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Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica

An autoantibody target on brain microvascular endothelial cells in patients with neuromyelitis optica may be exploited to manipulate blood-brain barrier permeability. Bringing down the blood-brain barrier Patients afflicted by neuromyelitis optica suffer from disruption of the blood-brain barrier. Shimizu et al. generated recombinant antibodies from patient cerebral spinal fluid and demonstrated that some antibodies targeting glucose-regulated protein 78 were able activate brain microvascular endothelial cells and induced protein extravasation in cell lines and in mice. These findings suggest that glucose-regulated protein 78–targeted antibodies could be instigating blood-brain barrier breakdown and development of hallmark anti–aquaporin-4 autoantibody pathology. Not only that, the application of these antibodies could help open up the blood-brain barrier for transit of treatments for many central nervous system diseases. Neuromyelitis optica (NMO) is an inflammatory disorder mediated by antibodies to aquaporin-4 (AQP4) with prominent blood-brain barrier (BBB) breakdown in the acute phase of the disease. Anti-AQP4 antibodies are produced mainly in the periphery, yet they target the astrocyte perivascular end feet behind the BBB. We reasoned that an endothelial cell–targeted autoantibody might promote BBB transit of AQP4 antibodies and facilitate NMO attacks. Using monoclonal recombinant antibodies (rAbs) from patients with NMO, we identified two that strongly bound to the brain microvascular endothelial cells (BMECs). Exposure of BMECs to these rAbs resulted in nuclear translocation of nuclear factor κB p65, decreased claudin-5 protein expression, and enhanced transit of macromolecules. Unbiased membrane proteomics identified glucose-regulated protein 78 (GRP78) as the rAb target. Using immobilized GRP78 to deplete GRP78 antibodies from pooled total immunoglobulin G (IgG) of 50 NMO patients (NMO-IgG) reduced the biological effect of NMO-IgG on BMECs. GRP78 was expressed on the surface of murine BMECs in vivo, and repeated administration of a GRP78-specific rAb caused extravasation of serum albumin, IgG, and fibrinogen into mouse brains. Our results identify GRP78 antibodies as a potential component of NMO pathogenesis and GRP78 as a candidate target for promoting central nervous system transit of therapeutic antibodies.