Predominance of Distinct Autoantibodies in Response to SARS-CoV-2 Infection
Authors: Liu Yunxian , Ebinger Joseph E. , Mostafa Rowann , Budde Petra , Gajewski Jana , Walker Brian , Joung Sandy , Bräutigam Manuel , Hesping Franziska , Schäfer Elena , Schubert Ann-Sophie , Zucht Hans-Dieter , Melmed Gil Y. , Sobhani Kimia , Braun Jonathan , McGovern Dermot P.B. , Van Eyk Jennifer E. , Cheng Susan , Fert-Bober Justyna 
Published: September 2021

ABSTRACTBackgroundImproved knowledge regarding the prevalence and clinical significance of the broad spectrum of autoantibodies triggered by SARS-CoV2 infection can clarify the underlying pathobiology, enhance approaches to evaluating heterogeneity of COVID-19 clinical manifestations, and potentially guide options for targeting immunosuppressive therapy as the need for more effective interventions continues to evolve. In this study, we sought to determine the prevalence of autoimmune antibodies in diverse cohort of SARS-CoV-2 positive healthcare workers and measure the extent to which factors associated with triggered autoimmunity are activated even following mild and asymptomatic infection.MethodsAntigen microarrays were used to profile reactivity of IgG autoantibodies against 91 proteins and cytokines based on autoantibody profiling studies in autoimmune diseases.ResultsIn this discovery screening study, we found that 90% of the IgG positive individuals demonstrated reactivity to at least one autoantibody. When compared to results of the same assays conducted on samples from pre-COVID-19 controls, our primary cohort of individuals with SARS-CoV-2 IgG antibody positivity had significantly elevated IgG against twelve additional proteins including CHD3, CTLA4, HARS, IFNA4, INS, MIF, MX1, RNF41, S100A9, SRP19, TROVE2, and VEGFA. These findings confirmed that all severity levels of SARS-CoV-2 infection, even asymptomatic infections, trigger a robust and diverse autoimmune response; our results also highlight the utility of multiparametric autoantibody detection in this setting.InterpretationTaken together, our findings underscore the serological diversity underlying the clinical heterogeneity of COVID-19 infection and its sequelae, including the long-Covid phenotypes.FundingThis work was supported in part by Cedars-Sinai Medical Center (JEE; SC), the Erika J Glazer Family Foundation (JEE; JEVE; SC), CSMC Precision Health Grant (JFB), the F. Widjaja Family Foundation (JGB, GYM, DM), the Helmsley Charitable Trust (JGB, GYM, DM), and NIH grants K23-HL153888 (JEE) and DK062413 (DPBM).RESEARCH IN CONTEXTEvidence before this studyCurrently, several studies have shown the possible involvement of autoimmunity in patients affected by coronavirus disease 2019 (COVID-19). In contrast to cytokine storms, which tend to cause systemic, short-duration problems, autoantibodies (AABs) are thought to result in targeted, longer-term damage and development of autoimmune diseases.Added value of this studyAccording to our knowledge, we evaluated the largest number of protein antigens to characterize the prevalence and heterogeneity of the AABs signature in SARS-CoV-2 convalescent individuals. We examined autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease to acknowledge the existence of AABs even among those who had mild-to-moderate or no symptoms during their illness, as a hallmark of ongoing long-COVID syndrome. Through our analysis we suggest that VEGFA, MIF, IFNA4, SPP1 and APOH could be used as hallmark for SARS-CoV-2 infection and activation of the autoimmune system.Implications of all the available evidenceOur study comprehensively characterized the heterogeneity of the AABs signature in SARS-CoV-2 convalescent individuals. The results established a list of diagnostic signatures and potential therapeutic targets for long-Covid-19 patients although follow-up long-term studies are required. We believe that our findings will serve as a valuable resource, to drive further exploration of long-COVID syndrome pathogenesis.