DOI: 10.3389/fimmu.2019.01625; PMCID: PMC6646417
Genetic mismatches in protein coding genes between allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipient and donor can elicit an alloimmunity response via peptides presented by the recipient HLA receptors as minor histocompatibility antigens (mHAs). While the impact of individual mHAs on allo-HSCT outcome such as graft-vs.-host and graft-vs.-leukemia effects has been demonstrated, it is likely that established mHAs constitute only a small fraction of all immunogenic non-synonymous variants. In the present study, we have analyzed the genetic mismatching in 157 exome-sequenced sibling allo-HSCT pairs to evaluate the significance of polymorphic HLA class I associated peptides on clinical outcome. We applied computational mismatch estimation approaches based on experimentally verified HLA ligands available in public repositories, published mHAs, and predicted HLA-peptide affinites, and analyzed their associations with chronic graft-vs.-host disease (cGvHD) grades. We found that higher estimated recipient mismatching consistently increased the risk of severe cGvHD, suggesting that HLA-presented mismatching influences the likelihood of long-term complications in the patient. Furthermore, computational approaches focusing on estimation of HLA-presentation instead of all non-synonymous mismatches indiscriminately may be beneficial for analysis sensitivity and could help identify novel mHAs.
Genotype; Graft vs Host Disease; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Histocompatibility; Histocompatibility Testing; Humans; Minor Histocompatibility Antigens; Siblings; Tissue Donors; Transplantation, Homologous
HLA; HSCT; genomics; graft-vs.-host; minor histocompatibility antigen; whole-exome sequencing
Ritari, J., Hyvärinen, K., Koskela, S., Niittyvuopio, R., Nihtinen, A., Salmenniemi, U., Putkonen, M., Volin, L., Kwan, T., Pastinen, T., Itälä-Remes, M., Partanen, J. Computational Analysis of HLA-presentation of Non-synonymous Recipient Mismatches Indicates Effect on the Risk of Chronic Graft-vs.-Host Disease After Allogeneic HSCT. Front Immunol 10, 1625-1625 (2019).