COVID-19 and Autoimmune Diseases

Yu Liu; Amr H. Sawalha; Qianjin Lu

Disclosures

Curr Opin Rheumatol. 2021;33(2):155-162. 

In This Article

Similarities in Immune Responses Between SARS-CoV-2 Infection and Autoimmune Diseases

Autoimmune diseases are characterized by the existence of autoantibodies and perpetuated inflammatory reactions due to the loss of immune tolerance and dysregulated immune system, leading to target organ damage and malfunction.[15] These immune-mediated injuries also exist in COVID-19 (Figure 1). Infection with SARS-CoV-2 induces immune reactions, which might have important implications in the development of vaccine strategies against this virus.[16] T cell immunity plays a central role in the control of SARS-CoV-2 infection. Antigen-specific CD4+ and CD8+ T cells and neutralizing antibody responses play protective roles against SARS-CoV-2, while impaired adaptive immune responses such as scarcity of naive T cells may lead to poor disease outcomes.[17]

Figure 1.

Similar immune reactions in SARS-CoV-2 infection and autoimmune diseases. Both COVID-19 and autoimmune diseases present with various clinical symptoms involving different organs and systems, such as the haematological system, cardiovascular system, digestive system, kidneys, lungs, neurological system and pancreas. Organ damage is caused by uncontrolled immune response characterized by excessive production of cytokines and overactivation of immune cells, and the break of immune tolerance leading to the production of autoantibodies. SARS-CoV-2 infection can trigger cross-reactivity through molecular mimicry, leading to autoimmunity in patients with COVID-19.

In clinical laboratory tests, lymphopenia (lymphocyte count ≤1.0 x 109/l) is associated with severe illness in COVID-19 patients and might be a prognostic factor for disease severity and mortality.[18–21] Another notable haemocytological change is neutrophilia and associated excessive neutrophil extracellular traps, which paralleled lung injury in severe COVID-19 patients.[12] Therefore, the immune response is a double-edged sword in COVID-19, with outcomes affected by the degree of cytokine imbalance and activation of immune cells. Excessive production and release of pro-inflammatory cytokines and chemokines can cause severe organ damage in critical cases, which is observed in autoimmune diseases as well. In COVID-19 patients, pro-inflammatory cytokines and chemokines, including interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10, IL-17, IL-18, CXCL10 and CCL2, increased significantly and the expression levels of some of these cytokines, such as IL-1, IL-6, IL-10 and IL-18, have been demonstrated to be associated with disease severity.[22–25] Similar to autoimmune diseases, damage-associated molecular patterns (DAMPs) also participate in the pathogenesis of COVID-19 and are related to disease outcome. Chen et al.[26] revealed that serum levels of S100A8/A9 and HMGB1 increased significantly in patients with severe COVID-19 and that significant elevation of the two DAMPs was associated with higher mortality.

Activation and infiltration of immune cells participate in the pathogenesis of organ injury in patients with COVID-19. Macrophage activation syndrome (MAS) could be a continuum of cytokine storm syndrome leading to life-threatening complications in COVID-19.[27] In this condition, activated macrophages will produce excessive pro-inflammatory cytokines, polarize into the inflammatory M1 phenotype and exhibit cytotoxic dysfunction.[28] Recently, Conti et al.[29] proposed that SARS-CoV-2 activated mast cells could release histamine to increase IL-1 levels to initiate cytokine storm and aggravate lung injury. Woodruff et al.[30] found extrafollicular B cell activation in critically ill patients with COVID-19, similar to what has been observed in autoimmunity. Further, extrafollicular B cell activation correlated strongly with the production of high concentrations of SARS-CoV-2 specific neutralizing antibodies and poor disease outcome.[30] Peripheral blood B-cell subpopulations are altered during COVID-19. In COVID-19 patients, atypical memory B-cells (CD21lo/CD27/CD10) expanded significantly, while classical memory B-cells (CD21+/CD27+/CD10) were significantly reduced.[31] Analysis of immune profiles of severe COVID-19 patients revealed an increased proportion of mature natural killer (NK) cells and decreased proportion of T-cell numbers.[32]

Similar to some autoimmune and immune-mediated thromboinflammatory diseases, including lupus, antiphospholipid syndrome and ANCA-associated vasculitis, neutrophil activation and neutrophil extracellular trap production (NETosis) appear to have a pathogenic role in COVID-19. Zuo et al.[33] reported increased markers of NETs in sera from patients with COVID-19, and significantly more in patients requiring mechanical ventilation. In-vitro experiments demonstrated that sera from COVID-19 patients triggered NETosis in normal neutrophils, similar to sera from patients with antiphospholipid syndrome.[33,34]

In severe and critical cases, immunomodulatory drugs and biological agents targeting pro-inflammatory cytokines have been applied to contain the robust immune response in COVID-19. Corticosteroids, JAK inhibitors, IL-1 blockade and IL-6 receptor antagonists, which are familiar to rheumatologists, have been used to treat COVID-19 patients.[35–38] Similarities in immunopathogenesis of COVID-19 and autoimmune diseases are summarized in Table 1.

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