Partners in crime: Autoantibodies complicit in COVID‐19 pathogenesis

Abstract

Autoantibodies (AABs) play a critical role in the pathogenesis of autoimmune diseases (AIDs) and serve as a diagnostic and prognostic tool in assessing these complex disorders. Viral infections have long been recognized as a principal environmental factor affecting the production of AABs and the development of autoimmunity. COVID‐19 has primarily been considered a hyperinflammatory syndrome triggered by a cytokine storm. In the following, the role of maladaptive B cell response and AABs became more apparent in COVID‐19 pathogenesis. The current review will primarily focus on the role of extrafollicular B cell response, Toll‐like receptor‐7 (TLR‐7) activation, and neutrophil extracellular traps (NETs) formation in the development of AABs following SARS‐CoV‐2 infection. In the following, this review will clarify how these AABs dysregulate immune response to SARS‐CoV‐2 by disrupting cytokine function and triggering neutrophil hyper‐reactivity. Finally, the pathologic effects of these AABs will be further described in COVID‐19 associate clinical manifestations, including venous and arterial thrombosis, a multisystem inflammatory syndrome in children (MIS‐C), acute respiratory distress syndrome (ARDS), and recently described post‐acute sequelae of COVID‐19 (PASC) or long‐COVID.

The development of anti-cyclic citrullinated peptide (Anti-CCP) antibody following severe COVID-19

“…The DNA in the neutrophil extracellular trap promotes the citrullination process that further ampli es the production of anti-CCP [28]. SARS-CoV-2 infection is a potent inducer of NETosis and citrullination, which leads to neoantigens that trigger the development of Anti-CCP (3). The anti-CCP can be detected in a median of 4.5 years before the development of RA phenotype (2).…”

“…Some antibodies like anti-CCP in rheumatoid arthritis become positive in the serum a median of 4.5 years before the initiation of clinical manifestation [2]. Viruses are among the most acknowledged environmental factor that elicits the production of AABs in systemic and organ-speci c autoimmune disorders [3].…”

“…COVID-19 has infected many individuals globally, with heterogeneous manifestations from mild to severe and critical clinical outcomes [4,5]. SARS-CoV-2, the viral agent of COVID-19, elicits the production of AABs through several mechanisms, including TLR engagement, eliciting extrafollicular B cell response, cytokine storm, and neutrophil extracellular traps (NETs) formation [3]. Previous investigations showed the production of AABs associated with rheumatologic disorders, especially systemic lupus erythematosus (SLE) in COVID-19, which was reviewed comprehensively by Taghadosi et al [3].…”

“…SARS-CoV-2, the viral agent of COVID-19, elicits the production of AABs through several mechanisms, including TLR engagement, eliciting extrafollicular B cell response, cytokine storm, and neutrophil extracellular traps (NETs) formation [3]. Previous investigations showed the production of AABs associated with rheumatologic disorders, especially systemic lupus erythematosus (SLE) in COVID-19, which was reviewed comprehensively by Taghadosi et al [3]. Among several AABs reported in COVID-19 patients, the AABs associated with systemic autoimmune disorders, including anti-nuclear antibodies (ANAs) and antiphospholipid antibodies (anti-aPLs), have an association with some clinical manifestations of COVID-19, including long-COVID, thrombosis, and venous occlusion [6][7][8][9].…”

The development of anticyclic citrullinated peptide (anti‐CCP) antibody following severe COVID‐19

“…[4][5][6] Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the viral agent of COVID-19, elicits the production of AABs through several mechanisms, including toll-like receptor (TLR) engagement, eliciting extrafollicular B cell response, cytokine storm, and neutrophil extracellular traps (NETs) formation. 3,6,7 Previous investigations, including studies conducted by Woodruff et al 7 and Anaya et al, 8 showed the production of AABs associated with rheumatologic disorders, especially systemic lupus erythematosus (SLE) in COVID-19, which was reviewed comprehensively by Taghadosi et al 3 Among several AABs reported in COVID-19 patients, the AABs associated with systemic autoimmune disorders, including antinuclear antibodies (ANAs) and antiphospholipid antibodies (aPLs), have an association with some clinical manifestations of COVID-19, including long-COVID, thrombosis, and venous occlusion. [9][10][11][12] The extent of antibody production in COVID-19 is enormous and the presence of COVID-19-specific AABs has implications in stratifying patients into specific disease phenotypes.…”