Immunoneuropsychiatry — novel perspectives on brain disorders

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Immune processes have a vital role in CNS homeostasis, resilience and brain reserve. Our cognitive and social abilities rely on a highly sensitive and fine-tuned equilibrium of immune responses that involve both innate and adaptive immunity. Autoimmunity, chronic inflammation, infection and psychosocial stress can tip the scales towards disruption of higher-order networks. However, not only classical neuroinflammatory diseases, such as multiple sclerosis and autoimmune encephalitis, are caused by immune dysregulation that affects CNS function. Recent insight indicates that similar processes are involved in psychiatric diseases such as schizophrenia, autism spectrum disorder, bipolar disorder and depression. Pathways that are common to these disorders include microglial activation, pro-inflammatory cytokines, molecular mimicry, anti-neuronal autoantibodies, self-reactive T cells and disturbance of the blood–brain barrier. These discoveries challenge our traditional classification of neurological and psychiatric diseases. New clinical paths are required to identify subgroups of neuropsychiatric disorders that are phenotypically distinct but pathogenically related and to pave the way for mechanism-based immune treatments. Combined expertise from neurologists and psychiatrists will foster translation of these paths into clinical practice. The aim of this Review is to highlight outstanding findings that have transformed our understanding of neuropsychiatric diseases and to suggest new diagnostic and therapeutic criteria for the emerging field of immunoneuropsychiatry.

Key points

  • At the interface of neurological and psychiatric disorders, immune processes are major factors in CNS health and disease; the immune system contributes to CNS homeostasis, resilience and brain reserve.

  • Although a certain level of neuroimmune interplay is required for optimal brain functioning, chronic inflammation and latent infections can cause higher-order network disturbances, resulting in cognitive and behavioural impairment.

  • Psychosocial stress correlates with inflammatory processes in the CNS.

  • Immune dysregulation plays a role not only in classical autoimmune brain diseases such as multiple sclerosis and autoimmune encephalitis but also in psychiatric disorders such as schizophrenia, autism spectrum disorder, bipolar disorder and depression.

  • Immune treatments are emerging as therapeutic options for subgroups of patients with brain disorders that are associated with an inflammatory phenotype.

  • New diagnostic and therapeutic criteria are required to translate immunopathogenic findings into individualized treatment options for patients with neuropsychiatric disorders.

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Fig. 1: The interplay between the immune system and the CNS.
Fig. 2: Overlap of neuropsychiatric disorders.
Fig. 3: A proposed clinical pathway for patients with new-onset neuropsychiatric symptoms.


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The authors thank C. Ernest, R. Gilchrist and S. Jennrich (all at the Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany) for proofreading the manuscript. The authors acknowledge financial support for the underlying original work from the German Research Foundation (DFG; CRC-TR 128, CRC 1080 and CRC 1292 to F.Z.) and from the Agence Nationale de la Recherche (ANR; I-GIVE Samenta 2013; 13-SAMA-0004-01), the Institut National de la Recherche Médicale and Fondation FondaMental (to M.L.). The views expressed are those of the authors.

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Nature Reviews Neurology thanks D. Agalliu and other anonymous reviewer(s) for their contribution to the peer review of this work.

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All authors conceived the article, performed literature searches, wrote the article and reviewed and edited the manuscript. K.P. designed the display items.

Correspondence to Frauke Zipp.

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