SOCIETAL CHALLENGES Lectures 2023
Immuno-psychiatry: towards precision medicine
25 January 2023, 14:00-15:30 CET
Psychiatric disorders are heterogeneous overlapping disorders needing valid biomarkers to define homogeneous subgroups leading the way to Precision medicine, as in cancer or cardiovascular settings. Identification of clinical and biological signatures further dissected in animal models will help the discovery of mechanism-based treatments. As of yet, there are different visions about this phenotypic approach. By splitting or lumping: we may either identify trans-nosographical dimensions that cut across diagnostic categories and/or, at the other extreme of the vision, we will identify very precise sub-phenotypes.
Among existing biological pathways that should help to foresee homogenous subgroups, immune dysfunction, now clearly recognized as being associated with psychiatric disorders, offer different type of biological markers at central, peripheral or gut levels. In that respect, we will describe three pathways, with inflammation as a common denominator, leading to specific subgroups according to (i) auto-autoimmunity against brain receptors, described under the term “auto-immune psychosis” (ii) re-activation of human endogenous retro-virus, or (iii) gut dysbiosis, all of them constituting targets for immuno-modulatory treatments.
The discovery that the immune system can influence brain function and structure has profoundly changed the landscape of psychiatry. Repeated report of association of pro-inflammatory cytokines with major psychiatric disorders led to exploration of the causes and consequences of this inflammatory background. This low-grade inflammation has been shown to be the consequence of interaction between environmental factors such as infections, stress, pollution, unhealthy life style with immune-genetic background. Association with particular immune-genetic variants of Toll-like receptor genes possibly explain diminished response to infections (TLR, NOD), association with mitochondrial genes contribute to maintenance of inflammation, while association with particular HLA haplotypes explains induction of auto-immune phenomena and/or exaggerated synaptic pruning. For example, association with the complement genes can induce abnormal pruning and microglial activation thereby increasing the risk of neurodevelopmental disorders such as early onset schizophrenia. In the context of the SARS-Cov2 pandemic, increased severity of COVID-19 in psychiatric patients is probably due to their reduced ability to fight infection. Systemic inflammation and persistent infections induce different pathways paving the way to biomarker-guided personalized medicine.
One of the best example is the identification of “autoimmune psychosis” defined by presence of anti-neuronal antibodies that has been confounded for long with atypical, mild, or attenuated forms of autoimmune encephalitis. Persistent infections are associated to activation of Human endogenous retrovirus (HERV). Systemic inflammation induced by microbial infection or psychosocial factors can also be at the origin of the activation of human endogenous retrovirus. Although many aspects of the complex relationship between immunity and brain function are not yet fully elucidated, the findings that have accumulated so far have transformed our understanding of psychiatric disorders and favored the consideration of other possible cellular and molecular targets for their treatment than just alterations in neuronal transmitters.
Marion Leboyer is a Professor of Psychiatry at the University of Paris Est Créteil, head of the Psychiatry and Addictology Unit at Hôpitaux Universitaires Henri Mondor and Director of the Genetic Psychiatry Laboratory (team 15) at Institut Mondor de Recherches Biomédicales (INSERM U955). She is director of the Fondation FondaMental since 2007 and also a member of ITMO neurosciences, cognition, neurology and psychiatry (AVIESAN), representing psychiatry. After studying medicine at the University of Paris-Descartes, she completed her research training at the genetics laboratory of Professor Ken Kidd at Yale University (New Haven, USA) and then completed her thesis in neurosciences in 1990 at the Université Pierre et Marie Curie.