Format

Send to

Choose Destination
Front Immunol. 2019 Jul 16;10:1625. doi: 10.3389/fimmu.2019.01625. eCollection 2019.

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

Author information

1
Finnish Red Cross Blood Service, Helsinki, Finland.
2
Stem Cell Transplantation Unit, Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki, Finland.
3
Stem Cell Transplantation Unit, Division of Medicine, Department of Hematology, Turku University Hospital, Turku, Finland.
4
Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, QC, Canada.
5
Center for Pediatric Genomic Medicine, Children's Mercy, Kansas City, MO, United States.

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.

KEYWORDS:

HLA; HSCT; genomics; graft-vs.-host; minor histocompatibility antigen; whole-exome sequencing

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center