Myelin Oligodendrocyte Glycoprotein-IgG Contributes to Oligodendrocytopathy in the Presence of Complement, Distinct from Astrocytopathy Induced by AQP4-IgG.

Immunoglobulin G against myelin oligodendrocyte glycoprotein (MOG-IgG) is detectable in neuromyelitis optica spectrum disorder (NMOSD) without aquaporin-4 IgG (AQP4-IgG), but its pathogenicity remains unclear. In this study, we explored the pathogenic mechanisms of MOG-IgG in vitro and in vivo and compared them with those of AQP4-IgG. MOG-IgG-positive serum induced complement activation and cell death in human embryonic kidney (HEK)-293T cells transfected with human MOG. In C57BL/6 mice and Sprague-Dawley rats, MOG-IgG only caused lesions in the presence of complement. Interestingly, AQP4-IgG induced astroglial damage, while MOG-IgG mainly caused myelin loss. MOG-IgG also induced astrocyte damage in mouse brains in the presence of complement. Importantly, we also observed ultrastructural changes induced by MOG-IgG and AQP4-IgG. These findings suggest that MOG-IgG directly mediates cell death by activating complement in vitro and producing NMOSD-like lesions in vivo. AQP4-IgG directly targets astrocytes, while MOG-IgG mainly damages oligodendrocytes.

Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica.

Intravenous human immunoglobulin G (IVIG) may have therapeutic benefit in neuromyelitis optica spectrum disorders (herein called NMO), in part because of the anti-inflammatory properties of the IgG Fc region. Here, we evaluated recombinant Fc hexamers consisting of the IgM µ-tailpiece fused with the Fc region of human IgG1. In vitro, the Fc hexamers prevented cytotoxicity in aquaporin-4 (AQP4) expressing cells and in rat spinal cord slice cultures exposed to NMO anti-AQP4 autoantibody (AQP4-IgG) and complement, with >500-fold greater potency than IVIG or monomeric Fc fragments. Fc hexamers at low concentration also prevented antibody-dependent cellular cytotoxicity produced by AQP4-IgG and natural killer cells. Serum from rats administered a single intravenous dose of Fc hexamers at 50 mg/kg taken at 8 h did not produce complement-dependent cytotoxicity when added to AQP4-IgG-treated AQP4-expressing cell cultures. In an experimental rat model of NMO produced by intracerebral injection of AQP4-IgG, Fc hexamers at 50 mg/kg administered before and at 12 h after AQP4-IgG fully prevented astrocyte injury, complement activation, inflammation and demyelination. These results support the potential therapeutic utility of recombinant IgG1 Fc hexamers in AQP4-IgG seropositive NMO.

Variable sensitivity to complement-dependent cytotoxicity in murine models of neuromyelitis optica.

BACKGROUND: Studies of neuromyelitis optica (NMO), an autoimmune disease of the central nervous system (CNS), have demonstrated that autoantibodies against the water channel aquaporin-4 (AQP4) induce astrocyte damage through complement-dependent cytotoxicity (CDC). In developing experimental models of NMO using cells, tissues or animals from mice, co-administration of AQP4-IgG and normal human serum, which serves as the source of human complement (HC), is required. The sensitivity of mouse CNS cells to HC and CDC in these models is not known. METHODS: We used HC and recombinant monoclonal antibodies (rAbs) against AQP4 to investigate CDC on mouse neurons, astrocytes, differentiated oligodendrocytes (OLs), and oligodendrocyte progenitors (OPCs) in the context of purified monocultures, neuroglial mixed cultures, and organotypic cerebellar slices. RESULTS: We found that murine neurons, OLs, and OPCs were sensitive to HC in monocultures. In mixed murine neuroglial cultures, HC-mediated toxicity to neurons and OLs was reduced; however, astrocyte damage induced by an AQP-specific rAb #53 and HC increased neuronal and oligodendroglial loss. OPCs were resistant to HC toxicity in neuroglial mixed cultures. In mouse cerebellar slices, damage to neurons and OLs following rAb #53-mediated CDC was further reduced, but in contrast to neuroglial mixed cultures, astrocyte damage sensitized OPCs to complement damage. Finally, we established that some injury to neurons, OLs, and OPCs in cell and slice cultures resulted from the activation of HC by anti-tissue antibodies to mouse cells. CONCLUSIONS: Murine neurons and oligodendroglia demonstrate variable sensitivity to activated complement based on their differentiation and culture conditions. In organotypic cultures, the protection of neurons, OLs, and OPCs against CDC is eliminated by targeted astrocyte destruction. The activation of human complement proteins on mouse CNS cells necessitates caution when interpreting the results of mouse experimental models of NMO using HC.