Differential modes of action of α1- and α1γ2- autoantibodies derived from patients with GABA A R encephalitis.

Autoantibodies against central nervous system proteins are increasingly being recognized in association with neurological 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 utilize patient derived cerebrospinal fluid (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 neurological symptoms, some of which reacted with specific GABA A receptor subunits, α1- and α1γ2-subunits, 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 α1ɣ2 subunit-specific antibodies have differential effects on the GABA A receptor. Namely, the α1-antibody was found to directly affect GABA A receptor 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 GABA A receptor away from synapses. In contrast, the α1γ2-antibody had no direct effect on GABA A receptor 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. Significance Statement It is increasingly apparent that neural autoimmune disorders can emerge as a consequence of immune responses to neural antigens. A precise diagnosis is further complicated, as individual patients express a combination of autoantibodies against several targets and/or to different epitopes on the same protein. It has therefore become critical to study the actions of individual autoantibodies to better understand their causal relationship and mode of action underlying patient's symptoms. In characterizing the difference between two monoclonal antibodies isolated from a single patient, we show that their distinct modes of action can contribute to the complexity of such auto-immune disorders, highlighting difficulties in both diagnosis and antigen specific therapies.