Minor histocompatibility antigen


Minor histocompatibility antigen 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. Minor histocompatibility antigens 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 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

Known minor histocompatibility antigens

The following table lists the known MiHAs, the variant of genes encode MiHA peptides and their restricted HLA alleles.
MiHA IDMiHA peptideRestricted HLAChromosomeCoordinateSNP IDGeneEnsembl Gene ID
HA-1/A2VLDDLLEAA*02:01chr191068739rs1801284HMHA1ENSG00000180448
HA-2YIGEVLVSA*02:01chr744977022rs61739531MYO1GENSG00000136286
HA-8TLDKVLEVA*02:01chr92828765rs2173904KIAA0020ENSG00000080608
HA-3VEPGTAQYA*01:01chr1585579423rs2061821AKAP13ENSG00000170776
C19ORF48CIPPDLLFPAA*02:01chr1950798945rs3745526C19ORF48ENSG00000167747
LB-ADIR-1FSVAPALALPAA*02:01chr1179082165rs2296377TOR3AENSG00000186283
LB-HIVEP1-1SSLPKHVTIA*02:01chr612123016rs2228220HIVEP1ENSG00000095951
LB-NISCH-1AALAPAPEVA*02:01chr352489389rs887515NISCHENSG00000010322
LB-SSR1-1SLAVAQDLTA*02:01chr67310026rs10004SSR1ENSG00000124783
LB-WNK1-1IRTLSPEITVA*02:01chr12889199rs12828016WNK1ENSG00000060237
T4AGLYTYWSAGA*02:01chr3140688418rs9876490TRIM42ENSG00000155890
UTA2-1QLNSVLTLA*02:01chr1231981704rs2166807KIAA1551ENSG00000174718
PANE1RVWDLPGVLKA*03:01chr2241940168rs5758511CENPMENSG00000100162
SP110SLPGTSTPKA*03:01chr2230207994rs1365776SP110ENSG00000135899
ACC-1CDYLQVLQIA*24:02chr1579971064rs1138357BCL2A1ENSG00000140379
ACC-1YDYLQVLQIA*24:02chr1579971064rs1138357BCL2A1ENSG00000140379
P2RX7WFHHCPKYA*29:02chr12121167552rs7958311P2RX7ENSG00000089041
ACC-4ATLPLLCAA*31:01chr1578944951rs2289702CTSHENSG00000103811
ACC-5WATLPLLCAA*33:03chr1578944951rs2289702CTSHENSG00000103811
LB-APOBEC3B-1KPQYHAEMCFB*07:02chr2238985821rs2076109APOBEC3BENSG00000179750
LB-ARHGDIB-1RLPRACWEAB*07:02chr1214942624rs4703ARHGDIBENSG00000111348
LB-BCAT2-1RQPRALLFVILB*07:02chr1948799813rs11548193BCAT2ENSG00000105552
LB-EBI3-1IRPRARYYQVB*07:02chr194236999rs4740EBI3ENSG00000105246
LB-ECGF-1HRPAIRRPLALB*07:02chr2250525826rs112723255TYMPENSG00000025708
LB-ERAP1-1RHPRQEQIALLAB*07:02chr596803547rs26653ERAP1ENSG00000164307
LB-FUCA2-1VRLRQGSWLB*07:02chr6143502020rs3762002FUCA2ENSG00000001036
LB-GEMIN4-1VFPALRFVEB*07:02chr17746265rs4968104GEMIN4ENSG00000179409
LB-PDCD11-1FGPDSSKTLCLB*07:02chr10103434329rs2986014PDCD11ENSG00000148843
LB-TEP1-1SAPDGAKVALB*07:02chr1420383870rs1760904TEP1ENSG00000129566
LRH-1TPNQRQNVCB*07:02chr173690983rs3215407P2X5ENSG00000083454
ZAPHIRIPRDSWWVELB*07:02chr1957492212rs2074071ZNF419ENSG00000105136
HEATR1ISKERAALB*08:01chr1236554626rs2275687HEATR1ENSG00000119285
HA-1/B60KECVLDDLB*40:01chr191068739rs1801284HMHA1ENSG00000180448
LB-SON-1RSETKQTVLB*40:01chr2133553954rs13047599SONENSG00000159140
LB-SWAP70-1QMEQLELELB*40:01chr119748015rs415895SWAP70ENSG00000133789
LB-TRIP10-1EPCGQDLTLB*40:01chr196751268rs1049229TRIP10ENSG00000125733
SLC1A5AETANGGLALB*40:02chr1946787917rs3027956SLC1A5ENSG00000105281
ACC-2KEFEDIINWB*44:03chr1579970875rs3826007BCL2A1ENSG00000140379
ACC-6MEIFIEVFSHFB*44:03chr1863953532rs9945924HMSDENSG00000221887
HB-1HEEKRGSLVWB*44:03chr5143820488rs161557HMHB1ENSG00000158497
HB-1YEEKRGSLVWB*44:03chr5143820488rs161557HMHB1ENSG00000158497
DPH1SLPEVDVWB*57:01chr172040586rs35394823DPH1ENSG00000108963
UTDP4-1RLAHFFCGWDPB1*04chr9128721272rs11539209ZDHHC12ENSG00000160446
CD19WEGEPPCPDQB1*02:01chr1628933075rs2904880CD19ENSG00000177455
LB-PI4K2B-1SSRSSAELDRSRDQB1*06:03chr425234395rs313549PI4K2BENSG00000038210
LB-MTHFD1-1QSSIIADIALKLDRB1*03:01chr1464442127rs2236225MTHFD1ENSG00000100714
LB-LY75-1KLGITYRKSLMWFDRB1*13:01chr2159819916rs12692566LY75ENSG00000054219
SLC19A1LVCYLCFYDRB1*15:01chr2145537880rs1051266SLC19A1ENSG00000173638
LB-PTK2B-1TVYMNDSPLTPEKDRB3*01:01chr827451068rs751019PTK2BENSG00000120899
LB-MR1-1RYFRLGVSDPIGDRB3*02:02chr1181049100rs2236410MR1ENSG00000153029

