Early demyelination by off-target complement injury in a mouse model of neuromyelitis optica

Abstract

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune CNS disease characterized by serum antibodies targeting astrocytes for complement-mediated lysis. NMOSD lesions show not only astrocyte loss but also early demyelination and oligodendrocyte injury - histological hallmarks that converge with those of other primary demyelinating conditions. How pathology spreads to cause demyelination, particularly in early lesions, remains unclear. Using spinal cord imaging in an acute mouse NMOSD model, we directly observe the spread of pathology from astrocytes to oligodendrocytes in evolving lesions. This spread is characterized by initial calcium dyshomeostasis in oligodendrocytes followed by delayed, non-lytic cell death. Oligodendrocyte death is driven not by astrocyte loss per se but by spill-over of soluble complement proteins, as oligodendrocytes can be cell-autonomously preserved by the cell-type-specific expression of the complement inhibitor CD59. Our findings explain the convergence of glial pathology in antibody-mediated CNS autoimmunity and point towards new approaches to prevent secondary glial injury.