Infections and Autoimmunity
Environmental factors are involved in the onset of systemic autoimmune rheumatic diseases in genetically predisposed individuals, as observed for numerous conditions. In particular in the case of idiopathic inflammatory myositis (IIMs), such as poly- and dermatomyositis (PM and DM) environmental factors such as smoking, sun exposure, infections, medications, vaccines, stressful life events and physical activity seem to be responsible for disease onset or flare. During the recent COVID-19 pandemic, the role of infections has become even more clearly associated with the onset of auto-inflammatory and autoimmune manifestations including myalgia and myositis.[3,4] Since the earliest reports, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with autoimmunity also from the serological point of view,[4,5] in some cases associated with chronic conditions and features typical of connective tissue diseases (CTD), DM in particular. First, numerous cytokines are shared by the macrophage activation syndrome observed in CTD and the cytokine release syndrome characterizing severe COVID-19,[8,9] in both cases culminating in endothelial dysfunction, vasculopathy, and thrombotic manifestations. Second, both sets of disease benefit from anti-inflammatory treatments, consisting of glucocorticoids and anticytokine agents. Third, the COVID-19 interstitial lung disease resembles what was observed in CTD.[11,12] Fourth and most relevant to our study, some CTD-associated autoantibodies are directed toward molecules involved in the innate immune response against viruses. In fact, antimelanoma differentiation-associated gene 5 (anti-MDA5) antibodies are linked to a specific form of DM, generally presenting as a clinically amyopathic cutaneous vasculopathy with a predominant and rapidly progressive interstitial lung disease. Fifth, MDA5 is a pattern recognition receptor of the RIG1-like receptor (RLR) family that recognizes intracellular viral RNA and triggers type I interferons, together with additional viral RNA sensors such as RIG1 or the DHX58 component in the DHX58-TBK1 pathway that may be induced by a viral trigger. When complexed with viral RNA and overexpressed during infections, MDA5 may be recognized by antigen-presenting cells and ultimately lead to autoantibody production, similarly to the production of anti-RIG1 or anti-DHX58 autoantibodies. Furthermore, three immunogenic linear epitopes with high sequence identity to SARS-CoV-2 proteins have been identified in patients with DM thus pointing at molecular mimicry to link COVID-19 and autoimmune manifestations. Similar mechanisms could be hypothesized also for other autoantibodies directed against intracellular proteins hyper-expressed or massively released in the extra-cellular space due to tissue damage. We hypothesized that COVID-19 may be associated with novel and established tissue disease-associated autoantibodies, particularly those directed against antigens involved in the antiviral immune response, and that these may be associated with a more severe form of infection.
The scope of the present review is to describe COVID-19 infection as the prototype of the environmental factor associated with the production of autoantibodies so far identified in DM patients affected by rapidly progressive interstitial lung disease.
Curr Opin Rheumatol. 2021;33(6):514-521. © 2021 Lippincott Williams & Wilkins