Neuromyelitis Optica (NMO): An Autoimmune Astrocytopathy (2186)
Vanda A. Lennon and Shannon R. Hinson
Mayo Clinic College of Medicine, Rochester, MN, USA
NMO was considered a severe variant of multiple sclerosis (MS), with prominent inflammation and highly destructive demyelinating lesions. However, demyelination is secondary in NMO. The primary effector, an IgG, targets astrocytic aquaporin-4 (AQP4) water channels. Studies of NMO lesional events emphasize complement-mediated inflammation and astrocyte lysis following blood-brain barrier (BBB) disruption. The BBB does not absolutely restrict IgG entry, but it excludes C1q, which activates the classical complement cascade. Early events are poorly understood. After IgG binds to astrocytic AQP4, AQP4 partially internalizes together with the EAAT2 glutamate transporter, glutamate and water uptake decrease, astrocytes synthesize and release cytokines, chemokines and complement, and inflammatory cells are recruited (Lucchinetti et al, Brain Pathol 2014; Hinson et al, J Exp Med 2008, PNAS 2012; T. Vincent et al, J Immunol 2008; Howe et al, Glia 2014; Walker-Caulfield et al, J Neuroinflamm 2015). To investigate early astrocytic membrane events preceding AQP4 endocytosis, we applied AQP4-IgG or healthy human IgG or (Fab')2 fragments, or mouse monoclonal IgGs specific for AQP4 extracellular domain (ECD) or C-terminal cytoplasmic domain (CCD), to live rodent astrocytes (wild-type and Fcγ receptor [R] gamma subunit-null), without complement. IgG lacking Fc redistributed AQP4 and induced IL-6 release, but AQP4 endocytosis required AQP4-ECD-bound IgG to engage an activating astrocytic FcγR (CD64) gamma subunit and involved sequential FcγR phosphorylations and transient membrane loss of the inhibitory (CD32B) FcγR through recruitment into the immune complex. Co-endocytosis and degradation of physically linked EAAT2 also required these FcγR-IgG-AQP4 complex interactions.
Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early intervention in NMO. Definition of the signaling pathways through which FcγRs mediate AQP4 and EAAT2 co-internalization may reveal new candidate therapeutic targets for prevention or amelioration of NMO relapses.
