Science Spotlight

Could the minor be a major after all? Histocompatibility antigens and GVHD

from Drs. Paul Martin and John Hansen (Clinical Research Division)
The figure represent the single nucleotide polymorphisms inheritance and mismatching between siblings.
Single Nucleotide Polymorphism inheritance and mismatching between siblings. A- Differential inheritance of paternal and maternal chromosomes causes mismatching between sibling pairs. If a pair of paternal chromosomes is designated “a” and “b” and the respective pair of maternal chromosomes is designated “c” and “d,” the chromosomes inherited by the offspring in the absence of meiotic recombination will be “ac” (siblings 1 and 2), “ad” (sibling 3), “bc” (sibling 4) or “bd” (sibling 5). Inheritance of the same chromosome pairs by a sibling pair (eg, “ac”) as shown for siblings 1 and 2 is described as identity by state (IBS). B- Meiotic recombination introduces different IBS values across segments of chromosomes inherited by sibling pairs. The figure shows results for 3 sibling pairs with high (top), medium (middle), and low (bottom) genome-wide mismatching across chromosome 6, analyzed as described by Roberson and Pevsner. HLA-matching of these pairs is indicated by IBS values of 2 (green) across the MHC region. Genome-wide mismatching increases as the length of segments with IBS values of 2 decreases. Segments with IBS values of 0 (red) and 1 (blue) have different probabilities of recipient mismatching. Figure adapted from the article.

Graft versus host disease (GVHD) occurs as an adverse event following hematopoietic stem cell transplantation, when the transplanted donor cells recognize the recipient’s normal cells and eliminate them in addition to the recipient’s tumor cells. This can happen when the donor and recipient cells have genetic variations in the same gene, called single nucleotide polymorphisms or SNPs.

Major histocompatibility antigens or Human Leukocyte Antigens (HLA) are encoded by genes in the major histocompatibility complex (MHC).  Minor histocompatibility antigens are products of protein degradation presented by HLA molecules at the cell surface of Antigen Presenting Cells (APCs). Polymorphic HLA mismatches between the donor and the recipient cells are a significant risk factor for GVHD development. For this reason, when possible, donor and recipient pairs will be either siblings (HLA-matched) or unrelated but HLA-matched. The matching is done according to the major antigens. Despite these precautions, GVHD can still occur within HLA-matched pairs. In this case, it has been recognized that the minor antigens might be responsible for the risk of GVHD. More than a hundred minor antigens have been identified so far but their implications in GVHD remain poorly understood.

In a recent study published in Blood, Drs. Paul Martin, John Hansen and collaborators from the Fred Hutch (Clinical Research Division) provided additional insight into the minor antigens. They investigated SNPs’ distribution across the genome and their association with the risk to develop GVHD following allogeneic (from a donor to a recipient) hematopoietic cells transplantation. To this end, the authors compared the risk to develop GVHD between three groups of transplanted individuals: siblings (HLA-matched), unrelated HLA-matched (including a molecule called HLA-DP) and unrelated with mismatching for HLA-DP.

Looking into the frequency of SNPs within these three groups of individuals revealed that unrelated patients had twice as many mismatching minor antigens (17.3% of SNP for the HLA-DP matched and 17.4% for the HLA-DP mismatched) relative to siblings (9.35% SNP mismatching). Each 1% higher frequency of minor SNPs increased the risk to develop stage III-IV GVHD by 20% in the siblings. Further, the risk of stage 2-4 gut GVHD increased by 22% in the siblings and by 38% in the unrelated individuals. Despite having twice as many SNPs mismatches, the risk of GVHD was not significantly higher in HLA-matched unrelated pairs relative to the HLA-matched siblings. However, this risk was much higher for HLA-DP mismatched versus HLA-matched pairs. These results suggest that the risk of GVHD is more influenced by mismatches in HLA than by minor antigen mismatches. However, the authors highlight that these observations do not exclude the implication of the minor antigens in GVHD development. Indeed, focus on SNP genetic variation does not account for transcripts or protein variants, as well as post-translational modifications such as glycosylation or sites of proteasomal cleavage between different variants, or the existence of immunodominant antigens.  Mismatch at any of these steps can lead to a donor-recipient mismatch independently of the SNPs.

These data may help to decipher the roles of the minor antigens in allogeneic hematopoietic cell transplantation. The authors are now trying to identify individual SNPs minor antigens that are associated with a higher or lower risk of GVHD.  The identification of specific SNP minor antigens leading or not to GVHD could make it possible for clinicians to treat malignancies through transplantation by graft versus tumor reactions while avoiding graft versus host disease. Dr. Martin further explained, “we would be very excited to find evidence showing that some minor antigen mismatches are associated with a decreased risk of recurrent malignancy but not with an increased risk of GVHD.  In theory, such a result is possible, if the minor antigen is expressed by hematopoietic cells but not by other cells in GVHD target organs.  Such results could encourage efforts to increase immune responses against these antigens”.


Funding for this study were provided by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NIH), and Cancer Center Support, National Cancer Institute (NIH), Department of Health and Human Services.


Martin PJ, Levine DM, Storer BE, Warren EH, Zheng X, Nelson SC, Smith AG, Mortensen BK, Hansen JA. 2017. Genome-wide minor histocompatibility matching as related to the risk of graft-versus-host disease. Blood 129(6):791-798.