Background/Purpose: Anti-citrullinated protein antibodies (ACPAs) in rheumatoid arthritis (RA) can be promiscuous, with cross-reactive binding to many antigens containing short motifs, or more private with little cross-reactivity. Also, ACPA reactivity patterns differ among people with RA, including for motif-containing epitopes in important self-antigens like type II collagen and IgG (the latter of which is bound by RA-associated rheumatoid factors, RFs), with limited understanding of the underlying mechanism. The objective of this study was to determine if HLA alleles associate with ACPA reactivity patterns.

Methods: For 100 ACPA+RF+ RA participants, serum IgG binding was quantified by enzyme-linked immunosorbent assay to five citrulline-containing peptides derived from type II collagen (all with citrulline-glycine motifs) and five citrulline-containing peptides derived from IgG1 (four with citrulline-serine motifs). Also, antibody and serum multi-reactivity were evaluated. HLA loci were genotyped, and HLA alleles present differentially in RA participants with high versus low IgG binding to specific peptides as well as with multi-reactivity versus limited reactivity were identified by Fisher’s exact test.

Results: Serum IgG multi-reactivity for citrulline-glycine motif-containing collagen peptides was high, at least partially due to promiscuous antibodies. HLA-DQA1*01:02 was present in more participants with anti-citrullinated collagen antibodies and sera multi-reactive with the collagen peptides. In contrast, serum multi-reactivity was low for IgG1-derived peptides due at least in part to more private antibodies. Shared epitope-containing HLA-DRB*04:01 and HLA-DRB*10:01 were present more frequently in participants with some RA-associated RFs that bind citrulline-containing IgG epitopes, irrespective of a citrulline-serine motif. Several HLA alleles associated with specific IgG reactivities.

Conclusion: These findings suggest that specific HLA alleles may contribute to the different reactivity patterns of promiscuous anti-citrullinated collagen antibodies and more private RA-associated RFs. Moreover, to the best of our knowledge, these findings provide the first evidence for a role for HLA-DQA1*01:02 in RA as well as the first HLA association with autoantibody multi-reactivity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-dqa10102-is-associated-with-igg-multi-reactivity-with-citrulline-containing-type-ii-collagen-epitopes-while-hla-drb0401-is-associated-with-more-private-reactivity-with-citrulline-containing-ig/