T cell Response to MiHAs

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. The lack of recognition of a T cell to this self antigen is the reason why allogeneic stem cell transplantation for an HLA matched gene or a developing fetus’s MiHAs during pregnancy may not be recognized by T cells and marked as foreign leading to an immune response. Although B cell receptors can also recognize MHCs, immune responses seem to only be elicited by T cells. The consequences of an immune response are seen in allogeneic hematopoietic stem cell transplantation when the peptides encoded by polymorphic genes differ between the recipient and the donor T cells. As a result, the donor T cells can target the recipients cells called graft-versus-host disease. Although graft or bone marrow rejection can have detrimental effects, there are immunotherapy benefits when cytotoxic T lymphocytes are specific for a self antigen and can target antigens expressed selectively on leukemic cells in order to destroy these tumor cells referred to as graft-versus- leukemia effect.
The recognition of a mature T cell to this self antigen should not induce an immune response. During thymic selection occurring in the thymus, only a thymocyte TCR that recognizes either class I or class II MHC molecule plus peptide should survive positive selection. However, there is death by apoptosis of thymocytes that do not interact with MHC molecules or have high-affinity receptors for self MHC plus self antigen a process referred to as negative selection. Therefore, the process of positive and negative selection means fewer self-reactive mature T cells will leave the thymus and lead to autoimmune problems.

Discovery of MiHAs

The significance of MiHAs in an immune response was recognized following transplantation. The recipient developed GVHD despite having a HLA- matched genes at the Major Histocompatibility locus.The experiment raised questions about the possibility of there being MiHAs. More specifically, the first MiHA was discovered when bone marrow transplantation occurred between opposite sexes. The female recipient obtained MHC-matched bone marrow cells but still had active cytotoxic T cells. The CD8+ T cells were active and targeted the male bone marrow cells. The male bone marrow cells were found to be presenting a peptide in the MHC groove encoded by a gene on Y chromosome. The peptide was foreign to the female T cells and females lack the Y chromosome and, thus, this MiHA. The MiHAs encoded by the Y chromosome are known as HY antigens.

H-Y Antigen

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 ubiquitiouly 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. 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 which is significant for CD8+ activation.

Histocompatibility Antigen 1 (HA1)

HA1 results from a SNP converting the nonimmunogenic allele to an immunogenic allele. This SNP results in better peptide binding ability to the groove of a particular MHC class I molecules found on antigen presenting cells. The significance of the peptide changing to an immunogenic form is that now specific HLA-A 0201 restricted T cells can recognize the peptide presented by MHC class I HLA-A0201 molecules. This recognition leads to an immune response if the T cells recognize the peptide as foreign. This recognition occurs when an individual lacks the immunogenic version of the peptide, but is exposed to the HA-1 peptide during pregnancy or allogeneic stem cell transplantation. During pregnancy, the fetal HA-1 has been found to originate in the placenta and specific maternal CD8+ T cells recognizing this MiHA have been identified.

Immunotherapy Graft-Versus- Leukemia Effect

CD8+ T cells that are specific for a MiHA can target these antigens when they are expressed specifically on tumor cells, which allows for the destruction of harmful tumor cells. In mice, allogeneic stem cell transplantation donor CD8+ T cells specific for a MiHA found in the recipient has been shown to inhibit the division of leukemic cells. However, there is a risk in developing GVHD if the T cells are specific for MiHAs expressed ubiquitously on epithelial cells. More specifically, HA-8, UGT2B17 and SMCY MiHAs that are ubiquitously expressed present a higher risk of developing GVHD. Therefore, in order to prevent adverse GVHD effects, immune cell restricted MiHAs are ideal targets for graft-versus- leukemia since not all nucleated cells are targeted by responding T cells. An example of an ideal target is the MiHA HB-1, which is highly expressed in harmful B cells, but has a low expression in other tissue cells.

Clinical implications

Immunisation of mothers against male-specific minor histocompatibility antigens has a pathogenic role in many cases of secondary recurrent miscarriage, that is, recurrent miscarriage in pregnancies succeeding a previous live birth. An example of this effect is that the male:female ratio of children born prior and subsequent to secondary recurrent miscarriage is 1.49 and 0.76 respectively.