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Rheumatoid factors (RFs), polyreactive antibodies canonically known to bind two conformational epitopes of IgG Fc, are a hallmark of rheumatoid arthritis but also can arise in other inflammatory conditions and infections. Also, infections may contribute to the development of rheumatoid arthritis and other autoimmune diseases. Recently, RFs only in rheumatoid arthritis were found to bind novel linear IgG epitopes as well as thousands of other rheumatoid arthritis autoantigens. Specific epitopes recognized by infection-induced polyreactive RFs remain undefined but could provide insights into loss of immune tolerance. Here, we identified novel linear IgG epitopes bound by RFs in COVID-19 but not rheumatoid arthritis or other conditions. The main COVID-19 RF was polyreactive, binding two IgG and multiple viral peptides with a tripeptide motif, as well as IgG Fc and SARS-CoV-2 spike proteins. In contrast, a rheumatoid arthritis-specific RF recognized IgG Fc, but not tripeptide motif-containing peptides or spike. Thus, RFs have disease-specific IgG reactivity and distinct polyreactivities that reflect the broader immune response. Moreover, the polyreactivity of a virus-induced RF appears to be attributable to a very short peptide motif. These findings refine our understanding of RFs and provide new insights into how viral infections may contribute to autoimmunity., Competing Interests: Declaration of competing interest M.A.S. is listed as an inventor on a patent filed related to this study (PCT/18/079,188; IgG EPITOPE PEPTIDES THAT BIND RHEUMATOID FACTOR AND METHODS OF USE THEREOF). M.H.P. became employed by JangoBio, R.R.A by Labcorp Drug Development, and Z.Z. by Google after completing their contributions to the project. S.S.M. is a consultant for Bristol Myers Squibb, Novartis, Otsuka/Visterra, Horizon, Target RWE, Horizon, and Kiniksa, none of which relate to the work in this manuscript. All other authors declare no conflicts of interest., (Published by Elsevier Ltd.)

Background: The consequences of past coronavirus disease 2019 (COVID-19) infection for personal and population health are emerging, but accurately identifying distant infection is a challenge. Anti-spike antibodies rise after both vaccination and infection and anti-nucleocapsid antibodies rapidly decline., Methods: We evaluated anti-membrane antibodies in COVID-19 naive, vaccinated, and convalescent subjects to determine if they persist and accurately detect distant infection., Results: We found that anti-membrane antibodies persist for at least 1 year and are a sensitive and specific marker of past COVID-19 infection., Conclusions: Thus, anti-membrane and anti-spike antibodies together can differentiate between COVID-19 convalescent, vaccinated, and naive states to advance public health and research., Competing Interests: Potential conflicts of interest. M. F. A., D. H. O., and M. A. S. are listed as inventors on a patent filed related to this study (PCT/US2021/051143; IDENTIFICATION OF SARS-COV-2 EPITOPES DISCRIMINATING COVID-19 INFECTION FROM CONTROL AND METHODS OF USE). Promega provided Lumit SARS-CoV-2 Immunoassay kits. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)