ABSTRACT Background Immune‐mediated necrotizing myopathy (IMNM) is a rare autoimmune disease characterized by prominent muscle involvement and usually associated with serum autoantibodies targeting signal recognition particle (SRP) or 3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGCR). Although the clinical manifestations, histopathological features, and disease classification of IMNM are well established, its etiopathogenesis remains incompletely understood. Objectives This review aims to provide an up‐to‐date overview on the pathogenesis of IMNM. Results Recent studies have implicated genetic susceptibility, autoantibodies, aberrant activation of immune cells and inflammatory mediators, and dysregulation of regulated cell death pathways in mediating tissue damage of IMNM. Anti‐SRP and anti‐HMGCR autoantibodies are pathognomonic for IMNM, and passive transfer animal models have confirmed that these autoantibodies directly mediate muscle damage, with complement activation playing a key role in this process. Dysregulation of immune cells including macrophages, T cells, and B cells, and inflammatory cytokines such as IFN‐γ, TNF‐α, and IL‐6 contributes to the inflammatory milieu and amplifies tissue injury. Furthermore, regulated cell death is involved in IMNM pathogenesis. Necroptosis may play an important role in myofiber damage in IMNM, with expression levels of RIPK3 and MLKL correlating with muscle disease severity. Pyroptosis and ER stress‐autophagy pathways have also been reported to participate in IMNM pathogenesis. Conclusion IMNM is a distinct autoimmune myopathy driven by pathogenic anti‐SRP and anti‐HMGCR autoantibodies and multifaceted immune dysregulation involving immune cells, inflammatory cytokines, and multiple cell death pathways. Further elucidation of these mechanisms may facilitate the development of novel therapeutic strategies for IMNM.
Gao et al. (Fri,) studied this question.