minor H peptide, should be present, as well, in the T-cell donor in order for the response to occur).
Example: HA-3 responses are only generated against the HA-3T minor H peptide when presented in HLA-A1. This means; this minor H antigen can only play a role in one immunogenic HA-3T allele on its chromosome 15 and the donor is homozygous for the HA-3M allele.
Minor H-Ag-specific T-cell response is related to CD8+cytotoxic T- lymphocytes (CTL) and CD4+ T-helper cells. In addition, minor H antigen disparity can lead to induction of Treg which is observed after kidney transplantation.
There is disagreement and limited information about the role of minor H antigen mismatch in graft survival. Some show no effect, while others show the correlation between HY mismatch and the outcome of kidney transplantation, that explained by antibodies mediated response rather than CTL response in graft rejection.
Female recipients of male kidneys more frequently show HY antibody development after transplantation than other gender combinations.
RPS4Y1 is the most commonly known antigen, which is an HY antigen against which CD4 positive, HLA class II-restricted.
In summary: when addressing the role of minor H antigens in organ transplantation, a focus on antibodies and HLA class ii-restricted T-helper epitopes might be preferred to the analysis of HLA class I-restricted CTL epitopes. (1)
Reference:
1. Spierings E. Minor histocompatibility antigens : past , present , and future. :13–7.
What is the effect of minor histocompatibility complex on graft survival?
Minor histocompatibility complex antigens are non-HLA polymorphic cellular proteins bound to MHC class1 of the recipient, can trigger rejection in HLA matched non identical twin sibling, therefore they need to continue on IS therapy, by principle any change in amino acid sequence in these minor proteins can trigger rejection.
with the improvement of our understanding of the molecular DNA -genetic testing for MHC antigens over years with the identification of more number of such minor MHC antigens which encoded by the Y chromosome in male which may cause rejection in male -female donation or bone marrow grafts by MHC-identical female recipients, another possibility that the peptide may be autosomal derived and represents polymorphisms among autosomal proteins or enzymes .we don’t have systematic studies in human to address their contribution to the human kidney transplant .
the mechanism of the allogenic response to this type of minor MHC antigens is similar to the response to microbial antigens in that host, like the minor -MHC -class1 related chain A (MICA) antigen which structurally similar to MHC Class1 antigen it can be expressed on different cells including monocytes epithelial and endothelial cell and can trigger the antibodies production and worsening graft survival.
these peptides recognized by cytotoxic T-cells, at the level of CD8, based on the animal studies in mouse model slight modification of such minor antigen result in the production of regulatory T Cells receptor (RTC) that can induce tolerance, Recently, Ca-et al, found coexisting CD8+memory regulatory and effector T-cells, both specific for the same HA-1 antigen, in renal transplant recipients who had apparently developed
graft tolerance (4), In contrast, Kr-ishnan et al. (5) found a significant association between
HA-1 mismatch and chronic kidney rejection, we need more studies to elaborate more about the definite roles of the Minor MHC petites in human kidney transplant and its possible therapeutic impact by inducing tolerance
Reference
1-Comprehensive Clinical Nephrology (Fourth Edition), 2010
2-handbook of kidney transplant, fifth edition, Gabril M.Danovitch
3- up to date, transplant immunology, minor MHC antigens in kidney transplant .
4-Role of Minor Histocompatibility Antigens in Renal Transplantation
A. Heinold,G. Opelz,S. Scherer,A. Ruhenstroth,G. Laux,B. Doehler,T. H. Tran
5-Krishnan NS, Higgins RM, Lam FT et al. HA-1 mismatch has significant effect in chronic allograft nephropathy in clinical renal transplantation. Transplant Proc 2007; 39: 1439– 1445.
The minor histocompatibility antigens (mHags) are polymorphic cell-derived self-peptides, encoded by sex-linked (Y-chromosomally encoded) or diallelic autosomal genes, which are presented at the cell surface by HLA molecules and recognized by alloreactive HLA class I-restricted CD8+ or HLA class II-restricted CD4+ T cells.
In the context of kidney graft rejection, mHag can only display its immunogenicity if an HLA molecule that is able to bind this mHag is present in the recipient (direct allorecognition, the mHag is presented by recipient antigen-presenting cells [APCs]) or donor (indirect allorecognition, the mHag is presented by donor passenger APCs within the graft).
In hematopoietic stem cell transplantation (HSCT), HLA-matched but mHag-mismatched transplants show increased rates of graft-versus-host disease (GVHD) and graft rejection.
In retrospective study, they selected HLA-A, -B and -DRB1 (two-digit) matched recipient/donor pairs of Caucasian origin in order to reduce the effect of HLA mismatches which may mask an impact of mHags. In addition, this selection criterion assures that recipient and donor both express the mHag-presenting HLA molecule; this allows the evaluation of a potential effect of both antigen recognition pathways (indirect and direct). They analysed only first transplants to reduce effects of sensitization. Out of 33 785 kidney transplants on which DNA and clinical data was available, only 702 transplants fulfilled the criteria: sufficient DNA available for mHag typing, first transplant, Caucasian origin, matched for HLA-A, -B and -DRB1
In summary, they found no significant effect of incompatibility for the mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1 or UGT2B17 on allograft survival in HLA-A, -B and -DRB1 matched first kidney transplants.
Results indicate that typing of mHags provides no useful information for predicting 5-year graft outcome in kidney transplantation.
Role of Minor Histocompatibility Antigens in Renal Transplantation
A. Heinold,G. Opelz,S. Scherer,A. Ruhenstroth,G. Laux,B. Doehler,T. H. Tran
Minor histocompatibility antigens(MiHA) are :
Minor histocompatibility antigens(MiHA):
Effect of minor histocompatibility Ag (MiHA)on graft survival :
Lancet. 2008 Jul 5;372(9632):49-53. doi:10.1016/S01406736(08)60992-7.
H-Y as a minor histocompatibility antigen in kidney transplantation:
a retrospective cohort study
Alois Gratwohl 1, Bernd Döhler, Martin Stern, Gerhard Opelz
(Stem Cells Dev. 2020 Sep 15;29(18):11791189.doi:10.1089/scd.2019.0299. Epub 2020 Aug 25.The H-Y Antigen in Embryonic Stem Cells Causes Rejection in Syngeneic Female Recipients)
Comparative Study Am J Physiol Renal Physiol. 2017 Aug 1;313(2):F326-F338. doi: 10.1152/ajprenal.00039.2017. Epub 2017 May 17
Cross-sex transplantation alters gene expression and enhances inflammatory response in the transplanted kidneys
Comparative Study Am J Transplant.
2008 Jan;8(1):95-102. doi: 10.1111/j.1600-6143.2007.02042.x. Epub 2007 Dec 18.
Role of minor histocompatibility antigens in renal transplantation
A Heinold 1, G Opelz, S Scherer, A Ruhenstroth, G Laux, B Doehler, T H Tran
The occurance of rejection in recipient of HLA matched grafts had lead to the discovery of antigens , they call it minor HLA or non HLA antigens. These antigens had lower effect on graft survival when compared with major HLA but can induce graft rejection.
MICA antigens ( MHC I related A) : MICA antigen is present on the surface of endothelium , monocytes and keratinocytes , it’s not present on the lymphocytes , so flow cross match will not be positive even if the recipient had anti MICA antibodies.
Different studies assessed the effect of presence of anti MICA antibodies on graft survival with different results .
Anti Angiotensin II Type I Receptor antibodies (AT1R ):
Many studies showed that the presence of aanti AT1R antibodies is associated increased rate of ABMR and transplant glomerulopathy and anti major HLA antibodies and poor graft survival.
