Minor histocompatibility antigen

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A single nucleotide change (SNP) in the coding region of the recipient is polymorphic or different from the amino acid sequence of a donor's T cell. The T cell receptor specific for peptide and MHC molecule; therefore, recognizes the self-peptide bound to the groove of HLA matched gene as foreign and initiates an immune response. The donor's CD8+ T cell targets the recipient’s nucleated cell resulting in graft-versus-host disease.

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.[1] 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.[2] Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions.[3] About a third of the characterized MiHAs come from the Y chromosome.[4] The proteins are composed of a single immunogenic HLA allele .[2] 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.[5]

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[4]

Known minor histocompatibility antigens[edit]

The following table lists the known MiHAs, the variant of genes encode MiHA peptides and their restricted HLA alleles.

MiHA ID MiHA peptide Restricted HLA Chromosome Coordinate SNP ID Gene Ensembl Gene ID
HA-1/A2 VL[H/R]DDLLEA A*02:01 chr19 1068739 rs1801284 HMHA1 ENSG00000180448
HA-2 YIGEVLVS[V/M] A*02:01 chr7 44977022 rs61739531 MYO1G ENSG00000136286
HA-8 [R/P]TLDKVLEV A*02:01 chr9 2828765 rs2173904 KIAA0020 ENSG00000080608
HA-3 V[T/M]EPGTAQY A*01:01 chr15 85579423 rs2061821 AKAP13 ENSG00000170776
C19ORF48 CIPPD[S/T]LLFPA A*02:01 chr19 50798945 rs3745526 C19ORF48 ENSG00000167747
LB-ADIR-1F SVAPALAL[F/S]PA A*02:01 chr1 179082165 rs2296377 TOR3A ENSG00000186283
LB-HIVEP1-1S SLPKH[S/N]VTI A*02:01 chr6 12123016 rs2228220 HIVEP1 ENSG00000095951
LB-NISCH-1A ALAPAP[A/V]EV A*02:01 chr3 52489389 rs887515 NISCH ENSG00000010322
LB-SSR1-1S [S/L]LAVAQDLT A*02:01 chr6 7310026 rs10004 SSR1 ENSG00000124783
LB-WNK1-1I RTLSPE[I/M]ITV A*02:01 chr12 889199 rs12828016 WNK1 ENSG00000060237
T4A GLYTYWSAG[A/E] A*02:01 chr3 140688418 rs9876490 TRIM42 ENSG00000155890
UTA2-1 QL[L/P]NSVLTL A*02:01 chr12 31981704 rs2166807 KIAA1551 ENSG00000174718
PANE1 RVWDLPGVLK A*03:01 chr22 41940168 rs5758511 CENPM ENSG00000100162
SP110 SLP[R/G]GTSTPK A*03:01 chr2 230207994 rs1365776 SP110 ENSG00000135899
ACC-1C DYLQ[Y/C]VLQI A*24:02 chr15 79971064 rs1138357 BCL2A1 ENSG00000140379
ACC-1Y DYLQ[Y/C]VLQI A*24:02 chr15 79971064 rs1138357 BCL2A1 ENSG00000140379
P2RX7 WFHHC[H/R]PKY A*29:02 chr12 121167552 rs7958311 P2RX7 ENSG00000089041
ACC-4 ATLPLLCA[R/G] A*31:01 chr15 78944951 rs2289702 CTSH ENSG00000103811
ACC-5 WATLPLLCA[R/G] A*33:03 chr15 78944951 rs2289702 CTSH ENSG00000103811
LB-APOBEC3B-1K [K/E]PQYHAEMCF B*07:02 chr22 38985821 rs2076109 APOBEC3B ENSG00000179750
LB-ARHGDIB-1R LPRACW[R/P]EA B*07:02 chr12 14942624 rs4703 ARHGDIB ENSG00000111348
LB-BCAT2-1R QP[R/T]RALLFVIL B*07:02 chr19 48799813 rs11548193 BCAT2 ENSG00000105552
LB-EBI3-1I RPRARYY[I/V]QV B*07:02 chr19 4236999 rs4740 EBI3 ENSG00000105246
LB-ECGF-1H RP[H/R]AIRRPLAL B*07:02 chr22 50525826 rs112723255 TYMP ENSG00000025708
LB-ERAP1-1R HPRQEQIALLA B*07:02 chr5 96803547 rs26653 ERAP1 ENSG00000164307
LB-FUCA2-1V RLRQ[V/M]GSWL B*07:02 chr6 143502020 rs3762002 FUCA2 ENSG00000001036
LB-GEMIN4-1V FPALRFVE[V/E] B*07:02 chr17 746265 rs4968104 GEMIN4 ENSG00000179409
LB-PDCD11-1F GPDSSKT[F/L]LCL B*07:02 chr10 103434329 rs2986014 PDCD11 ENSG00000148843
LB-TEP1-1S APDGAKVA[S/P]L B*07:02 chr14 20383870 rs1760904 TEP1 ENSG00000129566
LRH-1 TPNQRQNVC B*07:02 chr17 3690983 rs3215407 P2X5 ENSG00000083454
ZAPHIR IPRDSWWVEL B*07:02 chr19 57492212 rs2074071 ZNF419 ENSG00000105136
HEATR1 ISKERA[E/G]AL B*08:01 chr1 236554626 rs2275687 HEATR1 ENSG00000119285
HA-1/B60 KECVL[H/R]DDL B*40:01 chr19 1068739 rs1801284 HMHA1 ENSG00000180448
LB-SON-1R SETKQ[R/C]TVL B*40:01 chr21 33553954 rs13047599 SON ENSG00000159140
LB-SWAP70-1Q MEQLE[Q/E]LEL B*40:01 chr11 9748015 rs415895 SWAP70 ENSG00000133789
LB-TRIP10-1EPC G[E/G][P/S]QDL[C/G]TL B*40:01 chr19 6751268 rs1049229 TRIP10 ENSG00000125733
SLC1A5 AE[A/P]TANGGLAL B*40:02 chr19 46787917 rs3027956 SLC1A5 ENSG00000105281
ACC-2 KEFED[D/G]IINW B*44:03 chr15 79970875 rs3826007 BCL2A1 ENSG00000140379
ACC-6 MEIFIEVFSHF B*44:03 chr18 63953532 rs9945924 HMSD ENSG00000221887
HB-1H EEKRGSL[H/Y]VW B*44:03 chr5 143820488 rs161557 HMHB1 ENSG00000158497
HB-1Y EEKRGSL[H/Y]VW B*44:03 chr5 143820488 rs161557 HMHB1 ENSG00000158497
DPH1 S[V/L]LPEVDVW B*57:01 chr17 2040586 rs35394823 DPH1 ENSG00000108963
UTDP4-1 R[I/N]LAHFFCGW DPB1*04 chr9 128721272 rs11539209 ZDHHC12 ENSG00000160446
CD19 WEGEPPC[L/V]P DQB1*02:01 chr16 28933075 rs2904880 CD19 ENSG00000177455
LB-PI4K2B-1S SRSS[S/P]AELDRSR DQB1*06:03 chr4 25234395 rs313549 PI4K2B ENSG00000038210
LB-MTHFD1-1Q SSIIAD[Q/R]IALKL DRB1*03:01 chr14 64442127 rs2236225 MTHFD1 ENSG00000100714
LB-LY75-1K LGITYR[N/K]KSLMWF DRB1*13:01 chr2 159819916 rs12692566 LY75 ENSG00000054219
SLC19A1 [R/H]LVCYLCFY DRB1*15:01 chr21 45537880 rs1051266 SLC19A1 ENSG00000173638
LB-PTK2B-1T VYMND[T/K]SPLTPEK DRB3*01:01 chr8 27451068 rs751019 PTK2B ENSG00000120899
LB-MR1-1R YFRLGVSDPI[R/H]G DRB3*02:02 chr1 181049100 rs2236410 MR1 ENSG00000153029

