HLAand autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry
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Published:2019-12-23
Issue:1
Volume:117
Page:552-562
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ISSN:0027-8424
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Container-title:Proceedings of the National Academy of Sciences
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language:en
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Short-container-title:Proc Natl Acad Sci USA
Author:
Gourh PravittORCID, 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.ORCID, 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.
Abstract
Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examinedHLAassociations 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-predominantHLA-DRB1*08:04andHLA-DRB1*11:02alleles were associated with overall SSc risk, and theHLA-DRB1*08:04allele 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, theHLA-DPB1*13:01andHLA-DRB1*07:01alleles were more strongly associated with antitopoisomerase (ATA) and anticentromere antibody-positive subsets of SSc, respectively, than with overall SSc risk, emphasizing the importance ofHLAin defining autoantibody subtypes. The association of theHLA-DPB1*13:01allele with the ATA+subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence andHLA-DPB1*13:01allele 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 betweenHLAalleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.
Publisher
Proceedings of the National Academy of Sciences
Subject
Multidisciplinary
Cited by
47 articles.
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