Environmental Triggers for Connective Tissue Disease

The Case of COVID-19 Associated With Dermatomyositis-Specific Autoantibodies

Maria De Santis; Natasa Isailovic, Francesca Motta; Caterina Ricordi; Angela Ceribelli; Ezio Lanza; Elena Azzolini; Salvatore Badalamenti; Antonio Voza; Carlo Selmi

Disclosures

Curr Opin Rheumatol. 2021;33(6):514-521. 

In This Article

Infections and Autoimmunity

Environmental factors are involved in the onset of systemic autoimmune rheumatic diseases in genetically predisposed individuals, as observed for numerous conditions.[1] 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.[2] 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[6] and features typical of connective tissue diseases (CTD), DM in particular.[7] 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.[10] 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.[13] 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.[14] Furthermore, three immunogenic linear epitopes with high sequence identity to SARS-CoV-2 proteins have been identified in patients with DM[15] 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.[]

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