Rheumatoid factors (RFs) are antibodies of any isotype that bind the Fc region of IgG. Initially discovered in 1939 [1], RFs are a diagnostic marker for rheumatoid arthritis with 60–90 % sensitivity [2,3]. However, RFs also are found in people with other inflammatory conditions, including autoimmune diseases like Sjögren's disease and lupus, smokers, and both acute and chronic infections [[4], [5], [6], [7]]. In total, RFs are detectable in ∼4 % of “normal” individuals [8] despite being considered a hallmark of rheumatoid arthritis.

Canonically, RFs bind two conformational epitopes in the Fc region of IgG: the Ga determinant (an epitope comprised of loops from the CH2 and CH3 domains) [9] and an epitope in the hinge (a flexible region that connects the CH1 and CH2 domains) [10]. Of note, RFs do not bind native, circulating IgG; rather IgG must be enzymatically cleaved, be antigen-bound, or otherwise be modified to allow RF binding [11]. Recently, citrullinated and homocitrullinated linear IgG epitopes were identified as bound by IgG in rheumatoid arthritis and not in other autoimmune diseases, while a linear native IgG epitope in the hinge region was recognized in Sjögren's disease [12,13], suggesting that a distinct profile of IgG epitopes may be recognized by RFs in different autoimmune diseases. More recently, IgG Fc epitopes were demonstrated to be differentially targeted in rheumatoid arthritis, Sjögren's disease, and healthy donors [14]. However, which, if any, IgG epitopes are uniquely bound by RFs elicited by infection is unknown.

In addition to binding IgG Fc, RFs are commonly polyreactive, binding a variety of self and non-self-antigens [15,16]. For example, IgM-RFs (RFs of the IgM isotype) from rheumatoid arthritis and periodontitis patients can bind IgG and some oral bacteria [16]. Specific epitopes bound by polyreactive RFs in infection are unknown. However, a variety of infections, including respiratory infections, correlate with rheumatoid arthritis development [17,18]. Thus, defining infection-induced RF polyreactivity could provide insights into how immune tolerance is lost after an infection, ultimately leading to rheumatoid arthritis.

Unfortunately, studying infection-induced RFs in humans is challenging due to the difficulty of generating a uniform study cohort (i.e., adults infected by a known pathogen at a similar time with the same number of previous exposures). However, in 2020, severe acute respiratory syndrome coronavirus two (SARS-CoV-2) emerged. In addition to causing the devastating coronavirus disease 2019 (COVID-19) pandemic, SARS-CoV-2 created a large cohort of individuals who generated a primary immune response to the same virus at a similar time. Also, RFs develop in 5–20 % of COVID-19 patients [[19], [20], [21]]. Thus, COVID-19 presents a unique opportunity to study infection-induced RFs. Finally, since much of the world's population was infected with SARS-CoV-2, millions of people experienced a rheumatoid arthritis risk factor, i.e., a viral infection, and developed RFs, adding importance to the study of RFs in COVID-19.

In this study, we evaluated antibody binding to IgG and viral epitopes in COVID-19, rheumatoid arthritis, and other conditions to reveal novel and unique features of SARS-CoV-2-induced RF reactivity that have important implications for our understanding of RFs and potentially virus-induced autoimmunity.