T cell Response to MiHAs[edit]

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.[6] The consequences of an immune response are seen in allogeneic hematopoietic stem cell transplantation (HCT) 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 (GVHD).[5] 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 (GVL).[3]

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[edit]

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 (CD8+).[3] 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.[3]

H-Y Antigen[edit]

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.[7] 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.[3] 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.[8]

Histocompatibility Antigen 1 (HA1)[edit]

HA1 results from a SNP converting the nonimmunogenic allele (KECVLRDDLLEA) to an immunogenic allele (KECVLHDDLLEA). This SNP results in better peptide binding ability to the groove of a particular MHC class I molecules found on antigen presenting cells.[5] 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.[5]

Immunotherapy Graft-Versus- Leukemia Effect[edit]

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 (GVL) 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.[9]

Clinical implications[edit]

Immunisation of mothers against male-specific minor histocompatibility (H-Y) 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.[10]

See also[edit]


  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. 178 (6): 3558–65. doi:10.4049/jimmunol.178.6.3558. PMID 17339452.
  2. ^ a b Dzierzak-Mietla M, Markiewicz M, Siekiera U, Mizia S, Koclega A, Zielinska P, Sobczyk-Kruszelnicka M, Kyrcz-Krzemien S (2012). "Occurrence and Impact of Minor Histocompatibility Antigens' Disparities on Outcomes of Hematopoietic Stem Cell Transplantation from HLA-Matched Sibling Donors". Bone Marrow Research. 2012: 257086. doi:10.1155/2012/257086. PMC 3502767. PMID 23193478.
  3. ^ a b c d e 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. doi:10.1111/aji.12075. PMC 4048750. PMID 23398025.
  4. ^ a b Hirayama M, Azuma E, Komada Y (2012). Major and Minor Histocompatibility Antigens to Non-Inherited Maternal Antigens (NIMA), Histocompatibility. INTECH. p. 146. ISBN 978-953- 51-0589-3.
  5. ^ a b c d Bleakley M, Riddell SR (March 2011). "Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia". Immunology and Cell Biology. 89 (3): 396–407. doi:10.1038/icb.2010.124. PMC 3061548. PMID 21301477.
  6. ^ Perreault C, Décary F, Brochu S, Gyger M, Bélanger R, Roy D (1990). "Minor histocompatibility antigens" (PDF). Blood. 76 (7): 1269–80. PMID 2207305.
  7. ^ Nielsen HS (2011-07-01). "Secondary recurrent miscarriage and H-Y immunity". Human Reproduction Update. 17 (4): 558–74. doi:10.1093/humupd/dmr005. PMID 21482560.
  8. ^ Lissauer D, Piper K, Goodyear O, Kilby MD, Moss PA (July 2012). "Fetal-specific CD8+ cytotoxic T cell responses develop during normal human pregnancy and exhibit broad functional capacity". Journal of Immunology. 189 (2): 1072–80. doi:10.4049/jimmunol.1200544. PMID 22685312.
  9. ^ Bleakley M, Riddell SR (2004). "Molecules and mechanisms of the graft-versus-leukaemia effect". Nature Reviews. Cancer. 4 (5): 371–80. doi:10.1038/nrc1365. PMID 15122208.
  10. ^ Nielsen HS (2011). "Secondary recurrent miscarriage and H-Y immunity". Human Reproduction Update. 17 (4): 558–74. doi:10.1093/humupd/dmr005. PMID 21482560.

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