Differential Modes of Action of α1- and α1γ2-Autoantibodies Derived from Patients with GABAAR Encephalitis

Abstract

AbstractAutoantibodies against central nervous system proteins are increasingly being recognized in association with neurologic disorders. Although a growing number of neural autoantibodies have been identified, a causal link between specific autoantibodies and disease symptoms remains unclear, as most studies use patient-derived CSF-containing mixtures of autoantibodies. This raises questions concerning mechanism of action and which autoantibodies truly contribute to disease progression. To address this issue, monoclonal autoantibodies were isolated from a young girl with a range of neurologic symptoms, some of which reacted with specific GABAAreceptor (GABAAR) subunits, α1-subunit and α1γ2-subunit, which in this study we have characterized in detail using a combination of cellular imaging and electrophysiological techniques. These studies in neurons from wild-type mice (C57BL/6J; RRID:IMSR_JAX:000664) of mixed-sex revealed that the α1 and α1γ2 subunit-specific antibodies have differential effects on the GABAAreceptor. Namely, the α1-antibody was found to directly affect GABAAreceptor function on a short time scale that diminished GABA currents, leading to increased network excitability. On longer time scales those antibodies also triggered a redistribution of the GABAAreceptor away from synapses. In contrast, the α1γ2-antibody had no direct effect on GABAAreceptor function and could possibly mediate its effect through other actors of the immune system. Taken together, these data highlight the complexity underlying autoimmune disorders and show that antibodies can exert their effect through many mechanisms within the same disease.