Research ArticleENCEPHALITIS

Autoimmune receptor encephalitis in mice induced by active immunization with conformationally stabilized holoreceptors

See allHide authors and affiliations

Science Translational Medicine  10 Jul 2019:
Vol. 11, Issue 500, eaaw0044
DOI: 10.1126/scitranslmed.aaw0044

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

An active model of autoimmune encephalitis

Autoantibodies targeting the neurotransmitter N-methyl-d-aspartate receptor (NMDAR) have been found in patients with encephalitis. Although treatments reducing antibody titers have been developed, their effect is often incomplete. The lack of models recapitulating the pathophysiology of the human disease hinders the development of effective treatments. Now, Jones et al. developed a mouse model of NMDAR encephalitis using active immunization with intact NMDARs embedded in liposomes. Characterization of the model showed alterations resembling human anti-NMDAR encephalitis, including the presence of hippocampal inflammation, immune cell infiltration, and cognitive impairments. Moreover, the authors showed that the presence of T cell and B cell infiltrates is necessary for the induction of the disease.

Abstract

Autoimmunity to membrane proteins in the central nervous system has been increasingly recognized as a cause of neuropsychiatric disease. A key recent development was the discovery of autoantibodies to N-methyl-d-aspartate (NMDA) receptors in some cases of encephalitis, characterized by cognitive changes, memory loss, and seizures that could lead to long-term morbidity or mortality. Treatment approaches and experimental studies have largely focused on the pathogenic role of these autoantibodies. Passive antibody transfer to mice has provided useful insights but does not produce the full spectrum of the human disease. Here, we describe a de novo autoimmune mouse model of anti-NMDA receptor encephalitis. Active immunization of immunocompetent mice with conformationally stabilized, native-like NMDA receptors induced a fulminant encephalitis, consistent with the behavioral and pathologic characteristics of human cases. Our results provide evidence for neuroinflammation and immune cell infiltration as components of the autoimmune response in mice. Use of transgenic mice indicated that mature T cells and antibody-producing cells were required for disease induction. This active immunization model may provide insights into disease induction and a platform for testing therapeutic approaches.

View Full Text