Background/Purpose: Rheumatoid factors (RFs), polyreactive antibodies canonically known to bind two conformational epitopes of IgG, are a hallmark of rheumatoid arthritis but also can arise in other inflammatory conditions and infections. In turn, infections, such as respiratory infections, correlate with rheumatoid arthritis development, but the mechanisms are unclear. Recently, RF reactivity in rheumatoid arthritis, and not in other autoimmune diseases, was found to include citrullinated and homocitrullinated IgG epitopes as well as thousands of citrullinated and homocitrullinated antigens targeted by anti-citrullinated protein antibodies. Specific epitopes recognized by infection-induced RFs remain undefined. The purpose of this study was to evaluate the reactivity of RFs induced in a primary immune response in adults to better understand how a viral infection might lead to loss of immune tolerance and rheumatoid arthritis.

Methods: Clinical data and sera were obtained from adults five weeks post-COVID-19 (positive SARS-CoV-2 test in the spring of 2020) or the following subjects with no past COVID-19: rheumatoid arthritis, Sjögren’s disease, lupus, smokers, and age- and sex-matched controls. Sera were used in a high density peptide array to evaluate IgA, IgM, and IgG binding to all possible 16 amino acid peptides derived from human IgG1-4 and the proteomes and proteins of several viruses including SARS-CoV-2 with results confirmed by ELISA. Antibodies were purified to evaluate cross-reactivity by ELISA. Data were analyzed by Kruskal-Wallis with Dunn’s multiple comparisons tests, Mann-Whitney test, Wilcoxon matched-pairs signed rank test, and MixTwice.

Results: We identified three novel IgG epitopes (IgG1-131, IgG1-238, IgG1-293) bound by antibodies in COVID-19 but not rheumatoid arthritis, Sjögren’s disease, lupus, smokers, or controls. In contrast, a hinge peptide, IgG1-104, was recognized by rheumatoid arthritis and Sjögren’s disease antibodies. A polyreactive IgM-RF bound IgG1-131, IgG1-238, and many viral peptides with a tripeptide motif, as well as IgG Fc and SARS-CoV-2 spike proteins. In contrast, a previously identified rheumatoid arthritis-specific RF that binds homocitrullinated IgG1-219 recognized IgG Fc, but not motif-containing peptides or spike.

Conclusion: RFs are not a single entity in multiple diseases, but rather have disease-specific IgG reactivity and unique polyreactivities that reflect the broader immune response. Moreover, virus-induced, motif-driven polyreactivity, as opposed to molecular mimicry among a small number of antigens, can drive autoreactivity against IgG. These findings provide new insights into how viral infection may trigger immune tolerance loss with potential implications for rheumatoid arthritis and millions of people post-COVID-19.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-and-unique-rheumatoid-factors-cross-react-with-viral-epitopes-in-covid-19/