Anti Perlecan (LG3) antibodies:
The heparin sulfate proteoglycan (perlecan) had C terminal domain called LG3, and antibodies to this protien had been opserved as a cause of ABMR and poor graft survival by many studies.
H-Y antibodies :
H-Y antigen genes are genes located on chromosome Y . these antigens explains the slightly lower graft survival in female recipient of male donor kidneys.
There are many other antigen implicated in the ABMR like Vimentin Ag, Collagen 4 Ag, fibronectin .
Reference:
María Gutiérrez-Larrañaga, Marcos López-Hoyos , André Renaldo and David San Segundo Non-HLA Abs in Solid Organ Transplantation
Transplantology 2020, 1, 24–41; doi:10.3390/transplantology1010003
Minor Transplantation Antigens
A minor histocompatibility antigen is molecularly defined as a donor-derived peptide presented on a donor cell by an MHC molecule shared by a donor and a recipient.
Studies involving MHC identical grafts in mice indicate that minor histocompatibility antigens can also mediate rejection.
Minor antigens are responsible for the need for immunosuppression after donation between HLA-matched nonidentical twin siblings.
Minor histocompatibility antigens are polymorphic peptides consisting of 9–12 amino acids. After binding to the antigen recognition site of either class I or class II HLA molecules present on a cell surface MiHAs can be recognized by T-lymphocytes. Thus the occurrence of MiHA depends on the presence of specific HLA antigens, which is called the MHC restriction. MiHAs are encoded by either autosomal chromosomes or by Y-chromosome (1).
Recipient T cells can be directly primed to minor histocompatibility antigens.
Donor dendritic cells (DCs) directly prime CD8+ T cells to become effector cells without the need for further antigen processing by recipient APCs.
research of the human genome revealed that polymorphism of nucleotides in genes that are non-HLA related (e.g., NOD2/CARD15 or genes encoding cytokines: TNF-alpha, IL-10, IL-6, interferon gamma, IL-1, and TGF-beta) may also determine the individual immunological phenotype of donor-recipient pairs, thus influencing GVHD, infections, and overall survival (2).
In humans, it has been recognized for several years that minor histocompatibility antigens can be immunogenic from observations based on organ graft rejections and bone marrow graft-versus-host reactions in cases of genetically matched HLA antigens.
Two general families of such antigens have been identified:
1.H-Y antigens are proteins encoded on the Y chromosome. Females of the species may mount an immune response against these proteins.
2.T cells recognize peptidic antigens corresponding to polymorphisms among autosomal proteins expressed by individuals of the species. Examples include mitochondrial proteins and enzymes. In the presence of both major and minor incompatibilities, it is clear that the alloimmune response targeted against the MHC molecules predominates.
Several studies reported a detrimental role for minor H antigen-specific T cells in graft survival. However, some data indicate that minor H antigens might also be clinically involved in preventing rejection of solid organ grafts, possibly by induction of regulatory T cells.
Knowledge of MiHA alleles and genotypes enables to detect their disparities, which could be helpful not only in optimal matching of a donor/recipient pair and in understanding transplant results, but also it may create a chance to the use of MiHA in immunotherapy aiming to improve patients’ survival (3).
REFERENCE
1 E. Spierings, B. Wieles, and E. Goulmy, “Minor histocompatibility antigens—big in tumour therapy,” Trends in Immunology, vol. 25, no. 2, pp. 56–60, 2004.
2 B. E. Shaw and A. Madrigal, “Immunogenetics of allogeneic HSCT,” in Haematopoietic Stem Cell Transplantation, ESH-EBMT Handbook, J. Apperley, E. Carreras, E. Gluckman, and T. Masszi, Eds., pp. 74–89, 2012.
3 A. Dickinson, “Biomarkers in acute and chronic GVHD,” in Graft -Versus-Host Disease, H. T. Greinix, Ed., pp. 17–31, Unimed Verlag AG, 2008.
Minor histocompatibility antigen (also known as MiHA) are receptors on the cellular surface of donated organs that are known to give an immunological response in some organ transplants.They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides . These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins.Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. The proteins are composed of a single immunogenic HLA allele . Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules’s antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities’ proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.
Minor histocompatibility antigens are due to normal proteins that are in themselves polymorphic in a given population. Even when a transplant donor and recipient are identical with respect to their major histocompatibility complex genes, the amino acid differences in minor proteins can cause the grafted tissue to be slowly rejected. Several of the identified Autosomally and Y chromosome encoded MiHAs
Minor histocompatibility antigens are normal proteins that are poly-
morphic within a given species. Even when a transplant donor and
recipient are identical with regard to MHC genes, amino acid differ-
ences in these minor proteins can lead to rejection. Minor antigens are
encoded by a large number of chromosomes and are presented only as
peptides in the context of recipient MHC (indirect allorecognition).
Minor antigens are responsible for the need for immunosuppression
after donation between HLA matched but nonidentical twin siblings.
The prototypic minor histocompatibility antigen, the male or H-Y
antigen, is derived from a group of proteins encoded on the Y chro-
mosome. Alloresponses to this antigen are responsible for rejection of
male mouse skin grafts by otherwise identical female recipients and
may explain observations of reduced long-term graft survival in human
male-to-female donations.
MHC I–related chain A (MICA) antigens are surface glycoproteins
with functions related to innate immunity. Exposure to allogeneic MICA
during transplantation can elicit antibody formation.19 ABO blood group
glycolipids expressed on endothelial and red blood cells are other notable
non-MHC antigens. Finally, immune responses to autoantigens have
been associated with allograft damage
Reff= Bates RL, Frampton G, Rose ML, et al. High diversity of non-human
leukocyte antigens in transplant-associated coronary artery disease.
Transplantation. 2003;75:1347–1350.
You need to elaborate more and to use more updated references
Minor histocompatibility antigens are polymorphic normal proteins that are encoded by large numbers of chromosomes.
Slow graft rejection may be related to a large number of these antigens once it’s detected by T cells even when both donor and recipient are identical, the differences in amino acid are responsible for this rejection making the needs of immunosuppression is mandatory.
minor HC complex is a structure of polypeptide on top of cell surface. they are the cause of graft dysfunction in kidney transplantation even if the MHC matching is good.
•••The Minor histocompatability antigens are polymorphic cell-derived self-peptides, encoded by sex-linked (Y-chromosomally encoded) or diallelic autosomal genes, which are presented at the cell surface by HLA molecules and recognized by alloreactive HLA class I-restricted CD8+ or HLA class II-restricted CD4+ T cells .Most autosomally encoded mHags arise from nonsynonymous single nucleotide polymorphisms (SNPs) which result in an amino acid exchange within an HLA-binding peptide. This could either alter the affinity of the peptide to the transporter protein (TAP, transporter associated with antigen processing) or to the presenting HLA molecule or, alternatively, lead to cleavage of the peptide by the proteasome.
•••It can be reasonably hypothesized that an alloimmune response evoked by minor histocompatibility antigens (mHags) might lead to graft rejection.
