GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica

Background We previously reported the association between blood-brain barrier (BBB) dysfunction and glucose-regulated protein 78 (GRP 78) autoantibodies in neuromyelitis optica (NMO). Objective We clarify whether the BBB-endothelial cell activation induced by immunoglobulin G (IgG) is associated with the clinical phenotype, disease activity, and markers of BBB disruption. Methods We purified serum IgG from 24 serum samples from patients with NMO spectrum disorder (NMOSD), who were positive for anti-AQP4 antibodies (longitudinally extensive transverse myelitis [LETM], n = 14; optic neuritis [ON], n = 6; other phenotype, n = 4) and nine healthy controls. IgG was exposed to human brain microvascular endothelial cells (TY10) and the number of nuclear NF-kappa B p65-positive cells, as a marker of endothelial cell activation, was analyzed using a high-content imaging system. Change in BBB permeability was also measured. The presence of GRP78 autoantibodies was detected by Western blotting. Results In the LETM group, IgG significantly induced the nuclear translocation of NF-kappa B p65 in comparison to the ON and healthy control groups. A significant correlation was observed between the number of NF-kappa B nuclear-positive cells and clinical markers of BBB disruption, including Gd enhancement in spinal MRI and the cerebrospinal fluid/serum albumin ratio. This effect was significantly reduced at the remission phase in the individual NMOSD patients. Furthermore, GRP78 antibody positivity was associated with the LETM phenotype and disease severity in NMOSD patients. Conclusion Endothelial cell activation was associated with the LETM phenotype, clinical markers of BBB disruption and disease activity. These observations may explain the phenotypic differences between the NMOSD subtypes, LETM, and isolated ON.