Autoimmune encephalitis mediated by B-cell response against N-methyl-d-aspartate receptor

Abstract

Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease characterized by an antibody-mediated autoimmune response against NMDAR. Recent studies have shown that anti-NMDAR antibodies are involved in the pathophysiology of the disease. However, the upstream immune and inflammatory processes responsible for this pathogenic response are still poorly understood. Here, we immunized mice against the region of NMDA receptor containing the N368/G369 amino acids, previously implicated in a pathogenic response. This paradigm induced encephalopathy characterized by blood–brain barrier opening, periventricular T2-MRI hyperintensities and IgG deposits into the brain parenchyma. Two weeks after immunization, mice developed clinical symptoms reminiscent of encephalitis: anxiety- and depressive-like behaviours, spatial memory impairment (without motor disorders) and increased sensitivity to seizures. This response occurred independently of overt T-cell recruitment. However, it was associated with B220+ (B cell) infiltration towards the ventricles, where they differentiated into CD138+ cells (plasmocytes). Interestingly, these B cells originated from peripheral lymphoid organs (spleen and cervical lymphoid nodes). Finally, blocking the B-cell response using a depleting cocktail of antibodies reduced the severity of symptoms in encephalitis mice. This study demonstrates that the B-cell response can lead to an autoimmune reaction against NMDAR that drives encephalitis-like behavioural impairments. It also provides a relevant platform for dissecting encephalitogenic mechanisms in an animal model, and enables the testing of therapeutic strategies targeting the immune system in anti-NMDAR encephalitis.

Characteristics and Prognosis of Autoimmune Encephalitis in the East of China: A Multi-Center Study

“…In the past 10 years, with the advancement of diagnostic technology, the antibody spectrum of AE has continued to expand, and research on its diagnosis and treatment has also continued to progress (4)(5)(6). Disease incidence, clinical features of disease, and strategies used to treat AE patients in different countries and regions differ.…”

Antibody-mediated neuropsychiatric disorders

“…Several animal models of active immunization with NMDAR have been also reported. 8 An important contribution of these models is the demonstration of predominant B-cell or antibody-related mechanisms that support the neuropathological findings observed in human studies where neuronophagia or cytotoxic T-cell infiltrates are minimal or absent. 9 The current treatment approach to most AEs is immunotherapy and tumor removal (when it applies).…”

Immunotherapy for Refractory Autoimmune Encephalitis

“…If specific genotypes exist, through specific pathways, render patients with AE refractory to first - and second-line therapies, then targeted therapies for specific genotypes become possible. Given the low incidence of encephalitis and difficulty in its early diagnosis, more effort is required to established animal models ( 93 ). Unfortunately, only a few therapeutic options are available for AE.…”