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Minor histocompability antigens (MiHAs) are diverse segments of a protein known as peptides  that are bound to the major histocompatibility complex (MHC). These peptides are normally around 9-12 amino acids and are present in either MHC class I or II. . Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, insertions, or being encoded by the Y chromosome. These peptide sequences derive from proteins that are encoded by various autosomal chromosomes or about a third of the characterized MiHAs come from the Y chromosome. The proteins are composed of two alleles an immunogenic HLA allele and a nonimmunogenic allele. Prior to becoming a short peptide sequence, the proteins expressed by polymorphic or diverse genes need to be digested in the protesome 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 but proteins from outside cells could also bind to MHC class II molecule. The form of the MHC gene has a pattern that impacts which specific peptides can bind to it. These antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in only hematopoietic cells, the immune cells.

T cell Response to MiHAs

The MiHAs bound to a MHC presented on a cell surface may be either be recognized as a self peptide or not recognized by either CD8+ and CD4+ T cells. The lack of recognition of a T cell to this self antigen is the reason why allogeneic stem cell transplantation for a 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 (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). Although graft or bone marrow rejection can have determiental 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).

Discovery of MiHAs

The significance of MiHAs in an immune response was recognized following transplantation of a donor and recipient with the recipient developing GVHD despite having a HLA matched gene of the MHC complex. More specifically, when bone marrow transplantation occurred between opposite sexes, the first MiHA was discovered. The female recipient obtained bone marrow cells from a male donor with a matched HLA gene to prevent GVHD but still had active cytotoxic T cells (CD8+). The CD8+ were active in the sense that they were targeting the male bone marrow cells because these cells were presenting a forgein peptide on the MHC groove. The peptide is foreign to the female T cells since it is encoded by a Y chromosome and females lack this MiHA. The MiHAs encoded by Y chromosome are known as HY antigens.

Histocompatibility Antigen 1 (HA1)

HA1 results from a SNP from a nonimmunogenic allele (KECVLRDDLLEA) to a immunogenic allele (KECVLHDDLLEA) resulting in better peptide binding ability onto the groove of MHC class I molecules of antigen presenting cells. The significance of the peptide changing to immunogenic form is that now specific HLA-A 0201 restricted T cells can recognize the peptide presented on MHC class I groove encoded by a HLA-A gene leading to an immune response. However, for an immune response to be initiated, the T cells must recognize the peptide as foreign and this occurs when the T cells lack the immunogenic version of the peptide occurring in cases of pregnancy and allogeneic stem cell transplantation. In pregnancy, the fetal HA-1 has been found to originate in the placenta and specific maternal CD8+ T cells were identified for this MiHA.

H-Y Antigen

HY antigens are encoded by genes on the Ychromosome. 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 HY 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.

Immunotherapy Graft-Versus- Leukemia Effect

CD8+ T cells that are specific for a MiHA can target these antigens that are expressed specifically on tumor cells to destroy harmful tumor cells. Following allogeneic stem cell transplantation, in mice models, donor CD8+ T cells specific for an MiHA in the recipient have been found to inhibit the proliferation or dividing of leukemic cells and prevent leukemia. T cells can target early progenitor immature leukemic cells such as T cells specific for HA-1 and HA-2 MiHAs. However, there is a risk in developing GVHD if the T cells are specific for MiHAs expressed ubiquitiously on epithelial cells. More specifically, HA-8, UGT2B17 and SMCY MiHAs that are ubiquitously expressed have a higher risk with 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. An example of a ideal target are T cells that are specific for a MiHA encoded by HB-1 gene, which is highly expressed in harmful B cells, but has a low expression in other tissue cells containing a HLA-B*4402 or HLA-B*4403 MHC restriction.