NEUROIMMUNOLOGICAL BASIS OF ANTI-AMPAR ENCEPHALITIS

In the past two decades, the discovery that autoantibodies can affect brain function has led to a shift in the understanding of neurological diseases and opened new diagnostic and treatment options. Yet despite intense research focus on autoantibody mediated pathology, little is known about the neuroimmunological basis of the underlying autoimmune encephalitides. Here, we developed a set of AMPA receptor (AMPAR) antigens and elucidated AMPAR-specific autoimmune responses across the CNS and associated lymphoid tissues in a mouse model of anti-AMPAR encephalitis. We show that AMPAR proteoliposome immunized mice develop anti-AMPAR encephalitis like pathology characterized by rapidly progressing neuropsychiatric deficits, autoantibodies against the amino-terminal domain of AMPAR, intrathecal IgG deposition, loss of AMPAR immunoreactivity, and infiltration of T cells, B cells and antibody secreting cells (ASCs) into multiple AMPAR-rich brain regions. ASCs populated the CNS parenchyma and meninges and frequently consisted of class-switched post-proliferative potentially long-lived plasma cells. Utilization of fluorescent antigen probes revealed that most CNS-localized ASCs targeted AMPAR and that AMPAR-specificity increased with terminal B cell differentiation. Importantly, AMPAR-targeting ASCs were already detectable in the CNS shortly after symptom onset, accumulated during disease progression, and strongly correlated with disease severity. Together these findings confirm that anti-AMPAR encephalitis can be caused by ectopic exposure to AMPA receptors and support a revised working model for autoimmune encephalitis pathogenesis. Our findings also support two therapeutic priorities: early treatment initiation to prevent ASC formation, and the development of CNS-penetrating B cell receptor or ASC-targeting therapies.