Dermatomyositis (DM) is a complex autoimmune disorder characterized by diverse clinical manifestations, including skin rashes, muscle weakness, and interstitial lung disease (ILD). Recent advancements in the understanding of myositis-specific autoantibodies (MSAs) have significantly reshaped our approach to this heterogeneous disease. MSAs are not only clinically useful for diagnosis and prognosis but also play a crucial role in understanding the pathogenesis and pathophysiology of DM. This lecture will delve into the research on how MSAs define clinical subsets of dermatomyositis and their underlying disease mechanisms.
Studies over the last two decades have identified several key DM-specific MSAs, including anti-transcriptional intermediary factor 1 (anti-TIF1), anti-melanoma differentiation-associated gene 5 (anti-MDA5), anti-small ubiquitin-like modifier activating enzyme (anti-SAE), and anti-nuclear matrix protein 2 (anti-NXP2) antibodies, which are pivotal in diagnosing DM and predicting disease course and complications. For instance, anti-TIF1 antibodies are strongly associated with malignancy in adult patients, while anti-MDA5 is linked to rapidly progressive ILD, particularly in Asian populations. Moreover, the distinct cutaneous manifestations are correlated with these autoantibodies, demonstrating their importance in clinical practice.
In experimental models, we have shown that immunization with TIF1γ can induce myositis in mice, highlighting the central role of CD8+ T cells and type I interferon (IFN) pathways in disease development. These findings underscore the potential mechanisms by which autoimmune response against myositis-specific autoantigens expressed ubiquitously can directly contribute to myositis independent of MSAs. Additionally, we have explored the immunopathogenesis of anti-MDA5-associated ILD, a severe complication of DM. Our studies reveal that MDA5-specific immune responses can lead to fibrotic lung disease, mediated primarily by CD4+ T cells and interleukin-6 (IL-6). These insights elucidate how autoimmune response against MDA5 may be involved in the pathways in ILD associated with DM.
Thus, the identification and characterization of MSAs have reshaped the understanding of DM, allowing for more precise clinical phenotyping and revealing the underlying disease mechanisms. The elucidation of immune mechanisms underlying MSA-associated disease subsets offers promising avenues for developing targeted therapies, ultimately improving our comprehension of this complex disease.