Influence of HLA-B Leader (−21M/T) Dimorphism With Bw4/Bw6 Epitopes on Graft Versus Host Disease After Allogenic Haematopoietic Stem Cell Transplantation in North Indians

Abstract

High degree of variability in human leukocyte antigens (HLAs) system restricts availability of histocompatible HLA-matched-related donors, thus increasing reliance on worldwide bone marrow registries network. Nevertheless, due to limited coverage/accessibility/affordability of some ethnicities in these registries, haploidentical haematopoietic stem cell transplantation (HSCT) emerged as an alternative option, though with allorecognition-mediated graft versus host disease (GvHD) (>40% cases). A dimorphism [−21 methionine (M) or threonine (T)] in HLA-B leader peptide (exon 1) which differentially influences its HLA-E binding, plausibly regulates natural killer cell functionality, affecting GvHD vulnerability and clinically in practice for donor selection. Here, we analysed population-specific influence of this functionally relevant dimorphism on post HSCT GvHD occurrence and clinical utility (if any) towards defining donor permissibility. High resolution HLA-B genotyping data were analysed in 178 study participants, including 89 HSCT patient–donor pairs, for the frequency distribution of −21 leader dimorphism. Distribution of HLA-Bw4/Bw6 was deduced with killer cell immunoglobulin receptor ligand calculator tool in IPD-IMGT/HLA database. Though −21T (∼85%) was over represented in the study participants, no significant influence is observed for this variant between HLA-identical v/s haplo HSCT either with or without GvHD, at allelic and genotypic levels as well as in BLEAT (HLA-B Leader Assessment Tool)-based donor–recipient matching. Stratified analysis of −21 M/T into Bw4/Bw6 groups revealed a higher frequency of −21T + Bw4 in GvHD (+) group compared to GvHD (−) (p < 0.05), plausibly linking this haplotype with occurrence of GvHD post HSCT and importance of HLA class I-mediated NK cell functionality in GvHD.