학술논문
HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry
Document Type
article
Author
Gourh, Pravitt; Safran, Sarah A; Alexander, Theresa; Boyden, Steven E; Morgan, Nadia D; Shah, Ami A; Mayes, Maureen D; Doumatey, Ayo; Bentley, Amy R; Shriner, Daniel; Domsic, Robyn T; Medsger, Thomas A; Ramos, Paula S; Silver, Richard M; Steen, Virginia D; Varga, John; Hsu, Vivien; Saketkoo, Lesley Ann; Schiopu, Elena; Khanna, Dinesh; Gordon, Jessica K; Kron, Brynn; Criswell, Lindsey A; Gladue, Heather; Derk, Chris T; Bernstein, Elana J; Bridges, S Louis; Shanmugam, Victoria K; Kolstad, Kathleen D; Chung, Lorinda; Kafaja, Suzanne; Jan, Reem; Trojanowski, Marcin; Goldberg, Avram; Korman, Benjamin D; Steinbach, Peter J; Chandrasekharappa, Settara C; Mullikin, James C; Adeyemo, Adebowale; Rotimi, Charles; Wigley, Fredrick M; Kastner, Daniel L; Boin, Francesco; Remmers, Elaine F
Source
Proceedings of the National Academy of Sciences of the United States of America. 117(1)
Subject
Language
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 ancestry-predominant 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 ancestry-predominant 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.