New-Onset IgG Autoantibodies in Hospitalized Patients with COVID-19

Abstract

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. We developed three different protein arrays to measure hallmark IgG autoantibodies associated with Connective Tissue Diseases (CTDs), Anti-Cytokine Antibodies (ACA), and anti-viral antibody responses in 147 hospitalized COVID-19 patients in three different centers. Autoantibodies were identified in approximately 50% of patients, but in <15% of healthy controls. When present, autoantibodies largely targeted autoantigens associated with rare disorders such as myositis, systemic sclerosis and CTD overlap syndromes. Anti-nuclear antibodies (ANA) were observed in ∼25% of patients. Patients with autoantibodies tended to demonstrate one or a few specificities whereas ACA were even more prevalent, and patients often had antibodies to multiple cytokines. Rare patients were identified with IgG antibodies against angiotensin converting enzyme-2 (ACE-2). A subset of autoantibodies and ACA developed de novo following SARS-CoV-2 infection while others were transient. Autoantibodies tracked with longitudinal development of IgG antibodies that recognized SARS-CoV-2 structural proteins such as S1, S2, M, N and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. COVID-19 patients with one or more autoantibodies tended to have higher levels of antibodies against SARS-CoV-2 Nonstructural Protein 1 (NSP1) and Methyltransferase (ME). We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.

Bifurcated monocyte states are predictive of mortality in severe COVID-19

“…In this context, the inflammatory monocytes have been shown to promote the differentiation of naïve B cells into plasmablasts which can be the source of protective or pathogenic antibodies. In this regard we note that severe COVID-19 has been associated with various types of autoantibodies[31][32][33] .Our study highlights the importance of analyzing the initial immune state of COVID-19 patients early in their ICU course by deconvolution of genomic states of peripheral immune cells based on gene modules. Earlier work in non-COVID ARDS has defined monocyte signatures in PBMC that are indicative of progression to ARDS 34 ; our work demonstrates distinctive monocyte gene modules as part of a multivariate peripheral immune system state that is predictive of severe COVID-19 disease mortality.…”

Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19

“…Third, multiple studies, including autopsy studies, have demonstrated endotheliitis and microvascular thrombosis in acute COVID-19, with neutrophil extracellular traps as one contributing mechanism [39][40][41][42][43][44]; in addition to explaining severe disease, ongoing microvascular dysfunction may contribute to the pathobiology of PASC. Fourth, autoreactive immunity may be a significant contributor as IgG autoantibodies are highly prevalent in acute infection, including those associated with clinical disease entities similar to PASC [39,[45][46][47]. Importantly, some mechanisms may contribute to certain organ-specific morbidity, whereas others might be common among various PASC phenotypes.…”

Interferon system deficiencies exacerbating severe pandemic virus infections

“…It is apparent from multiple studies that some COVID-19 patients have autoantibodies against a diverse range of self-antigens beyond type I interferons, and that these autoantibodies can have both short-and long-term pathogenic consequences [12,23,[26][27][28][29]. Thus, there is already some debate as to whether individuals with pre-existing subclinical autoimmune conditions are more likely to develop severe COVID-19, or whether severe SARS-CoV-2 infections trigger de novo autoreactivity against various antigens [12,30].…”

“…Thus, there is already some debate as to whether individuals with pre-existing subclinical autoimmune conditions are more likely to develop severe COVID-19, or whether severe SARS-CoV-2 infections trigger de novo autoreactivity against various antigens [12,30]. Longitudinal analyses of autoantibody reactivity in COVID-19 patient cohorts have indicated that both mechanisms may actually apply, but perhaps in an antigen-dependent manner [23,29]. Specifically, autoantibodies targeting type I interferons were found to pre-exist in several individuals who went on to develop severe COVID-19 [12,23], suggesting that the SARS-CoV-2 infection itself did not drive the primary production of anti-interferon autoantibodies.…”

“…Notably, only IgG anti-interferon autoantibodies have so far been detected in APS1 patients [12,19], suggesting a potential immunotypic difference between acute COVID-19 and APS1 patient cohorts. Thus, it cannot be ruled out that there is heterogeneity with regard to antiinterferon autoantibody production, with SARS-CoV-2 infections possibly driving de novo breaking of interferon immune-tolerance in some individuals [30], anti-interferon autoantibodies pre-existing in other individuals [12,23], and some SARS-CoV-2 infections stimulating an increase in the titers and/or affinity of pre-existing anti-interferon autoantibodies [29].…”