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.

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Opinion statement Cutaneous fibrosing disorders encompass a diverse array of diseases united by the presence of varying degrees of dermal sclerosis. The quality and distribution of skin involvement, presence or absence of systemic complications and unique associated laboratory abnormalities often help to distinguish between these diseases. It is imperative that an effort is made to accurately differentiate between scleroderma and its mimics, in order to guide long-term management and facilitate implementation of the appropriate treatment modality where indicated.