•••Even organs transplanted between HLA-matched individuals (for example, between two-haplotype matched siblings) are not safe from rejection. This is because any protein that is present in the graft but not the recipient, or that is sufficiently dis-similar (polymorphic) between the graft and the recipient, will behave as a foreign, transplantation antigen. Such non-HLA transplantation antigens are called minor histocompatibility antigens (mHA). A single mHA disparity is not as potent at inducing alloimmunity as a single HLA disparity (thus, the designation “minor”), but since many mHA mismatches exist between donors and recipients, the cumulative anti-mHA response is significant. A particular mHA that has garnered attention in transplantation is the H-Y antigen present only in males of the species. Clinical data suggest that it possibly compromises the survival of male renal allografts transplanted to female
recipients. The role of mHA in graft-versus-host disease is well established as the vast majority of hematopoietic stem cell transplants are performed between HLA-matched individuals, making the contribution of mHA more noticeable. Polymorphic mitochondrial proteins are another type of mHA that can trigger alloimmunity. This is
particularly relevant to transplanting-induced pluripotent stem (iPS) cells generated by nuclear transfer, wherein the nucleus is “self” but the mitochondria are foreign.
References:
~Hu M, Wang YM, Wang Y, et al. Regulatory T cells in kidney disease and transplantation. Kidney Int 2016;90:502-514.
~Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274-293.
~Liu Z, Fan H, Jiang S. CD4+ T-cell subsets in transplantation. Immunol Rev 2013;252:183-191.
Mori DN, Kreisel D, Fullerton JN, et al. ~Inflammatory triggers of acute rejection of organ allografts. Immunol Rev 2014;258:132-144.
~Murphy K, Weaver C. Janeways Immunobiology. 9th ed. New York: Garland Science; 2016.
~Oberbarnscheidt MH, Lakkis FG. Innate allorecognition. Immunol Rev 2014;258:145-149
~Opelz G for the Collaborative Transplant Study. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 2005; 365: 1570– 1576.
~Terasaki PI. Deduction of the fraction of immunologic and non-immunologic failure in cadaver donor transplants. In: JM Cecka, PI Terasaki, eds. Clinical transplants. Los Angeles , CA : UCLA Tissue Typing Laboratory, 2003: 449– 452.
Thanks Dr Amal
Minor histocompatibility antigens ( non -MHC polymorphic molecules) which are small peptides presented on MHC class l and MHC class ll with inter individual difference due to heterogenecity they are recognised by the recepient T cells by indirect pathway where donor-derived peptides loaded onto self-MHC molecules expressed by self-APCs, which lead to immune response
Mechanism is poorly understood, but some studies showed its ability to induce rejection in HLA identical donor and recipient not identical twins .
they mediate acute graft versus host disease in setting of HLA-matched allogeneic hemopoietic stem cell transplantation (HSCT).
Sánchez‐Fueyo, Alberto, and Francesco Dazzi. “On minor histocompatibility antigens, mixed chimerism, and transplantation tolerance.” (2021): 919-920.
Giesler S, Zeiser R. Deciphering the role of Minor histocompatibility antigens for acute graft-versus-host disease. Transplant Cell Ther. 2021 Jul;27(7):523-524.
Heinold A, Opelz G, Scherer S, Ruhenstroth A, Laux G, Doehler B, Tran TH. Role of minor histocompatibility antigens in renal transplantation. Am J Transplant. 2008 Jan;8(1):95-102.
Thanks Alyaa
minor histocompatibility antigens are many. It was found to adversely affect renal graft survival. one of the prototypes H-Y may be the reason for less survival of grafts donated to women from men as this is found in the Y chromosome. minor HLA antigens are more in number and more polymorphic but still less immunogenic. they are known to cause graft versus host disease as graft versus leukemia in bone marrow transplantation.
Major HLA are antigens encoded on short arm of chromosome 6 and get identified by immune system by direct,indirect and semidirect pathways
Minor HLA antigens are other proteins and receptors presented on the surface of the graft and usually not strongly stimulate immune system
It’s role still not clear but still play important role in rejection in dizygotic twins with zero major HLA mismatch and so they still need to receive immune suppression medications
One example of minor HLA is HY antigens which are encoded on Y chromosome and several studies showed that it was responsible for 30% rejection of graft from male donor to female recipient
Our center experience in screening for these circulating antibodies just if we have biopsy proven ABMR and we have negative DSA.
Always appear to be positive….and respond well to usual protocol of treatment of ABMR which usually consist of IVIG and plasma exchange(only if happened in first year post transplant)+rutiximab
But multiple questions here still not answered like
Do we need to respect it in matching?
Do we need to screen antibodies against it before and after transplant
Antibodies against it are they denovo or they already preformed pre-transplant?
Are they really the cause of rejection or there are other factors like epitopic mismatch , hormonal effect, or noncompliance
This topic need randomized control trials to be clinical applied in better way
But it should be kept in mind when we see a crime(ABMR) and we can’t find the criminal (DSA)
References:
1)Danovitch G.M handbook of kidney transplantation sixth edition
Karl Womer, Hamid Rabb, in Comprehensive Clinical Nephrology (Fourth Edition), 2010
Tan JC, Wadia PP, Coram M, et al.H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation 2008; 86: 75
2) Reindl-Schwaighofer R, Heinzel A, Gualdino GA, et al. Novel insights into non-HLA alloimmunity in kidney transplantation. Transplant Int 2020;33:5-17.
3) Terasaki PI. Deduction of the fraction of immunologic and nonimmunologic failure in cadaver donor transplants. Clin Transpl 2003:449-452.
4) Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Org Transpl 2009;14:419-425.
5) Heinold A, Opelz G, Scherer S, et al. Role of minor histocompatibilty antigens in renal transplantation. Am J Transpl 2008;8:95-102.
Minor HLA antigens are peptides composed of amino acids and bound to both class I and class ll major histocompatibility complex on the cell surface.
Even if the donor and recipient are identical regarding major histocompatibility complex, they will be different in minor HLA antigens, and this explain why we use immunosuppressive drugs in case of non identical twins.
Minor HLA antigens play a role in chronic allograft rejection.
Ref:
Minor Histocompatibility Antigen – an overview | ScienceDirect Topics
Minor histocompatibilty complex antigens (mHA) are peptides present over cell surface which develop immune response by indirect allorecognition by a T cell post transplant. (1) So even if someone gets a transplant with HLA matched organ, these minor histocompatibility antigens can cause immune mediated reactions leading to graft injury.
A number of mHA have been evaluated in organ transplants, especially in HLA matched transplants. The most important mHA is HY encoded antigen, which is encoded on the Y chromosome. In a study comparing HLA identical siblings for graft failure, 38% graft failure was due to non-HLA factors like mHA mismatch, MICA, ABO incompatibility etc. (2)
mHA impacting graft function include autosomally encoded as well as Y chromosome encoded antigens. Studies have shown that mHA A2/HY has been associated with decreased graft survival of male renal graft in female HLA-A2 recipients. HY based cytotoxicity was seen in HLA identical sibling renal transplants. Denovo HY antibody formation was associated with acute rejection. A2/HA-1 mismatch has been shown to be associated with chronic allograft nephropathy (but not with acute rejection). (3)
Another study by Heinold et al demonstrated that certain mHA mismatches (HA-1, HA-1, HA-3, HA-8, HB-1, ACC-1, UGT2B17) had no significant effect on death censored graft survival at 5 years. (4)
The importance of all these studies lie in the search for criteria to choose patients in whom immunosuppression can be stopped.
References:
1) Reindl-Schwaighofer R, Heinzel A, Gualdino GA, et al. Novel insights into non-HLA alloimmunity in kidney transplantation. Transplant Int 2020;33:5-17.
2) Terasaki PI. Deduction of the fraction of immunologic and nonimmunologic failure in cadaver donor transplants. Clin Transpl 2003:449-452.
3) Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Org Transpl 2009;14:419-425.
4) Heinold A, Opelz G, Scherer S, et al. Role of minor histocompatibilty antigens in renal transplantation. Am J Transpl 2008;8:95-102.
