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Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica

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Abstract

Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease of the central nervous system in which immunoglobulin G antibodies against astrocyte water channel aquaporin-4 (AQP4-IgG) cause demyelination and neurological deficit. Injury to oligodendrocytes, which do not express AQP4, links the initiating pathogenic event of AQP4-IgG binding to astrocyte AQP4 to demyelination. Here, we report evidence for a complement ‘bystander mechanism’ to account for early oligodendrocyte injury in NMO in which activated, soluble complement proteins following AQP4-IgG binding to astrocyte AQP4 result in deposition of the complement membrane attack complex (MAC) on nearby oligodendrocytes. Primary cocultures of rat astrocytes and mature oligodendrocytes exposed to AQP4-IgG and complement showed early death of oligodendrocytes in close contact with astrocytes, which was not seen in pure oligodendrocyte cultures, in cocultures exposed to AQP4-IgG and C6-depleted serum, or when astrocytes were damaged by a complement-independent mechanism. Astrocyte-oligodendrocyte cocultures exposed to AQP4-IgG and complement showed prominent MAC deposition on oligodendrocytes in contact with astrocytes, whereas C1q, the initiating protein in the classical complement pathway, and C3d, a component of the alternative complement pathway, were deposited only on astrocytes. Early oligodendrocyte injury with MAC deposition was also found in rat brain following intracerebral injection of AQP4-IgG, complement and a fixable dead-cell stain. These results support a novel complement bystander mechanism for early oligodendrocyte injury and demyelination in NMO.

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Acknowledgements

This work was supported by Grants EY13574, EB00415, DK35124, and DK72517 from the National Institutes of Health, and a Grant from the Guthy-Jackson Charitable Foundation. We thank Dr. Jeffrey Bennett (University of Colorado Denver, Aurora, CO) for providing recombinant monoclonal NMO antibody rAb-53.

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  1. Departments of Medicine and Physiology, University of California, San Francisco, 1246 Health Sciences East Tower, San Francisco, CA, 94143-0521, USA

    Lukmanee Tradtrantip, Xiaoming Yao, Tao Su, Alex J. Smith & Alan S. Verkman

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  1. Lukmanee Tradtrantip
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Correspondence to Alan S. Verkman.

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Tradtrantip, L., Yao, X., Su, T. et al. Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica. Acta Neuropathol 134, 35–44 (2017). https://doi.org/10.1007/s00401-017-1734-6

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  • DOI: https://doi.org/10.1007/s00401-017-1734-6

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