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. GVHD initiation.jpeg
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 peptides presented 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] 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]

Contents

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

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/A2VL[H/R]DDLLEAA*02:01chr191068739rs1801284HMHA1ENSG00000180448
HA-2YIGEVLVS[V/M]A*02:01chr744977022rs61739531MYO1GENSG00000136286
HA-8[R/P]TLDKVLEVA*02:01chr92828765rs2173904KIAA0020ENSG00000080608
HA-3V[T/M]EPGTAQYA*01:01chr1585579423rs2061821AKAP13ENSG00000170776
C19ORF48CIPPD[S/T]LLFPAA*02:01chr1950798945rs3745526C19ORF48ENSG00000167747
LB-ADIR-1FSVAPALAL[F/S]PAA*02:01chr1179082165rs2296377TOR3AENSG00000186283
LB-HIVEP1-1SSLPKH[S/N]VTIA*02:01chr612123016rs2228220HIVEP1ENSG00000095951
LB-NISCH-1AALAPAP[A/V]EVA*02:01chr352489389rs887515NISCHENSG00000010322
LB-SSR1-1S[S/L]LAVAQDLTA*02:01chr67310026rs10004SSR1ENSG00000124783
LB-WNK1-1IRTLSPE[I/M]ITVA*02:01chr12889199rs12828016WNK1ENSG00000060237
T4AGLYTYWSAG[A/E]A*02:01chr3140688418rs9876490TRIM42ENSG00000155890
UTA2-1QL[L/P]NSVLTLA*02:01chr1231981704rs2166807 KIAA1551 ENSG00000174718
PANE1RVWDLPGVLKA*03:01chr2241940168rs5758511CENPMENSG00000100162
SP110SLP[R/G]GTSTPKA*03:01chr2230207994rs1365776SP110ENSG00000135899
ACC-1CDYLQ[Y/C]VLQIA*24:02chr1579971064rs1138357BCL2A1ENSG00000140379
ACC-1YDYLQ[Y/C]VLQIA*24:02chr1579971064rs1138357BCL2A1ENSG00000140379
P2RX7WFHHC[H/R]PKYA*29:02chr12121167552rs7958311P2RX7ENSG00000089041
ACC-4ATLPLLCA[R/G]A*31:01chr1578944951rs2289702CTSHENSG00000103811
ACC-5WATLPLLCA[R/G]A*33:03chr1578944951rs2289702CTSHENSG00000103811
LB-APOBEC3B-1K[K/E]PQYHAEMCFB*07:02chr2238985821rs2076109APOBEC3BENSG00000179750
LB-ARHGDIB-1RLPRACW[R/P]EAB*07:02chr1214942624rs4703ARHGDIBENSG00000111348
LB-BCAT2-1RQP[R/T]RALLFVILB*07:02chr1948799813rs11548193BCAT2ENSG00000105552
LB-EBI3-1IRPRARYY[I/V]QVB*07:02chr194236999rs4740EBI3ENSG00000105246
LB-ECGF-1HRP[H/R]AIRRPLALB*07:02chr2250525826rs112723255TYMPENSG00000025708
LB-ERAP1-1RHPRQEQIALLAB*07:02chr596803547rs26653ERAP1ENSG00000164307
LB-FUCA2-1VRLRQ[V/M]GSWLB*07:02chr6143502020rs3762002FUCA2ENSG00000001036
LB-GEMIN4-1VFPALRFVE[V/E]B*07:02chr17746265rs4968104GEMIN4ENSG00000179409
LB-PDCD11-1FGPDSSKT[F/L]LCLB*07:02chr10103434329rs2986014PDCD11ENSG00000148843
LB-TEP1-1SAPDGAKVA[S/P]LB*07:02chr1420383870rs1760904TEP1ENSG00000129566
LRH-1TPNQRQNVCB*07:02chr173690983rs3215407P2X5ENSG00000083454
ZAPHIRIPRDSWWVELB*07:02chr1957492212rs2074071ZNF419ENSG00000105136
HEATR1ISKERA[E/G]ALB*08:01chr1236554626rs2275687HEATR1ENSG00000119285
HA-1/B60KECVL[H/R]DDLB*40:01chr191068739rs1801284HMHA1ENSG00000180448
LB-SON-1RSETKQ[R/C]TVLB*40:01chr2133553954rs13047599SONENSG00000159140
LB-SWAP70-1QMEQLE[Q/E]LELB*40:01chr119748015rs415895SWAP70ENSG00000133789
LB-TRIP10-1EPCG[E/G][P/S]QDL[C/G]TLB*40:01chr196751268rs1049229TRIP10ENSG00000125733
SLC1A5AE[A/P]TANGGLALB*40:02chr1946787917rs3027956SLC1A5ENSG00000105281
ACC-2KEFED[D/G]IINWB*44:03chr1579970875rs3826007BCL2A1ENSG00000140379
ACC-6MEIFIEVFSHFB*44:03chr1863953532rs9945924HMSDENSG00000221887
HB-1HEEKRGSL[H/Y]VWB*44:03chr5143820488rs161557HMHB1ENSG00000158497
HB-1YEEKRGSL[H/Y]VWB*44:03chr5143820488rs161557HMHB1ENSG00000158497
DPH1S[V/L]LPEVDVWB*57:01chr172040586rs35394823DPH1ENSG00000108963
UTDP4-1R[I/N]LAHFFCGWDPB1*04chr9128721272rs11539209ZDHHC12ENSG00000160446
CD19WEGEPPC[L/V]PDQB1*02:01chr1628933075rs2904880CD19ENSG00000177455
LB-PI4K2B-1SSRSS[S/P]AELDRSRDQB1*06:03chr425234395rs313549PI4K2BENSG00000038210
LB-MTHFD1-1QSSIIAD[Q/R]IALKLDRB1*03:01chr1464442127rs2236225MTHFD1ENSG00000100714
LB-LY75-1KLGITYR[N/K]KSLMWFDRB1*13:01chr2159819916rs12692566LY75ENSG00000054219
SLC19A1[R/H]LVCYLCFYDRB1*15:01chr2145537880rs1051266SLC19A1ENSG00000173638
LB-PTK2B-1TVYMND[T/K]SPLTPEKDRB3*01:01chr827451068rs751019PTK2BENSG00000120899
LB-MR1-1RYFRLGVSDPI[R/H]GDRB3*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. [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