Minor histocompatibility antigens are normal proteins that are themselves polymorphic in a given population. During transplantation of a donor and a recipient with identical MHC genes, amino acid differences in these minor proteins can lead to rejection and are responsible for the need of immunosuppression after donation between HLA-matched non identical twin siblings.
In HLA-matched transplants, minor histocompatibility antigens (mHAs) are important targets for alloimmunity.
H-Y antigens provide an important model for alloimmunity because they serve as significant immunogenic targets with clinical consequences in either the donor graft or the recipient in sex-mismatched transplantation.
H-Y antigens are expressed only on tissues from male donors, and are therefore at risk of being recognized as foreign by female-but not male-recipients
Allo-responses to this antigen may explain reduced long-term survival of the graft observed in male-to-female donations
kidney grafts from male donors to female recipients experience increased rates of graft rejection. The rationale behind this increase in graft rejection is that the recipient’s lymphocytes develop an allo-immune response against the H-Y antigens present on the donor graft
Clinical impact of H-Y alloimmunity
Rakesh Popli, Bita Sahaf, Hideki Nakasone, Joyce Yeuk Yu Lee, and David B. Miklos
Immunol Res. 2014 May; 58(0): 249–258.
Novel insights into non-HLA alloimmunity in kidney transplantation.
Roman Reindl Schwaighofer,Andreas Heinzel,Guido A. Gualdoni,Laurent Mesnard,Frans H.J. Claas,Rainer Oberbauer
25 October 2019.Transplant International
miHA is “any non-MHC gene product which, when transplanted, is sufficiently antigenic to induce CD4and CD8T cells to trigger an immune response.” These peptides are derived from intracellular proteins and show polymorphisms among related and unrelated individuals. Thus even people with identical HLA phenotypes can experience immune rejection.
The role of non-HLA histocompatibility systems, such as minor histocompatibility antigens (miHA), albeit known many years ago, is still a mystery. miHA are polymorphic proteins that vary even in monozygotic twins. The best known is the H-Y antigen, but there are also other autosomal miHA and MICA (MHC class I chain-related gene A). miHA have been well studied in transplantation of hematopoietic precursors, but not in solid organ transplantation. The most important studies in this field relate to the incompatibility of H-Y antigen as a risk factor in kidney transplantation, although the findings are still inconclusive.
The minor histocompatibility antigen HY encoded in the Y chromosome is associated with acute rejection episodes and decreased transplant survival, specifically when a donor is a man and the recipient a woman.
References:
1. Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Organ Transplant. 2009 Aug;14(4):419-25.
2. Pabón MA, Navarro CE, Martin R, Rodríguez M, Martin I, Gaitán L, Gómez A, Lozano E. Minor histocompatibility antigens as risk factor for poor prognosis in kidney transplantation. Transplant Proc. 2011 Nov;43(9):3319-23.
3. Kumbala D, Zhang R. Essential concept of transplant immunology for clinical practice. World J Transplant. 2013 Dec 24;3(4):113-8.
Minor antigens
minor antigens are peptides protein recognized by CD8 positive T-cell (cytotoxic cell)and do not induce allo antibody responce and derived from polymorphic celular protein which is bound to MHC class I of recipient.
minor antigen are encoded by Y chromosome in male (H-Y)So This will induce an allo immune responce when male Kidney Transplanted to female recipient.so these antigens lead to decreased long term graft survival in male to female donation
minor antigens have important role in graft- versus-host disease and can cause allograft rejection even when transplant donner and recipient have identical MHC antigens and it’s responsible for using immune suppression drugs in HLA matched non identical twin transplantation
Reference
1-Transplantation immunobiology ,up to date 2021.
2- Womer K, Rabb H. Immunologic Principles in Kidney Transplantation
in Comprehensive Clinical Nephrology (Fourth Edition), 2010
We are looking for more replies.
The transplant between 2 haplotype matched are not protected from rejection because any protein can be present in the graft but not in the recipient can considered as transplant antigens which called minor histocompatible (mHA).
if just one mHA is incompatible it can not induce strong immune response, but if there are numerous antigens are mismatched the immunological response will be insignificant. mHA has important role in graft-versus-host disease. H-Y antigen is one of mHA that present only in male so a male donor carry this antigen & the recipient is female it will affect the graft survival. Another types of mHA :
REFERENCES:
Numerous mHA mismatch can cause significant immune response
Dear All
I was watching and reading your entries. There is a confusion between minor HLA and non-HLA. The good thing, many of you recently realised the difference. For example MICA and MICB are non-HLA, while H-Y is minor HLA.
Dear All
What is the effect of H-Y antigen on the outcome of transplant?
Does transplanting a kidney from a male donor into a female recipient makes a difference on the outcome of transplantation compared to transplanting between same sex?
On an epidemiological level, transplantation of male donor kidneys into female recipients was associated with a negative impact on long-term graft function in a retrospective cohort study in 200 000 kidney transplant recipients
Reference:
Reindl-Schwaighofer, R., Heinzel, A., Gualdoni, G.A., Mesnard, L., Claas, F.H. and Oberbauer, R. (2020), Novel insights into non-HLA alloimmunity in kidney transplantation. Transpl Int, 33: 5-17. https://doi.org/10.1111/tri.13546
————–
There is increased rate of graft failure in female recipients transplanted with male kidneys. This is consistent with the results of Gratwohl et al. [1] and Tan et al. [2]. This may be owing to the effect of histocompatibility H-Y antibodies [1].
Reference :
I. Elmenyawia AA, Donia A, Ahmed TT. The impact of Recipient and Donor Characteristics on Kidney Transplant Graft Survival. J Med Sci Res 2021;4:11-25
[1]Gratwohl A, Dohler B, Stern M, Opelz G. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 2008; 372:49–53.
[2]Tan JC, Kim JP, Chertow GM, Grumet FC, Desai M. Donor-recipient sex mismatch in kidney transplantation. Gend Med 2012; 9:335–347.
The male H-Y antigen is derived from a group of proteins encoded on the Y chromosome and associated with reduced long-term graft survival observed in male to female donations.
H-Y antigens are a group of minor histocompatibility antigens
The pattern of sex differences in graft outcomes is likely due to a complex interplay of several factors,
including age-related differences in immune potency,
the effects of sex hormones on immune activation,
sex differences in adherence to immunosuppressive medications,
differing metabolic demands on the basis of sex-related differences in body size,
donor sex-related differences in nephron mass,
and immune reactivity to sexually determined minor histocompatibility antigens (H-Y effect).
Changes in the potency of the immune response with increasing age may also modify the effects of other factors affecting graft survival.
Among the youngest recipients,
poorer graft outcomes in females are likely driven primarily by the H-Y effect—present only in the setting of a male donor; any effect of sex hormones is likely small in a group that is largely prepubertal.
Fanny Lepeytre, Mourad Dahhou, Xun Zhang, Julie Boucquemont, Ruth Sapir-Pichhadze, Heloise Cardinal and Bethany J. Foster
JASN October 2017, 28 (10) 3014-3023; DOI: https://doi.org/10.1681/ASN.2016121380
Thanks Weam
Yes, it is complex and no straightforward answer. I agree for the reasons you kindly mentioned.
The minor histocompatibility antigen HY encoded in the Y chromosome is associated with acute rejection episodes and decreased transplant survival, specifically when a donor is a man and the recipient a woman. Studies in solid organ transplantation, have suggested that women receiving grafts from men are at higher risk of acute rejection episodes. Nonetheless, the Y chromosome is not the only one with a minor antigen generating a gender mismatch. Wang et al found a new peptide closely related to the H-Y antigen that is present in the MHC class I HLA-B7 and encoded by the Smcx gene in the X chromosome.
