Finding NMO

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with lesions found primarily in the spinal cord and optic nerve. Although originally classified as a subtype of multiple sclerosis (MS), the finding of autoantibodies against the astrocyte water channel aquaporin-4 (AQ4) has defined this as a specific autoimmune disorder. Important questions have arisen as to how AQ4 antibodies (NMO– immunoglobulin G [IgG]) lead to the neuropathology associated with NMO. One major thought is that NMO-IgG binding to AQ4 leads to complementdependent lysis of astrocytes recruiting immune cells, including granulocytes and eosinophils, generating an inflammatory lesion. Recently, however, 6 different types of histologically distinct lesions have been identified, some characterized by complement deposition (lesions 1, 2) and some lacking complement (lesions 4–6). Therefore, a major question is how NMO-IgG causes lesion formation in the absence of complement. In this issue of Neurology® Neuroimmunology & Neuroinflammation, Takeshita et al. aim to identify complement-independent pathways by which NMOIgG cause lesion formation. They generated both static and flow-based in vitro brain–blood barrier co-culture models utilizing human brain microvascular endothelial cells and a human astrocyte cell line, either expressing AQ4 or not expressing AQ4. They identified that NMO-IgG increased endothelial cell permeability to dextran tracers with a corresponding decrease in Claudin 5 expression, suggesting that the paracellular tight junctions were disrupted. NMO-IgG also led to an increased inflammatory state of the endothelial cell layer, elevating CCL2 and CXCL8 expression and leukocyte migration across the monolayer. These results were mediated through astrocyte AQ4, as NMO-IgG had no effect on the co-cultures utilizing AQ4 negative astrocytes. They further demonstrated that NMO-IgG induced interleukin (IL)–6 expression by AQ41 astrocytes, and IL-6 was sufficient to increase barrier permeability and the inflammatory state of the endothelial cells. These data provide a potential mechanism for complement-independent lesion formation in patients with NMO: NMO-IgG binds to AQ4 on astrocyte endfeet, driving the production of IL-6, generating local BBB breakdown and neuroinflammation. This leads to several important questions about the pathogenesis and treatment of NMO. First, while this mechanism was discovered in vitro, it is not clear whether this same mechanism causes complement-independent lesion formation in patients with NMO. The testing of IL-6 blocking antibodies in NMO therapy may establish the role of IL-6-dependent mechanisms, including its possible role on Th17 differentiation in NMO, and potentially help distinguish the significance of complement-independent lesion formation. Another interesting question that arises is how this mechanism leads to neuropathology and symptomology. NMOhas traditionally been described as a demyelinating disorder, yet both the mechanism described by Takeshita et al. and the complement-dependent mechanism affect astrocytes and not myelin. One option is that NMO-IgG drives local BBB opening and inflammation, which would allow specific antimyelin T cells or antibodies to enter the parenchyma and destroy myelin. A second possibility is that demyelination is a secondary bystander effect following a specific anti-astrocyte immune response likely destroying astrocyte buffering of glutamate leading to excitotoxic axonal and myelin damage. A final option is that demyelination is secondary to nonspecific IL-6-mediated BBB opening and neuroinflammation. This study also leads to speculation about how different types of lesions can be formed within the same patient; specifically, how NMO-IgG could elicit complement-dependent astrocyte lysis in some locations but lead to astrocyte-derived IL-6-mediated BBB opening in others. One potential distinguishing feature may be the total amount of NMO-IgG in each lesion, with lower amounts leading to IL-6 production and greater amounts of antibody more likely