The evolving mystery of why skeletal muscle is spared in seropositive neuromyelitis optica

摘要

Autoantibodies against aquaporin-4 (AQP4) in seropositive neuromyelitisoptica spectrum disorders (called here NMO) initiatepathology in the central nervous system by binding to AQP4 on astrocytes.It has been puzzling why skeletal muscle, which also expressesAQP4, is rarely affected in NMO, despite easy access of circulatingNMO autoantibody (AQP4-IgG) to AQP4 on skeletal muscle.Rosito et al. [1] report evidence that differences in thesupramolecular organization of AQP4 in skeletal muscle versus brainastrocytes are responsible for the sparing of skeletal muscle in NMO,arguing that the size of AQP4 supramolecular clusters (called orthogonalarrays of particles, OAPs) is smaller in skeletal muscle than inastrocytes resulting in reduced AQP4-IgG binding. This mechanism ismotivated by the observation that some AQP4-IgG autoantibodiesbind better to AQP4 OAPs than to separated AQP4 tetramers [2] andthat AQP4 OAPs are required for C1q binding and complement activation[3]. Although the study of Rosito et al. [1] is a novel and earnestattempt to solve the puzzle of skeletal muscle sparing in NMO, in ouropinion their explanation lacks theoretical plausibility and contradictsavailable data.