H-Y antigens are expressed only on tissues from male donors, and are therefore at risk of being recognized as foreign by female-but not male-recipients.
kidney grafts from male donors to female recipients experience increased rates of graft rejection and reduced graft survival. The rationale behind this increase in graft rejection is that the recipient’s lymphocytes develop an allo-immune response against the H-Y antigens present on the donor graft
H-Y antigens are minor histocompatibility antigens encoded on chromosome Y …it is sex linked antigen …it affects graft outcome as antibodies formed against this antigen will induce graft versus host disease.
transplantation from male donor to female will initiate antibody formation in the female against male H-Y antigen and this will lead to graft rejection
also, there is antibody formation against H-Y antigen in the pregnant female in boy baby.
Rakesh Popli, Bita Sahaf, Hideki Nakasone, Joyce Yeuk Yu Lee, and David B. Miklos. Clinical impact of H-Y alloimmunity. Immunol Res. 2014 May; 58(0): 249–258.
HY antigen has been shown to be associated with reduced graft survival of male organs in female HLA-A2 recipients. De-novo HY antibody formation has been shown to be associated with acute rejection. (1,2)
1) Dierselhuis M, Goulmy E. The relevance of minor histocompatibility antigens in solid organ transplantation. Curr Opin Org Transpl 2009;14:419-425.
2) Tan JC, Wadia PP, Coram M, et al. H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation 2008;86:75-81.
Clinical data suggest that H-Y antigen compromises the survival of male allograft transplanted to a female recipient. As H-Y antigen encoded in Y chromosome and is expressed in male donors and being recognized by female recipient as a foreign.
In general females produce more severe cellular and humoral immune reaction than male, this is partly due to:
1.Immune enhancing effect of estrogen and the suppressive effect of androgen. this hormonal effect vary with age particularly in post-menopausal woman when sex hormone levels drop sharply.
2.Medication adherence differ by sex.
3.The difference in body size and the resultant difference in the metabolic demand.
4. The effect of H-Y antigen among female recipient for male donor.
The relationship between sex and graft survival is complex and likely to be affected by age and donor sex.
Reference:
Lepeytre F., Dahhou M., Zhang X., Boucquemont J. Association of Sex with Risk of Kidney Graft Failure Differs by Age. J Am Soc Nephrol. 2017, 28: 3014–3023.
the outcomes in other solid organs transplants are mixed, but regarding KIDNEY some studies showed a negative impact though I think may not be proved. as in Immunol Res. Author manuscript; available in (Immunol Res. 2014 May; 58(0): 249–258.doi: 10.1007/s12026-014-8514-3 Clinical impact of H-Y alloimmunity) a study of 26 transplants found 54% more deposition of H_Y antibodies)
***A particular mHA that has garnered attention in transplantation is the H-Y antigen present only in males of the species. Clinical data suggest that it possibly compromises the survival of male renal allografts transplanted to female recipients.
*** The most successful transplants, based on donor-recipient gender, were seen in male donors to male recipients, and then male donors to female recipients. Contradictory, the most unsuccessful transplant was observed when the donor was female and the recipient was male. In female transplant recipients, the level of serum cratinine, and eGFR, positive dialysis history before transplant, and low donor hemoglobin levels can be good prognostic factors in kidney transplant survival. By Judging these results based on hemoglobin yields, if we take Gender into account, we get inconsistent results. Therefore, further studies are needed to complete this section.
References:
••Auglienė R, Dalinkevičienė E, Kuzminskis V, Jievaltas M, Peleckaitė L, Gryguc A, et al. Factors influencing renal graft survival: 7-year experience of a single center. Med. 2017;53(4):224–32.
••Muhammad AS, Naicker S. HLA matching and kidney allograft function, experience from a south African transplant Centre. Trop J Nephrol. 2018;13(1):17–20.
••Danovithch G. Hand book of Kidney Transplantation , 6th ed.
the most successful transplants, based on donor-recipient gender, were seen in male donors to male recipients, and then male donors to female recipients. Contradictory, the most unsuccessful transplant was observed when the donor was female and the recipient was male. In female transplant recipients, the level of serum cratinine, and eGFR, positive dialysis history before transplant, and low donor hemoglobin levels can be good prognostic factors in kidney transplant survival.
studies on renal transplantation observed that male donor to female recipient combination is an independent risk factor for poor graft survival [19, 20] and the significantly higher percentage of H-Y antibody production in the male donor-female recipient population could play a role in this phenomenon (2)
There are many other factors determine the outcome also such as age of doner ,
HB level, cardiac condition of recipient, difference in body size , all these factors may also play a role
1 Gholamhossein Naderi, Amin Azadfar, Seyed Reza Yahyazadeh, Fatemeh Khatami & Seyed Mohammad Kazem Aghamir -Show fewer authors BMC Nephrology volume 21, Article number: 5 (2020).
2 Scott DM, Ehrmann IE, Ellis PS, Chandler PR, Simpson E. Why do some females reject males? The molecular basis for male-specific graft rejection. J Mol Med. 1997;75:103–14.
I am still confused a little between minor HLA and non HLA
In patients who are HLA matched transplantation, microhistocompatibility antigens are targeted for alloimmunity .
What is mHA
-peptides – represented in HLA Class 1 and 2
-to elicit an adaptive response
-encode in Y chromosome
-H-Y – highly expressed in whole body and show a great similarity to homologous H-X located on X chromosomes
-important – significant immunologic targets with clinical consequences in donor graft or the recipient sex-mismatched
H-Y alloimmunity in KT
-Even in HLA matched KT, significant levels of graft rejection occurs
-Terasaki found that 38% of kidney failure due to non-HLA immunologenic factors
Sex-mismatched KT and graft rejection
-Female host lymphocytes recognise mHA such as H-Y proteins in the male graft as foreign
-this mechanism leads to decreased engraftment and increased in graft rejection
-Male to Female (M -> F) KT involves transfer of an immune system target (kidney graft) from the male host to female recipient but opposed to F-> M in which functional immune system from female(donor) to male (recipient)- so higher rate of graft rejection in M->F
-alloimmunity against mHA ( H-Y) may be major cause of rejection
Reference
Rakesh Popli et al 2014-Clinical impact of H-Y alloimmunity
–H-Y antigens are a group of minor histocompatibility antigens on the Y chromosome with homologous H-X antigens on the X chromosome
they are highly immunogenic with affection
on graft survival on whom sex mismatched transplantation
kidney grafts from male donors to female
recipients have increased rates of graft rejection because female recipient*s
lymphocytes develop an alloimmune response against H-Y on the donor graft.
Although H-Y is minor, it can still adversely affect the graft outcome. Theoretically , Yes because the female may develop antibodies against H-y antigen and this can lead poor outcome, but transplantation is not all about H-Y antigen. Females specially wives, they are usually sensitised during conception and receiving kidney from the the husband is increase chances of poor outcomes.
Minor histocompatibility antigens are normal proteins that are themselves polymorphic in a given population.
Even when a transplant donor and recipient are identical with regard to MHC genes, amino acid differences in these minor proteins can lead to rejection.
Minor antigens are encoded by a large number of chromosomes and are presented only as peptides in the context of recipient MHC (indirect allorecognition).
Minor antigens are responsible for the need for immunosuppression after donation between HLA-matched nonidentical twin siblings.
The prototypic minor histocompatibility antigen, the male or H-Y antigen, is derived from a group of proteins encoded on the Y chromosome.
Alloresponses to this antigen may explain reduced long-term graft survival observed in male-to-female donations. MHC I–related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity.
