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

Abstract

Systemic sclerosis (SSc) is a clinically heterogeneous autoimmune disease characterized by mutually exclusive autoantibodies directed against distinct nuclear antigens. We examined <i>HLA</i> 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 <i>HLA-DRB1</i>*<i>08:04</i> and <i>HLA-DRB1</i>*<i>11:02</i> alleles were associated with overall SSc risk, and the <i>HLA-DRB1</i>*<i>08:04</i> 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 <i>HLA-DPB1</i>*<i>13:01</i> and <i>HLA-DRB1</i>*<i>07:01</i> 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 <i>HLA</i> in defining autoantibody subtypes. The association of the <i>HLA-DPB1</i>*<i>13:01</i> allele with the ATA⁺ subset of SSc in both AA and EA patients demonstrated a transancestry effect. A direct correlation between SSc prevalence and <i>HLA-DPB1</i>*<i>13:01</i> allele frequency in multiple populations was observed (<i>r</i> = 0.98, <i>P</i> = 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 <i>HLA</i> alleles, autoantibodies, and environmental triggers in the pathogenesis of SSc.