Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes

Abstract

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.T he most abundant water channel in the central nervous system (CNS) is aquaporin-4 (AQP4), which is confined to astrocytes and ependyma; is enriched at glial-pial and glialendothelial interfaces; and surrounds nodes of Ranvier and paranodes, adjacent oligodendroglial loops, and synapses (1). In 2005, we identified AQP4 as the target of pathogenic autoantibodies in a spectrum of inflammatory CNS disorders of varying severity that is unified by detection of the serum biomarker neuromyelitis optica (NMO)-IgG (2, 3). These disorders are now recognized collectively as IgG-mediated autoimmune astrocytopathies. Before discovery of this antibody, NMO spectrum disorders were misclassified as multiple sclerosis variants. NMOIgG is centrally involved in the pathogenesis of NMO spectrum disorders. Its detection predicts frequent relapses that cause cumulative neurological impairment. Lesions characteristically affect the spinal cord and optic nerve, but do not spare the brain. Independent laboratories have demonstrated that NMO-IgG binding initiates AQP4 down-regulation with accompanying endocytosis of its physically associated glutamate transporter, EAAT2, complement activation, impairment of blood-brain barrier integrity, inflammation, and astrocyte injury (4-8). Demyelination is a proposed consequence of both pa...

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor

“…We previously demonstrated that NMO-IgG binding to AQP4 in live cells causes membrane AQP4 to relocate to the endolysosomal path (6,9,10). To separate early events from downstream Fc-dependent events, we investigated F(ab′) 2 prepared from NMO patients and healthy subjects.…”

“…Focally enhanced BBB permeability (7,12) plausibly accounts for initially reversible early NMO symptoms and MRI abnormalities. Early lesions contain viable, phenotypically activated astrocytes lacking AQP4 and EAAT2 (6,15), with myelin intact but focally edematous (9).…”

“…Outcomes documented in vitro after NMO-IgG binds to the AQP4 extracellular domain on astrocytes include AQP4 endocytosis and lysosomal degradation, loss of its physically linked major excitatory amino acid transporter 2 (EAAT2), reduced glutamate uptake, impaired water fluxes, granulocyte chemotaxis, and complement factor transcription, secretion, and activation (1,(6)(7)(8)(9)(10)(11). Ensuing endothelial permeation of circulating immunoglobulins, complement components, and leukocytes magnifies the initial inflammatory response (6)(7)(8)(9)(10)(11)(12). Immunopathological analyses of NMO patients' CNS tissues attest to these events occurring in vivo and inform lesional evolution at the target astrocyte level (1).…”

Conventional and Advanced Imaging in Neuromyelitis Optica

“…While cord pathology in NMO is traditionally associated with a severe clinical phenotype, including the need for ventilatory support in association with high cervical lesions, excellent clinical and radiologic recovery may be seen in some patients. This observation implicates reversible vasogenic edema, a phenomenon described in cerebral NMO lesions 8 and attributed to transient functional impairment of water transport mediated by AQP4 antibodies, 21,22 in the pathogenesis of some NMO cord syndromes.…”

“The more we know”

“…This is particularly relevant when the involved autoantibodies are known to be unambiguously pathogenic in cultured cells (astrocytes, oligodendrocytes, or neurons) or in animal models. [1][2][3] Indeed, if, after hundreds of patients are reported with a specific antibodyassociated syndrome, one encounters a patient with atypical manifestations, it is more reasonable to search for an additional pathogenic mechanism than to label the case as an "expansion" of the syndrome. These cases add a new level of complexity to the differential diagnosis of antibody-associated encephalitis, as exemplified by 3 articles in the current issue.…”