Exposure to allogeneic MICA during transplantation can elicit antibody formation.20 ABO blood group glycolipids expressed on endothelial and red blood cells are other notable non-MHC antigens. immune responses to autoantigens have been associated with allograft damage.
Karl Womer, Hamid Rabb, in Comprehensive Clinical Nephrology.
The role of minor histocompatibility complex was 1st introduced in the context of bone marrow transplantation, when they noticed significant failure rates even among HLA matched Siblings, so they started searching human genom , of another polymorphic genes that could induce immune responses .
Minor antigens are responsible for the need immunosuppression after donation between HLA-matched nonidentical twin siblings
Because only amino acid differences in these minor histocompatibility antigens , can lead to immune responses .
differences in these peptides may arise from single nucleotide polymorphism in the coding region of genes, gene deletions, frameshift mutations, or insertions
The minor histocompatibility complex are
polymorphic self-peptides, which are presented at the cell surface of HLA molecule .
They are encoded either by Y chromosome or autosomal chromosomes .
The H-Y antigen which is encoded by the Y chromosome , is responsible for the reduced long term survival of graft donated from males to females .
They are recognized by CD8+ and CD4+ T cells ( after binding to antigen recognition sites of either class I or II major histocompatibility molecules ) .
Thus, minor histocompatibility antigens are capable of causing cell-mediated graft rejection.
MHC I–related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity.
Exposure to allogeneic MICA during transplantation can elicit antibody formation.
Examples of minor histocompatibility antigens include:-
HA-1/A2
HA-2
HA-8
HA-3
BCL2A1/ACC-1 and ACC-2
P2X5/P2RX5/LRH-1
1) Wallny HJ, Rammensee HG. Identification of classical minor histocompatibility antigen as cell-derived peptide. Nature 1990; 343: 275–278.
2) Linscheid C, Petroff MG (April 2013). “Minor histocompatibility antigens and the maternal immune response to the fetus during pregnancy”. American Journal of Reproductive Immunology. 69 (4): 304–14.
Dear All, excellent start
Please consider not mentioning these minor MHC only; the critical issue is how they are affecting transplant outcomes? This is the core question.
Best Luck
Minor histocompatibility antigens are small peptides that are found on the cell surface in
association with class I or class II major histocompatibility complex (MHC) molecules. (1, 2).
The origin mHC antigen is not known but any single or multiple amino acid polymorphism
in protein can present as foreign antigen.
Minor histocompatibility antigen are weaker antigen but still can cause rejection in 30%
of patient with HSC transplantation
More than 100 mHC is found, 10 minor antigen located in autosomal chromosomes
being identified among the 100 mihc.(3)
Examples of minor HA Chromosome
HA -1 19
HA- 2 6
HA -8 9
HB- 1 5
HY- A 1 Y
HY- A 2 Y
HY -B 7 Y
HY –B8 Y
HY –B60 Y
HY-DQ5 Y
Others minor histocompatibility antigen antigen:
Anti-MICA Abs:
MHC I-related chain gene A (MICA) ,present in 7 % of transplant cases and associated
with delayed graft function and acute rejection(4).
.
Anti-Angiotensin II Type 1 Receptor (AT1R) Abs and Anti-Endothelin Receptor (ETAR) Abs:
I has being associated with acute rejection of kidney transplant.it augment AntiHLA in
reduce graft survival.
Anti-Perlecan (LG3) Abs:
Is associated with increased risk of vascular rejection in kidney transplant.
Anti-Collagen Abs and Anti-K-Alpha-Tubulin Abs:
The development of post-transplant Abs against Col-IV and fibronectin as well as anti-
HLA DSA were associated with Transplant glomerulopathy.
Anti-Vimentin Abs:
Anti-vimentin IgG Abs could play a role in patients developing IFTA and delayed graft
function.
HY antigen is known to cause rejection in male to female transplantation, due to
absence of Y chromosomes in female.
HA-2:
Cause GVHD mHC antigen.
Best approach to minor histocompatibility antigen identification relies on proteomic analysis using mass spectrometry.
Genome sequencing can help identification of coding single nucleotide polymorphisms
(SNPs) provide a reasonable estimation of minor histocompatibility antigens.
Reference:
1-Denis Claude Roy,Claude Perreault . Major vs minor histocompatibility antigens.
Blood (2017) 129 (6): 664–666.
3-Faculte de medecine de Genève, Minor histocompatibility Antigen, Jan. Transplant
immunology. Review, 21 Jan.201.
4-María Gutiérrez-Marcos López-Hoyos . Non-HLA Abs in Solid Organ Transplantation.
Transplantology 2020, 1(1), 24-41.
.
Thank you for the response
We should understand the terms of Major MHC. Minor MHC, and HLA AND Non-HLA antibody testing.
Screening for HLA antibody:
DNA-Based Histocompatibility testing:
By PCR.
Minor histocompatibility antigens are the non-HLA antigens which are Non MHC antigens capable if inducing an immunological reaction. They can result in ABMR in absence of DSAs and chronic renal allograft nephropathy as well hence studying and understanding them was crucial.
Many of these non-HLA antibodies are direted against endothelial or epithelial cells .
Examples include :
Angiotensin II type 1-receptor antibodies (anti-AT1R)
Major Histocompatibility Complex class I chain-related molecule A (MICA)
H-Y antigen
Endothelin receptor type A (ETAR)
Anti-endothelial cell antibodies (AECA)
Danovitch G.M handbook of kidney transplantation sixth edition
Karl Womer, Hamid Rabb, in Comprehensive Clinical Nephrology (Fourth Edition), 2010
Tan JC, Wadia PP, Coram M, et al.H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation 2008; 86: 75
Minor histocompatibility antigens (mHA) are diverse proteins from non-HLA antigen origin. m-HA are peptides/receptors on the cellular surface of kidney allograft that could be implicated in the development of immunological response in some organ transplants. This is because this receptor or protein is not found in the recipient and consequently will induce the immune response of the recipient to be activated. Although the mismatch will not induce potent reaction as with HLA mismatch but cumulative response could occur in the setting of multiple m-HA mismatches.
Examples:
H-Y antigen which is present only in males account for arounf 30 % of m-HA. This m-HA could induce immune response when transplanted into female recipients leading to shortening of the graft survival.
Histocompatibility antigen 1(HA1)
HA1 results from conversion of a nonimmunogenic allele into an immunogenic allele. This conversion results in better peptide binding ability to the groove of a particular MHC class I molecules found on antigen presenting cells. As a result, T cells can recognize the modified allele as foreign, leading to activation of immune response.
Graft versus host immune response between HLA matched individuals is also an example to the role of m-HA in inducing rejection
Minor histocompatibility antigens (mHA):
It refers to non-HLA antigens defined as “any non-MHC antigens encoded polymorphic proteins that is sufficiently antigenic to induce an immune response through indirect allorecognition by a T cell when transplanted into an individual with absent or altered gene expression” (1)
It is well studied in hematopoietic stem cell transplantation and has an effect on graft versus host disease & graft versus leukemia effect in HLA identical matches. (2)
mHA antibodies are classified into
H-Y antigen:
polymorphic Y-chromosomal encoded proteins that act as mHA in gender mismatched transplantation,
humoral allograft immunity can target H-Y antigen (4)
Major Histocompatibility Complex class I chain-related molecule A (MICA)
highly polymorphic, alloantigen
not well determined as the pre transplant cross match is not sensitive enough to detect MICA DSA (5)
Anti endothelial cell antibodies (AECA)
most endothelial antigens are unknown
endothelial cell injury include complement mediated cell injury & endothelial cell activation. (6)
cell based cross match using endothelial cells showed that AECA was associated with higher rates of rejection (7)
Angiotensin II type 1-receptor antibodies (anti-AT1R):
associated with high risk of graft failure irrespective of HLA system with high prevalence of HTN & more vascular rejection with arterial inflamation (8)
anti-AT1R were associated with antibody mediated rejection in absence of DSA (9)
Endothelin receptor type A (ETAR)
G protien coupled receptor, also considered endothelial antigen
AT1r & ETAR are considered autoantibodies as they were detected in patients without transplant& associated with HTN, cardiovascular disease and preeclampsia (10)
(1) Reindl‐Schwaighofer, Roman, Andreas Heinzel, Guido A. Gualdoni, Laurent Mesnard, Frans HJ Claas, and Rainer Oberbauer. “Novel insights into non‐HLA alloimmunity in kidney transplantation.” Transplant International 33, no. 1 (2020): 5-17.
