Myositis Autoantigen Expression Correlates With Muscle Regeneration but Not Autoantibody Specificity

Abstract

Objective Although more than a dozen myositis‐specific autoantibodies (MSAs) have been identified, most patients with myositis are positive for a single MSA. The specific overexpression of a given myositis autoantigen in myositis muscle has been proposed as initiating and/or propagating autoimmunity against that particular autoantigen. The present study was undertaken to test this hypothesis. Methods In order to quantify autoantigen RNA expression, RNA sequencing was performed on muscle biopsy samples from control subjects, MSA‐positive patients with myositis, regenerating mouse muscles, and cultured human muscle cells. Results Muscle biopsy samples were available from 20 control subjects and 106 patients with autoantibodies recognizing hydroxymethylglutaryl‐coenzyme A reductase (n = 40), signal recognition particles (n = 9), Jo‐1 (n = 18), nuclear matrix protein 2 (n = 12), Mi‐2 (n = 11), transcription intermediary factor 1γ (n = 11), or melanoma differentiation–associated protein 5 (n = 5). The increased expression of a given autoantigen in myositis muscle was not associated with autoantibodies recognizing that autoantigen (all q > 0.05). In biopsy specimens from both myositis muscle and regenerating mouse muscles, autoantigen expression correlated directly with the expression of muscle regeneration markers and correlated inversely with the expression of genes encoding mature muscle proteins. Myositis autoantigens were also expressed at high levels in cultured human muscle cells. Conclusion Most myositis autoantigens are highly expressed during muscle regeneration, which may relate to the propagation of autoimmunity. However, factors other than overexpression of specific autoantigens are likely to govern the development of unique autoantibodies in individual patients with myositis.

Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies

“…Overall, these results indicate that netting neutrophils infiltrate clinically affected tissues in MSA-positive IIM, particularly in association with anti-MDA5. Given the association between anti-MDA5 and the presence of NETs in tissues, and previous reports of high MDA5 mRNA expression during muscle regeneration (18), we assessed whether the MDA5 protein could be detected in these biopsies. Indeed, MDA5 antigen was present in DM muscle and skin tissue biopsies (Supplemental Figure 2A).…”

Autoantibody Biomarkers in Rheumatic Diseases

“…Many of myositis-specific autoantigens, including ARS, are ubiquitously expressed intracellular proteins involved in various cell functions, particularly transcription or translation (Table 1). They are overexpressed and modified in apoptotic and regenerating muscle fibers [42], some of which are also expressed in tumor cells showing a link between cancer and autoimmunity to muscles [43].…”

Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis

“…TRIM epitopes did not form a separate phylogenetic cluster but were dispersed throughout the viral epitope phylogenetic tree, suggesting that accumulated antibodies against TRIM proteins might be the product of a primal molecular mimicry event and subsequent epitope spreading rather than increased TRIM protein production. This is supported by the observation that the gene expression levels of autoantigens in myositis muscle biopsies do not correlate with the levels of circulating autoantibodies recognizing each cognate endogenous autoantigen; instead they are directly associated with the expression of muscle regeneration markers (Pinal-Fernandez et al, 2019).…”

“…The finding that in myositis, autoantigen expression correlates with expression of muscle regeneration markers (Pinal-Fernandez et al, 2019) suggests that after initial viral presentation, the increased concentrations of muscle proteins may then be sufficient even in the absence of viral proteins to invoke periodic rises of autoantibodies. Moreover, the continuous activation of innate immunity observed in DM (Neely, 2019;Pinal-Fernandez et al, 2019;Walsh et al, 2007;Wong et al, 2012) can also potentiate autoimmunity through chronic immune-mediated tissue damage resulting in autoantigen release without the need for specific activation of auto-reactive T cells by a microbial mimic (Panoutsakopoulou et al, 2001). Therefore, following the initial viral exposure there is a high chance that this effect will spread amongst related proteins within specific signalling pathways (since protein homology is related to function) of the initial hit.…”