Human leukocyte antigen (HLA) genes, autoantibodies, and environmental triggers may collectively play a role in the pathogenesis of systemic sclerosis (SSc), according to study results published in Proceedings of the National Academy of Sciences of the United States of America.

Previous studies have shown that HLA alleles have been associated with risk for scleroderma. Researchers of this study investigated the relationships between HLA alleles and autoantibody subsets that may promote the pathogenesis of SSc among patients with black and white backgrounds.

Researchers evaluated genotype data and serum SSc-specific autoantibody data from 662 black patients with SSc and 946 genetically similar healthy controls. They assessed similar genotype and phenotype data from 723 white patients with SSc and 5347 healthy controls; logistic regression analysis was used to identify HLA alleles and amino acids associated with SSc risk.

Researchers revealed that among patients who were black, 2 independent class II HLA alleles were significantly associated with SSc risk: HLA-DRB1*08:04 and HLA-DRB1*11:02. The HLA-DRB1*08:04 allele was strongly associated with the severe antifibrillarin antibody subset of SSc (odds ratio [OR], 7.4 [95% CI, 4.9-11.3]). 

Among patients who were white, 3 independent HLA classical alleles were significantly associated with SSc risk: HLA-DQB1*02:02, HLA-DPB1*13:01, and HLA-DRB1*11:04. The HLA-DQB1*02:02 allele was found to be disease-protective in this population (OR, 0.5 [95% CI, 0.4-0.6]), and the HLA-DPB1*13:01 and HLA-DRB1*07:01 alleles were found to be more strongly associated with antitopoisomerase and anticentromere antibody-positive subsets of SSc compared with the overall SSc risk. 

Researchers observed a direct correlation between SSc prevalence in any population and the frequency of HLA-DPB1*13:01 with a correlation coefficient of 0.98 and P =1.8 × 10-6. They revealed through conditional analysis that several amino acid residues were associated with SSc, most of which were part of the peptide-binding groove of class II HLA molecules. They also bioinformatically predicted immunodominant peptides of self-antigens (topoisomerase 1, fibrillarin, and centromere protein A) and found these were homologous to viral protein sequences from the Mimiviridae and Phycodnaviridae families.

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Researchers emphasized the relevance of class II HLA genes in the pathogenesis of SSc and that scleroderma-specific autoantibodies may suggest potential molecular mimicry in this disease.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Gourh P, Safran SA, Alexander T, et al. HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry. Proc Natl Acad Sci U S A. 2020;117(1):552-562.