(2) Bertinetto FE, Dall’Omo AM, MazzolaGA, et al. Role of non-HLA geneticpolymorphisms in graft-versus-hostdisease after haematopoietic stem celltransplantation. Int J Immunogenet2006; 33: 375
(3) Danovitch G.M handbook of kidney transplantation sixth edition
(4) Tan JC, Wadia PP, Coram M, et al.H-Y antibody development associateswith acute rejection in female patientswith male kidney transplants.Transplantation 2008; 86: 75
(5) Baranwal AK, Mehra NK. Majorhistocompatibility complex class Ichain-related A (MICA) molecules:relevance in solid organtransplantation. Front Immunol 2017;8: 182
(6) Dragun D, Catar R, Philippe A. Non-HLA antibodies against endothelialtargets bridging allo- andautoimmunity. Kidney Int 2016; 90:280
(7) Breimer ME, Rydberg L, Jackson AM,et al. Multicenter evaluation of a novelendothelial cell crossmatch test inkidney transplantation. Transplantation2009; 87: 549.
(8) Lefaucheur C, Viglietti D, Bouatou Y,et al. Non-HLA agonistic anti-angiotensin II type 1 receptorantibodies induce a distinctivephenotype of antibody-mediatedrejection in kidney transplantrecipients. Kidney Int 2019; 96: 189.
(9) Reinsmoen NL, Lai CH, Heidecke H, et al. Anti-angiotensin type 1receptor antibodies associated with antibody mediated rejection indonor HLA antibody negative patients. Transplantation 2010; 90:1473–1477.
(10) Philogene MC, Johnson T, Vaught AJ,Zakaria S, Fedarko N. Antibodiesagainst angiotensin II type 1 andendothelin A receptors: relevance andpathogenicity. Hum Immunol 2019; 80 :561.
Alloimmune response caused by Minor histocompatibility antigens (mHags) can cause graft rejection.
The mHags are polymorphic self-peptides, encoded by sex-linked or diallelic autosomal genes, presented by HLA molecules and recognized by HLA class I-restricted CD8+ or HLA class II-restricted CD4+ T cells.Different HLA alleles bind different repertoires of peptides. In renal graft rejection, mHag can be immunogenic if an HLA molecule that can bind to that specific mHag is present in the recipient (direct allorecognition)or donor (indirect allorecognition) serum (1)
MiHA vary even in monozygotic twins. The best known is the H-Y antigen, but there are also other autosomal miHA and MICA. Incompatibility of H-Y antigen as a risk factor in kidney transplantation is the most significant finding in the studies done(2)
Two articles opposing each others on the role of mHags in renal transplantation were published. Cai et al. identified the association of CD8+ memory regulatory and effector T cells specific for HA-1 in renal transplant recipients who had developed graft tolerance and on the other hand , Krishnan et al. detected an important corelation between HA-1 mismatch and chronic kidney rejection. (1)
1-Heinold A.etal , Role of Minor Histocompatibility Antigens in Renal Transplantaion, American journal of transplantation,2008 .8,92-102.
2-M A Pabón MA et al. Minor histocompatibility antigens as risk factor for poor prognosis in kidney transplantation. Transplant Pro2011 Nov;43(9):3319-23.
Thank you Doaa
I’ll quit your sentence ” Two articles opposing each others on the role of mHags in renal transplantation were published. Cai et al. identified the association of CD8+ memory regulatory and effector T cells specific for HA-1 in renal transplant recipients who had developed graft tolerance and on the other hand , Krishnan et al. detected an important corelation between HA-1 mismatch and chronic kidney rejection. (1)”
This needs to be rephrased in a more clear way. Both the references dated more than 10 years. Please check
The donor specific antibodies (DSAs), which are anti-HLA antibodies, are the major cause of most case of antibody-mediated rejection (ABMR) —–> (ABMR h DSA pos)
However, many cases of ABMR are diagnosed without presence of DSAs, which explained by identification of non-HLA antibodies ——> (ABMR h DSA neg).
And this also gives explanation for graft rejection and failure from HLA- matched identical donors and among HLA-matched monozygotic twin siblings.
Therefore, many recent researches and evidences that confirm that minor histocompatibility complex, which may be refered as non-HLA antigens, is an important player in immunology of kidney transplantation.
Examples
• H-Y antigen (male to female donations).
• MHC Class I Polypeptide-Related Sequence A (MICA)
• Antibodies against autoantigens like angiotensin II type 1 receptor (AT1R-Ab), endothelin-1 type A receptor (ETAR-Ab),
☆ Reference
• Crespo M, Llinàs-Mallol L, Redondo-Pachón D, Butler C, Gimeno J, Pérez-Sáez MJ, Burballa C, Buxeda A, Arias-Cabrales C, Folgueiras M, Sanz-Ureña S, Valenzuela NM, Reed EF and Pascual J (2021) Non-HLA Antibodies and Epitope Mismatches in Kidney Transplant Recipients With Histological Antibody-Mediated Rejection. Front. Immunol. 12:703457. doi: 10.3389/fimmu.2021.703457
• Etta PK, Madhavi T, Parikh N. Pathobiology of non‑HLA immunity in renal transplantation. Indian J Transplant 2021;15:147‑56.
acute and chronic allograft rejection can occur in HLA identical silblings, transplantion implicating the importnance of immune responce aganist non HLA targets
Many of these non-HLA antibodies are directed against endothelial or epithelial cells and represent a heterogeneous group of antibodies comprising both IgM and IgG subclasses. These non-HLA antibodies are classified as either alloantibodies such as MICA or tissue-specific autoantibodies depending on whether they are directed against polymorphic antigens that differ between the host and donor, or if they represent an immune response to a self-antigen.
Antibodies specific for alloantigens such as MICA and autoantigens such as agrin, angiotensin II type I receptor (AT1R) have been implicated in acute and/or chronic renal allograft injury.
Known non-HLA targets such as AT1R antibody can be measured using ELISA assays, while cell-based crossmatch assays using endothelial cells can be used to identify non-HLA antibodies in the sera of transplant recipients.
Advantages include the ability to detect antibodies specific for novel antigens, in particular, polymorphic antigens, which may differ between cell donors.
However, incomplete knowledge of the non-HLA targets make it diifucult understanding of the clinical significance of the assay
Missing references
I will post it
Organs transplanted between HLA-matched individuals are not safe from rejection because any protein that is present in the graft but not in the recipient will behave as a foreign transplantation antigen. Non-HLA transplantation antigens are called Minor histocompatibility antigens(mHA). They are normal proteins that are themselves polymorphic in a given population and it bound to MHC class I and class II protein. mHA is encoded by a large number of chromosomes.
