Computational Analysis of HLA-presentation of Non-synonymous Recipient Mismatches Indicates Effect on the Risk of Chronic Graft-vs.-Host Disease After Allogeneic HSCT

Abstract

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.

Optimized Whole Genome Association Scanning for Discovery of HLA Class I-Restricted Minor Histocompatibility Antigens

“…SNP disparities in the same range have been reported by others (37). Martin et al (40) showed that a higher number of SNP disparities in patients transplanted with sibling donors was associated with an increase in grade III-IV GVHD and stage 2-4 acute gut GVHD, whereas Ritari et al (41) found an association between a higher number of mismatching peptide ligands and chronic GvHD. All SNP disparities as measured by Koparde et al (39) were also investigated to encode 9-mer peptides with predicted binding to patients' HLA class I alleles using NetMHCpan 2.8.…”

“…Whole transcriptome RNA sequencing and HLA ligandome analysis by mass spectrometry can be implemented as additional steps to select for peptides that are expressed and presented on the cell surface. These techniques significantly decrease false discovery (31,38,41,42), but also reduce the sensitivity and lead to a higher chance that antigens are missed (38), illustrating that prediction tools for minor histocompatibility antigens still require optimization.…”

Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

“…We discovered pathways associated with aGvHD pathogenesis, implicating immunological responses in processes such as T cell function, cytokines, JAK-STAT signaling, and regulation of the TRAF6 gene. The risk for GvHD has mainly been investigated during past decades by concentrating on the MHC region and specific candidate genes (10,11), and only in recent years has the use of genome-wide approaches emerged in the field (16,17,(19)(20)(21)(22). These studies have shown the importance of genetic component in HSCT complications, but the results remain diverse, and their replication is incomplete.…”

“…We obtained no results for cGvHD, which may be due to the smaller number of available studies or lack of strong genetic component in this condition. We recently reported that the severity of cGvHD is associated with the overall immunogenetic differences between HSCT pairs (22); hence, its genetic background may differ from that of aGvHD.…”

“…In 2017, Goyal et al reported three HLA-DP region loci in recipient genomes associated with severe aGvHD in a population with European-American ancestry (19). A genomewide approach was also employed by Martin et al (20) and Ritari et al (21,22), who both studied the effect of genome-wide recipient-donor mismatching. They concluded that an increase in genome-wide recipient mismatching is associated with an increased risk for GvHD.…”