The intersection of COVID-19 and autoimmunity

Abstract

Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This Review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.

Figure 1. Some patients with severe COVID-19 exhibit autoantibodies antagonizing type I IFN immunity.

(A) Type I IFNs bind to the IFN-α/β receptor (IFNAR) to induce the expression of IFN-stimulated genes (ISGs) that are essential for antiviral immunity. (B) Anti-IFN autoantibodies block IFN binding to its receptor, preventing the upregulation of ISG expression and impairing antiviral immunity. Uncontrolled replication of SARS-CoV-2 may then result in hyperinflammation and tissue damage.

Figure 2. Potential downstream mechanisms of autoantibodies identified in patients with severe COVID-19.

(A) A subset of patients with severe COVID-19 have anti-phospholipid antibodies (aPLs) and/or anti–neutrophil extracellular trap (anti-NET) autoantibodies. aPLs may activate endothelial cells and platelets and stimulate neutrophils to release NETs. Anti-NET antibodies bind to NETs, impairing NET degradation by DNase. Together, these autoantibodies may activate complement and promote thrombosis. (B) In some patients with severe COVID-19, antibodies can prevent the expression of ISGs by antagonizing signaling through the type I IFN receptor in an FcγRIIb-dependent fashion, impairing antiviral immunity.

Figure 3. Potential mechanisms of de novo autoimmunity in COVID-19.

Naive B cells can be activated via both the germinal center and the extrafollicular pathway. The extrafollicular pathway lacks some tolerance checkpoints that prevent the activation and maturation of autoreactive B cells and is, therefore, more prone to generating autoantibodies. Patients with severe COVID-19 exhibit higher levels of extrafollicular B cells lacking IgD, CD27, CXCR5, and CD21 (known as double-negative [DN2] cells) and plasma cells. They may also lack germinal centers. Red arrows indicate increased or reduced levels in patients with severe COVID-19 compared with patients with mild COVID-19.