Neuromyelitis optica (NMO) pathogenesis involves binding of anti-aquaporin-4 (AQP4)
autoantibodies (NMO-
IgG) present in serum to AQP4 on astrocytes, which causes
complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Human
immunoglobulin G (
hIgG) is effective for treatment of humorally mediated neurological
autoimmune diseases and has been reported to improve disease outcome in a limited number of NMO patients. Here, we investigated
hIgG actions on NMO-
IgG pathogenicity using an in vivo rat model of NMO and in vitro assays. In rats administered NMO-
IgG by intracerebral injection, the size of neuroinflammatory demyelinating lesions was reduced by ~50% when
hIgG was administered by
intraperitoneal injection to reach levels of 10-25mg/mL in rat serum, comparable with human therapeutic levels. In vitro,
hIgG at 10mg/mL reduced by 90% NMO-
IgG-mediated CDC following addition of NMO-
IgG and human
complement to AQP4-expressing cells. The
hIgG effect was mainly on the classical complement pathway.
hIgG at 10mg/mL also reduced by up to 90% NMO-
IgG-mediated ADCC as assayed with human natural killer cells as effector cells. However,
hIgG at up to 40mg/mL did not affect AQP4 cell surface expression or its supramolecular assembly in orthogonal arrays of particles, nor did it affect NMO-
IgG binding to AQP4. We conclude that
hIgG reduces NMO-
IgG pathogenicity by inhibition of CDC and ADCC, providing a mechanistic basis to support further clinical evaluation of its therapeutic efficacy in NMO.