Advances in research on the role of autoimmunity in psychiatric sequelae of viral encephalitis

Jinyu Wang¹, Ke Shi1, Peng Ji¹, Yi Chen¹, Huanwen Li¹, Jingwen Bian¹, Guangtai Han¹, Di Zhang¹, Zhui Ke^2*

¹Xiangshui County People's Hospital, Xiangshui 224600, Jiangsu, China.

²Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China.

*Correspondence:

Zhui Ke; Email: kezhui1314@163.com

Abstract

The pathophysiological understanding of viral encephalitis is shifting from a paradigm of direct viral injury to one emphasizing combined infection–immune–mediated damage. This review focuses on how viral infection and autoimmunity act synergistically to promote encephalitis-related psychiatric sequelae. In addition to disrupting the blood–brain barrier and activating innate neuroinflammation, viral infections can induce neuron-specific autoantibodies, such as anti–N-methyl-D-aspartate receptor (NMDAR) antibodies, leading to sustained immune-mediated synaptic dysfunction and neuronal injury. These immunopathological processes preferentially affect the prefrontal cortex, temporal lobe, and limbic system, providing a mechanistic explanation for the high prevalence of acute and long-term psychiatric manifestations, including delirium, cognitive impairment, mood disorders, and psychosis. By integrating evidence from clinical phenotypes, cytokine signaling, exosomes, and neuroimaging, this review underscores the limitations of antiviral therapy alone and highlights the rationale for early combined immunomodulatory interventions to improve long-term neuropsychiatric outcomes following viral encephalitis.

Keywords: viral encephalitis, autoimmunity, neuroinflammation, herpes simplex virus, anti-NMDAR encephalitis, psychiatric symptoms, cognitive impairment