2026 年 43 巻 3 号 p. 309-314
Inclusion body myositis (IBM) is a chronic, progressive myopathy of older adults characterized by asymmetric weakness predominantly affecting the quadriceps and finger flexor muscles, often accompanied by dysphagia. IBM displays a unique coexistence of inflammatory and degenerative muscle pathology, including endomysial T cell infiltration, rimmed vacuoles, and abnormal protein aggregates such as TDP–43 and p62, yet remains notably refractory to conventional immunosuppressive therapies.
In this study, we focus on the interplay between protein aggregation and autoimmunity, particularly involving TDP–43 and cytosolic 5′–nucleotidase 1A (cN1A), to elucidate disease mechanisms in IBM. Using a Japanese IBM cohort fulfilling the ENMC 2011 criteria, we demonstrate that anti–cN1A autoantibodies are present in approximately half of patients and are associated with distinct clinical features, including more pronounced finger flexor weakness and greater asymmetry of grip strength, whereas seronegative patients more often present with gait disturbance as an initial symptom.
To investigate the pathogenic role of anti–cN1A antibodies, we performed passive and active immunization experiments in cell and mouse models. Passive transfer of patient–derived IgG from anti–cN1A–positive IBM cases induced upregulation of p62, reduction of cN1A expression, and accumulation of p62–positive aggregates, together with macrophage infiltration in muscle tissue, partially recapitulating degenerative aspects of IBM. Active immunization with cN1A–derived peptides reproduced both inflammatory and degenerative changes, including mononuclear cell infiltration of non–necrotic fibers and p62/LC3–positive aggregates, providing stronger evidence for a pathogenic contribution of anti–cN1A antibodies.
On the basis of these findings, we propose a model in which TDP–43 aggregation within the endoplasmic reticulum promotes co–aggregation and mislocalization of cN1A, facilitating its interaction with MHC class II molecules and subsequent anti–cN1A autoantibody production, thereby linking protein aggregation to autoimmunity and muscle fiber damage in IBM. Finally, we summarize the current status of disease–modifying therapeutic strategies targeting both inflammatory and degenerative pathways, highlighting the need for interventions that simultaneously modulate immune responses and proteostasis in IBM.
