HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry

Pravitt Gourh, Sarah A. Safran, Theresa Alexander, Steven E. Boyden, Nadia D. Morgan, Ami A. Shah, Maureen D. Mayes, Ayo Doumatey, Amy R. Bentley, Daniel Shriner, Robyn T. Domsic, Thomas A. Medsger, Paula S. Ramos, Richard M. Silver, Virginia D. Steen, John Varga, Vivien Hsu, Lesley Ann Saketkoo, Elena Schiopu, Dinesh KhannaJessica K. Gordon, Brynn Kron, Lindsey A. Criswell, Heather Gladue, Chris T. Derk, Elana J. Bernstein, S. Louis Bridges, Victoria K. Shanmugam, Kathleen D. Kolstad, Lorinda Chung, Suzanne Kafaja, Reem Jan, Marcin Trojanowski, Avram Goldberg, Benjamin D. Korman, Peter J. Steinbach, Settara C. Chandrasekharappa, James C. Mullikin, Adebowale Adeyemo, Charles Rotimi, Fredrick M. Wigley, Daniel L. Kastner*, Francesco Boin, Elaine F. Remmers

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens.We examined HLA associations in SSc and its autoantibody subsets in a large, newly recruited African American (AA) cohort and among European Americans (EA). In the AA population, the African ancestrypredominant HLA-DRB1∗08:04 and HLA-DRB1∗11:02 alleles were associated with overall SSc risk, and the HLA-DRB1∗08:04 allele was strongly associated with the severe antifibrillarin (AFA) antibody subset of SSc (odds ratio = 7.4). These African ancestrypredominant alleles may help explain the increased frequency and severity of SSc among the AA population. In the EA population, the HLA-DPB1∗13:01 and HLA-DRB1∗07:01 alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance of HLA in defining autoantibody subtypes. The association of the HLA-DPB1∗13:01 allele with the ATA+ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and HLA-DPB1∗13:01 allele frequency in multiple populations was observed (r = 0.98, P = 3 × 10-6). Conditional analysis in the autoantibody subsets of SSc revealed several associated amino acid residues, mostly in the peptide-binding groove of the class II HLA molecules. Using HLA α/β allelic heterodimers, we bioinformatically predicted immunodominant peptides of topoisomerase 1, fibrillarin, and centromere protein A and discovered that they are homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families. Taken together, these data suggest a possible link between HLA alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.

Original languageEnglish (US)
Pages (from-to)552-562
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number1
DOIs
StatePublished - Jan 7 2020

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry'. Together they form a unique fingerprint.

Cite this