Immune-mediated pathology in Duchenne muscular dystrophy

Abstract

Immunological and inflammatory processes downstream of dystrophin deficiency as well as metabolic abnormalities, defective autophagy, and loss of regenerative capacity all contribute to muscle pathology in Duchenne muscular dystrophy (DMD). These downstream cascades offer potential avenues for pharmacological intervention. Modulating the inflammatory response and inducing immunological tolerance to de novo dystrophin expression will be critical to the success of dystrophin-replacement therapies. This Review focuses on the role of the inflammatory response in DMD pathogenesis and opportunities for clinical intervention.

Fig. 1. Initiation and perpetuation of inflammatory responses in dystrophic muscle

Dystrophin-deficient muscle cells are susceptible to contraction-induced injury, culminating in muscle necrosis and the release of DAMP molecules including ATP (adenosine 5′-triphosphate) and nucleic acids. Released muscle proteins may serve as neoantigens. Engagement by DAMPs of TLR7 and the ionotropic receptor P2X7 on skeletal muscle cells and macrophages triggers innate immune activation and a chronic inflammatory response. Concomitantly, MHC presentation of peptides derived from muscle antigens initiates an adaptive immune response. Cytokines and chemokines released in the milieu attract and activate additional infiltrating immune cells including neutrophils and antigen presenting cells (APCs), such as M1 macrophages and dendritic cells. The APCs, in turn, activate recruited lymphocytes (CD4⁺ and CD8⁺ T cells), leading to propagation of adaptive immune responses (T_H1, T_H2), which are dampened by T_regs. Although B cells have been detected in DMD muscle, there is no known role for B cells in antigen presentation or antibody production in the context of DMD. The balance between the T_H1 and the T_H2 adaptive immune response creates a regulatory feedback mechanism that leads to activation of either M1 or M2 macrophages, which affects the severity of muscle inflammation or the efficiency of muscle regeneration, respectively.

Fig. 2. Normal but not dystrophic skeletal muscle regenerates after injury

(A) Stages of regeneration in normal mouse muscle after injury. Regeneration of skeletal muscle in response to injury is a highly synchronized process. Within 24 hours of injury, mouse muscle becomes infiltrated with neutrophils. Within 2 to 3 days, the injured muscle is infiltrated by pro-inflammatory M1 macrophages. During days 5 to 10, the resolution and repair phases of regeneration take place and muscle is predominantly populated by remodeling M2 macrophages. M2 macrophages are essential for complete muscle regeneration, which is achieved by day 14. (B) Asynchronous degeneration/regeneration in human dystrophin-deficient muscle. Repair of human dystrophin-deficient muscle after injury is impaired due to asynchronous bouts of degeneration and regeneration, leading to the release of cytokines, such as TGF-β, that initiate and perpetuate fibrosis. Shown is a muscle biopsy from a DMD patient revealing regions of nearly normal myofibers; chronic inflammation (between myofibers); phagocytosis by neutrophils and macrophages, and necrosis; and fibrosis (failed regeneration).