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Disordered Antigens and Epitope Overlap Between Anti–Citrullinated Protein Antibodies and Rheumatoid Factor in Rheumatoid Arthritis
Author(s) -
Zheng Zihao,
Mergaert Aisha M.,
Fahmy Lauren M.,
Bawadekar Mandar,
Holmes Caitlyn L.,
Ong Irene M.,
Bridges Alan J.,
Newton Michael A.,
Shelef Miriam A.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41074
Subject(s) - epitope , rheumatoid arthritis , rheumatoid factor , antigen , antibody , immunology , medicine
Objective Anti–citrullinated protein antibodies ( ACPA s) and rheumatoid factor ( RF ) are commonly present in rheumatoid arthritis ( RA ) without a clear rationale for their coexistence. Moreover, autoantibodies develop against proteins with different posttranslational modifications and native proteins without obvious unifying characteristics of the antigens. We undertook this study to broadly evaluate autoantibody binding in seronegative and seropositive RA to identify novel features of reactivity. Methods An array was created using a total of 172,828 native peptides, citrulline‐containing peptides, and homocitrulline‐containing peptides derived primarily from proteins citrullinated in the rheumatoid joint. IgG and IgM binding to peptides were compared between cyclic citrullinated peptide ( CCP )–positive RF +, CCP + RF −, CCP − RF +, and CCP − RF − serum from RA patients (n = 48) and controls (n = 12). IgG‐bound and endogenously citrullinated peptides were analyzed for amino acid patterns and predictors of intrinsic disorder, i.e., unstable 3‐dimensional structure. Binding to IgG‐derived peptides was specifically evaluated. Enzyme‐linked immunosorbent assay confirmed key results. Results Broadly, CCP + RF + patients had high citrulline‐specific IgG binding to array peptides and CCP + RF − and CCP − RF + patients had modest citrulline‐specific IgG binding (median Z scores 3.02, 1.42, and 0.75, respectively; P < 0.0001). All RA groups had low homocitrulline‐specific binding. CCP + RF + patients had moderate IgG binding to native peptides (median Z score 2.38; P < 0.0001). The highest IgG binding was to citrulline‐containing peptides, irrespective of protein identity, especially if citrulline was adjacent to glycine or serine, motifs also seen in endogenous citrullination in the rheumatoid joint. Highly bound peptides had multiple features predictive of disorder. IgG from CCP + RF + patients targeted citrulline‐containing IgG‐derived peptides. Conclusion Disordered antigens, which are frequently citrullinated, and common epitopes for ACPA s and RF are potentially unifying features for RA autoantibodies.