The astrocytic aquaporin-4 (AQP4)
water channel is the target of pathogenic
antibodies in a spectrum of relapsing autoimmune inflammatory
central nervous system disorders of varying severity that is unified by detection of the serum
biomarker neuromyelitis optica (NMO)-
IgG.
Neuromyelitis optica is the most severe of these disorders. The two major AQP4
isoforms, M1 and M23, have identical extracellular residues. This report identifies two novel properties of NMO-
IgG as determinants of pathogenicity. First, the binding of NMO-
IgG to the ectodomain of astrocytic AQP4 has
isoform-specific outcomes. M1 is completely internalized, but M23 resists internalization and is aggregated into larger-order orthogonal arrays of particles that activate
complement more effectively than M1 when bound by NMO-
IgG. Second, NMO-
IgG binding to either
isoform impairs water flux directly, independently of
antigen down-regulation. We identified, in nondestructive central nervous system lesions of two NMO patients, two previously unappreciated histopathological correlates supporting the clinical relevance of our in vitro findings: (i) reactive astrocytes with persistent foci of surface AQP4 and (ii) vacuolation in adjacent myelin consistent with
edema. The multiple molecular outcomes identified as a consequence of NMO-
IgG interaction with AQP4 plausibly account for the diverse pathological features of NMO:
edema,
inflammation,
demyelination, and
necrosis. Differences in the nature and anatomical distribution of NMO lesions, and in the clinical and imaging manifestations of disease documented in pediatric and adult patients, may be influenced by regional and maturational differences in the ratio of M1 to M23
proteins in astrocytic membranes.