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

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. [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)

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

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

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

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

Histocompatibility, or tissue compatibility, is the property of having the same, or sufficiently similar, alleles of a set of genes called human leukocyte antigens (HLA), or major histocompatibility complex (MHC). Each individual expresses many unique HLA proteins on the surface of their cells, which signal to the immune system whether a cell is part of the self or an invading organism. T cells recognize foreign HLA molecules and trigger an immune response to destroy the foreign cells. Histocompatibility testing is most relevant for topics related to whole organ, tissue, or stem cell transplants, where the similarity or difference between the donor's HLA alleles and the recipient's triggers the immune system to reject the transplant. The wide variety of potential HLA alleles lead to unique combinations in individuals and make matching difficult.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Human leukocyte antigen</span> Genes on human chromosome 6

The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

<span class="mw-page-title-main">Transplant rejection</span> Rejection of transplanted tissue by the recipients immune system

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

<span class="mw-page-title-main">Graft-versus-host disease</span> Medical condition

Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.

Alloimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigens and histocompatibility antigens. In alloimmunity, the body creates antibodies against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.

<span class="mw-page-title-main">MHC class I</span> Protein of the immune system

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway.

<span class="mw-page-title-main">HLA-DR</span> Subclass of HLA-D antigens that consist of alpha and beta chains

HLA-DR is an MHC class II cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31. The complex of HLA-DR and peptide, generally between 9 and 30 amino acids in length, constitutes a ligand for the T-cell receptor (TCR). HLA were originally defined as cell surface antigens that mediate graft-versus-host disease. Identification of these antigens has led to greater success and longevity in organ transplant.

