Diverse Functional Autoantibodies in Patients with COVID-19

Abstract

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1–8. While pathological innate immune activation is well documented in severe disease1, the impact of autoantibodies on disease progression is less defined. Here, we used a high-throughput autoantibody discovery technique called Rapid Extracellular Antigen Profiling (REAP) to screen a cohort of 194 SARS-CoV-2 infected COVID-19 patients and healthcare workers for autoantibodies against 2,770 extracellular and secreted proteins (the “exoproteome”). We found that COVID-19 patients exhibit dramatic increases in autoantibody reactivities compared to uninfected controls, with a high prevalence of autoantibodies against immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins. We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signaling and by altering peripheral immune cell composition, and found that murine surrogates of these autoantibodies exacerbate disease severity in a mouse model of SARS-CoV-2 infection. Analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics and disease severity. In summary, these findings implicate a pathological role for exoproteome-directed autoantibodies in COVID-19 with diverse impacts on immune functionality and associations with clinical outcomes.

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.…”

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

“…In this regard, a positive correlation between total antibodies against SARS-CoV-2 and clinical severity was observed late during infection (two weeks after illness onset) [69] and severe forms of COVID-19 were characterised by a surprising variety of auto-antibodies [70,71], suggesting that dysregulated humoral immunity contribute to COVID-19. In particular, neutralising (IgG) auto-antibodies against IFN-I, appear to contribute to severe forms of COVID-19 by antagonising innate antiviral responses [70,71], but also anti-ACE2 non-neutralising (IgM) auto-antibodies have been recently associated with severe clinical complications in some COVID-19 patients [72]. The IgM auto-antibody expansion is a condition that has been shown to correlate with upregulation of IL-6 (and IL-10) [73], suggesting that it might both be sustained by a compensatory inflammatory response and be inhibited by IL-6-targeted therapies, which could be more effective, for example, in specific cases of COVID-19 IgM expansion.…”

“…However, its extensive use is limited by both the organisational complexity of selecting, collecting, storing and infusing convalescent plasma and latent risk of virus transfusion and/or of antibody-dependent enhancement of disease [5]. In this regard, a positive correlation between total antibodies against SARS-CoV-2 and clinical severity was observed late during infection (two weeks after illness onset) [69] and severe forms of COVID-19 were characterised by a surprising variety of auto-antibodies [70,71], suggesting that dysregulated humoral immunity contribute to COVID-19. In particular, neutralising (IgG) auto-antibodies against IFN-I, appear to contribute to severe forms of COVID-19 by antagonising innate antiviral responses [70,71], but also anti-ACE2 non-neutralising (IgM) auto-antibodies have been recently associated with severe clinical complications in some COVID-19 patients [72].…”

“…It is tempting to speculate that, triggered by SARS-CoV-2 infection, hypertranscription of ACE2downstream and immune-response pathways may induce the generation of several new gene attempts encoding non-functional proteins and/or new proteins which can be sensed as non-self by the immune system. In this regard, it has been shown that severe COVID-19 patients have either auto-antibodies that impact a wide range of immunological functions and, in particular, neutralising auto-antibodies against IFN-I or rare gene mutations predicted to be loss-of-function at 13 different loci that govern IFN-I immunity [70,71,78]. In this regard, despite early contradictory results regarding IFN-I response, there is increasing evidence of a robust IFN-I response in patients with severe COVID-19 [36,79,80], which is consistent with a hypertranscription of IFN-I genes and, following the above hypothesis, with the generation of non-functional IFN-I and anti-IFN-I auto-antibodies.…”

Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic

“…The hyaline membrane was attributed to an increase in vascular permeability (termed as 'bradykinin storm') and accumulation of hyaluronic acid in the alveolar space, leading to trapping of high volume of water (154). Moreover, serum autoantibodies directed against many immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins were found in a high throughput extracellular antigen profiling study which may add to the tissue damage by immune complex deposition and complement (155). These autoantibodies may also impair immune function and virological control by inhibiting immunoreceptor signalling.…”