Multisystem Inflammatory Syndrome and Autoimmune Diseases Following COVID-19: Molecular Mechanisms and Therapeutic Opportunities

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has led to huge concern worldwide. Some SARS-CoV-2 infected patients may experience post-COVID-19 complications such as multisystem inflammatory syndrome, defined by symptoms including fever and elevated inflammatory markers (such as elevation of C reactive protein (CRP), erythrocyte sedimentation rate, fibrinogen, procalcitonin test, D-dimer, ferritin, lactate dehydrogenase or IL-6, presence of neutrophilia, lymphopenia, decreased albumin, and multiple organ dysfunction). Post-COVID-19 complications may also manifest as autoimmune diseases such as Guillain-Barré syndrome and systemic lupus erythematosus. Signaling disorders, increased inflammatory cytokines secretion, corticosteroid use to treat COVID-19 patients, or impaired immune responses are suggested causes of autoimmune diseases in these patients. In this review, we discuss the molecular and pathophysiological mechanisms and therapeutic opportunities for multisystem inflammatory syndrome and autoimmune diseases following SARS-CoV-2 infection with the aim to provide a clear view for health care providers and researchers.

Keywords: COVID-19; SARS-CoV2; autoimmune disease; multisystem inflammatory syndrome; multisystem inflammatory syndrome in children (MIS-C).

FIGURE 1

Underlying mechanisms of multisystem inflammatory syndrome in children. (A,B) The binding of SARS-CoV-2 spike protein to ACE2 receptors on respiratory epithelial cells leads to its cell entry and viral genome replication via RNA-dependent RNA polymerase (RdRP). Membrane-bound immunologic receptors and downstream signaling pathways mediate the pro-inflammatory response resulting in cytokine storm through the infiltration of neutrophils and macrophages into the lung tissue. (C) SARS-CoV-2 viral genomic ssRNA or other RNA compositions may act as PAMPs and bind to TLRs and RLRs, leading to the activation of IRF3, NF-κB, MAPK/ERK, AP-1, and JNK signaling pathways and secretion of IL-6, IL-8, TNF-α, and IFN-I. (D) Cytokines produced by macrophages, neutrophils, and dendritic cells cause T cell–dependent activation of B cells and production of antibodies and autoantibodies (e.g., anti-endoglin). (E) Neutrophils can form NETs, which are released subsequent to the rupture of the plasma membrane. NETs, IL-6, IL-8, TNF-α, and PAI-1 induce endothelial damage and thrombosis. (F) Cytokine storm, autoantibodies, and activation of immune cells lead to multiple organ damage, including the lungs, brain (e.g., cellular edema of neurons), heart (e.g., acute viral myocarditis), and kidneys (e.g., acute kidney injury).