Bare lymphocyte syndrome is a condition caused by mutations in certain genes of the major histocompatibility complex or involved with the processing and presentation of MHC molecules. It is a form of severe combined immunodeficiency.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, now bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation, where it can be recognized by a T-cell receptor. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

<span class="mw-page-title-main">MHC class II</span> Protein of the immune system

MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.

<span class="mw-page-title-main">HLA-A</span> Protein-coding gene in the species Homo sapiens

HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of human MHC class I transmembrane proteins. The others are HLA-B and HLA-C. The protein is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule. The β2 microglobulin protein is encoded by the B2M gene, which is located at chromosome 15q21.1 in humans.

<span class="mw-page-title-main">HLA-DM</span>

HLA-DM is an intracellular protein involved in the mechanism of antigen presentation on antigen presenting cells (APCs) of the immune system. It does this by assisting in peptide loading of major histocompatibility complex (MHC) class II membrane-bound proteins. HLA-DM is encoded by the genes HLA-DMA and HLA-DMB.

<span class="mw-page-title-main">HLA-G</span>

HLA-G histocompatibility antigen, class I, G, also known as human leukocyte antigen G (HLA-G), is a protein that in humans is encoded by the HLA-G gene.

<span class="mw-page-title-main">Major histocompatibility complex, class II, DQ alpha 1</span> Protein-coding gene in the species Homo sapiens

Major histocompatibility complex, class II, DQ alpha 1, also known as HLA-DQA1, is a human gene present on short arm of chromosome 6 (6p21.3) and also denotes the genetic locus which contains this gene. The protein encoded by this gene is one of two proteins that are required to form the DQ heterodimer, a cell surface receptor essential to the function of the immune system.

Human leukocyte antigens (HLA) began as a list of antigens identified as a result of transplant rejection. The antigens were initially identified by categorizing and performing massive statistical analyses on interactions between blood types. This process is based upon the principle of serotypes. HLA are not typical antigens, like those found on surface of infectious agents. HLAs are alloantigens, they vary from individual to individual as a result of genetic differences. An organ called the thymus is responsible for ensuring that any T-cells that attack self proteins are not allowed to live. In essence, every individual's immune system is tuned to the specific set of HLA and self proteins produced by that individual; where this goes awry is when tissues are transferred to another person. Since individuals almost always have different "banks" of HLAs, the immune system of the recipient recognizes the transplanted tissue as non-self and destroys the foreign tissue, leading to transplant rejection. It was through the realization of this that HLAs were discovered.

Alloantigen recognition refers to immune system recognition of genetically encoded polymorphisms among the genetically distinguishable members of same species. Post-transplant recognition of alloantigens occurs in secondary lymphoid organs. Donor specific antigens are recognized by recipient’s T lymphocytes and triggers adaptive pro-inflammatory response which consequently leads to rejection of allogenic transplants. Allospecific T lymphocytes may be stimulated by three major pathways: direct recognition, indirect recognition or semidirect recognition. The pathway involved in specific cases is dictated by intrinsic and extrinsic factors of allograft and directly influence nature and magnitude of T lymphocytes mediated immune response. Furthermore, variant tissues and organs such as skin or cornea or solid organ transplants can be recognized in different pathways and therefore are rejected in different fashion.

Mixed lymphocyte reaction (MLR) is a test used by pharmaceutical and biotech organizations to show the safety of a drug or implantable material. It is commonly used as part of the FDA clearance process. Put simply, it is mixing populations of T-lymphocytes together, and measuring the reaction that occurs. Technically, it is an ex-vivo cellular immune assay that occurs between two allogeneic lymphocyte populations. In a one-way MLR, only one lymphocyte population can respond or proliferate. In a two-way MLR, both populations can proliferate. MLR’s are performed to assess how T-cells react to external stimuli. T cells are a type of white blood cell that scans for cellular abnormalities and infections. They are essential to human immunity.

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. 178 (6): 3558–65. doi:10.4049/jimmunol.178.6.3558. PMID   17339452.
  2. ↑ 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. 1 2 3 4 5 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. 1 2 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. 1 2 3 4 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. doi:10.1182/blood.V76.7.1269.1269. 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. S2CID   35740723.
  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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