The male H-Y antigen is derived from a group of proteins encoded on the Y chromosome and associated with reduced long-term graft survival observed in male to female donations.
MHC I-related chain A (MICA) antigens are surface glycoproteins with functions related to innate immunity. During transplantation MICA, can lead to antibodies formation.
ABO blood group glycolipids are mHA.
The single mHA is not potent to induce immune response but commonly many mHA mismatches exist between donor and recipient, the cumulative Anti-mHA is significant that can lead to graft damage.
References
1.Karl Womer, Hamid Rabb, in Comprehensive Clinical Nephrology (Fourth Edition), 2010
2.Danovitch G.M handbook of kidney transplantation sixth edition.
Even organ transplantation between HLA-matched individuals such as two haplotype siblings is not sufficiently safe from rejection because any proteins expressed by allograft and not the recipient, behave as foreign antigen and induce alloreactivity those called minor histocompatibility antigens.
Although these minor histocompatibility antigens (mHA) don’t induce an alloreactive response as much as HLA disparity, since many mHA antigens exist, cumulate response to these antigens can be significant and important.
These minor antigens are recognized by T cells (most often by CD8-positive cytotoxic T cells) in the context of self MHC (such as indirect allorecognition)
Minor antigens are derived from polymorphic cellular proteins that are bound to MHC class I of recipient. Possibly these antigens are derived autosomally and represent polymorphism among autosomal proteins and enzymes.
One of the specific and important mHA is H-Y antigen that is presented only in males, so in donation of males’ kidney allografts to female recipients it may have a negative influence on graft survival. Another noticeable mHA antigens are polymorphic mitochondrial proteins.
Minor histocompatibility antigens (mHAs) can be any polymorphic gene product encoded outside the MHC that differs between donor and recipient and that can stimulate a T-cell response
Minor histocompatibility antigens are normal proteins that are polymorphic within a given species. Even when a transplant donor and recipient are identical with regard to MHC genes, amino acid differences in these minor proteins can lead to rejection. Minor antigens are encoded by a large number of chromosomes and are presented only as peptides in the context of recipient MHC (indirect allorecognition). Minor antigens are responsible for the need for immunosuppression after donation between HLA matched but nonidentical twin siblings. The prototypic minor histocompatibility antigen, the male or H-Y antigen, is derived from a group of proteins encoded on the Y chromosome. Alloresponses to this antigen are responsible for rejection of male mouse skin grafts by otherwise identical female recipients and may explain observations of reduced long-term graft survival in human male-to-female donations.
examples : HY antigen, ABO blood group glycolipids
Comprehensive Clinical Nephrology
Womer, Karl L.. Published December 31, 2018. © 2019.
Dear All
Thank you for your replies. Well done. I will wait for more colleagues to participate. This topic has a very important clinical significance which will be addressed later
Major histocompatibility antigens are antigens encoded by MHC genes, they have antigen binding sites on its surface that enable binding to forgin peptide protein (either endogenous intracelluller in class I or exogenous extracellular in class II) that is to present it either to CD8- cytotoxic T cells (HLA class I) or to CD4 hellper Tcells (HLA class II)
It was found that these antigen binding sites are occupied by small sized endogenous peptides these are known as minor histocompatibility antigens (MiHA).
Evidence
1- Rejection can occur between HLA matched non identical twins without immunosuppression
2- Male has H-Y antigens derived from gene on Y chromosome which constitute MiHA present in male, thus it was found that graft survival is lower when donor is male and recipient is female.
REFERANCES
1- Zou Y, Stastny P, Süsal C, et al. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med 2007; 357:1293.
MiHA are related to HLA class I so when recognized as a foreign immune response develop (CD8 T cell- mediated), but chronic low level stimulation of TCR may lead to tolerance by production of regulatory T cells.
Minor histocompatibility is still in early phase of recognition in the research.
Major histocompatibility is critical in organ transplantation, but minor histocompatibility system also affects graft outcome and survival, as graft of HLA identical siblings can be rejected and lost, this denotes that there is other histocompatibility antigens sensitization.
Minor histocompatibility antigens are responsible of delayed or chronic or slow rejection of the graft.
J. Michael Cecka. Significance of histocompatibility in organ transplantation. Current Opinion in Organ Transplantation 2007, 12:402–408.
Karl Womer, Hamid Rabb, Immunologic Principles in Kidney Transplantation. Comprehensive Clinical Nephrology 2010 4th ed.
The term minor histocompatibility antigen is used to refer to non-HLA antigens. They are defined as any non-MHC encoded polymorphic protein that is sufficiently antigenic to induce immune response through indirect allorecognition by T cells when transplanted to an individual with absent or altered gene expression.1
The occurrence of ABMR in HLA identical kidney transplantation highlights the importance of non-HLA antigens in allorecognition. Studies showed that around 38% of graft loss could be due to non-HLA antigens while only 18% were due to HLA antigens. Other studies concluded that non-HLA alloimmunity associated with chronic allograft loss.1
Antibodies to the following non-HLA antigens have been associated with graft dysfunction or rejection (Even though the detection of many non-HLA antigens remains elusive):2
Major histocompatibility complex class I chain related gene A( MICA)
HY antigen
Angiotensine II type I receptor
Endothelin type A receptor
Heat shock protein
Phospholipid
K-α- tubulin
Vimentin
Endothelial cell antigen
References:
Thank you, Huda, for mentioning the effect on graft loss after ABMR.
The idea is not to know the presence or absence of Non-HLA antibodies BUT how they affect the transplant outcome.
Excellent citation for reference 1 Transplant International 2020; 33: 5–17.
Even transplants between HLA-identical siblings result in progressive graft loss, characterized by a 10-year death-censored graft survival rate of 82.5% according to the data of the Collaborative Transplant Study (CTS) . Terasaki deduced that 38% of graft failures are due to non-HLA factors, 18% to HLA factors and 43% to nonimmunologic factors .
Incompatibilities for the mHags HA-1 , HA-2 , HA-3 , HA-8 , HB-1 , ACC-1 and UGT2B17 had no statistically significant effect on graft survival.
Disparities for the mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1 or UGT2B17 did not significantly influence graft survival in deceased donor transplants.
Role of Minor Histocompatibility Antigens in Renal Transplantation
A. Heinold et al
H-Y antigens are encoded by genes on the Y chromosome. Both HLA class I and II alleles have been found to present these antigens. Some of these antigens are ubiquitously expressed in nucleated male cells, and the presence of these antigens has been associated with a greater risk of developing GVHD allogeneic stem cell transplantation for a HLA matched gene when there’s a male recipient and female donor.
Compared with all other combinations of sex, transplantation of male donor kidneys into female recipients was associated with an increased risk of graft failure during the first year and between 2 and 10 years.
H-Y minor histocompatibility affects human kidney transplantation.
H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study
Alois Gratwohl et al
The minor histocompatibility complex are polymorphic and are presented at the cell surface association with class I or class II major histocompatibility complex (MHC) molecules
It may be encoded either by Y chromosome or autosomal chromosomes and are recognized by CD8+ and CD4+ T cells.
An example of mHC : HY antigen is responsible for the reduced graft survival especially graft donated from males to females , and it is encoded by the Y chromosome .
Thus, minor histocompatibility antigens are capable of causing cell-mediated graft rejection.
in dizygotic twins with zero major HLA mismatch and so they still need to receive immune suppression medications
Other examples of minor histocompatibility antigens include:-
HA-1/A2
HA-2
HA-8
HA-3
BCL2A1/ACC-1 and ACC-2
P2X5/P2RX5/LRH-