Literatura científica selecionada sobre o tema "Immunopsychiatrie"

Immunopsychiatry is a fledgling research field with great potential in the etiological research of psychotic disorders and can turn out to be helpful in finding novel treatment strategies and repurposing existing therapeutic agents. The clinical applications of Neuroquantology complement some of the etiological views of psychotic disorders that are evolving in immunopsychiatry. The pathogenesis of psychotic process may involve an underlying immune disturbance leading to neuro-quantological disorders. The cytokine storm that occurs due to COVID-19 and the resulting neurotoxic effects illustrate how an autoimmune reaction can potentially form psychotic symptoms through the mediation of the brain. Studying the interconnection between neurotransmission and immunity has significant relevance in the etiopathogenesis of psychiatric disorders. Immunopsychiatry alone may not be adequate to explain the development of psychotic symptoms, but Neuroquantology and immunopsychiatry complement each other in this endeavor. An expanded model of the brain–mind consciousness complex is required to understand the intricacies of psychotic symptomatology and contributions from Neuroquantology are highly enrichening. The claims of the practitioners of quantum immunotherapies need further exploration. Quantum-brain and immunity triangle can result in a huge paradigmatic shift in our understanding of psychiatric disorders and the evolving landscape of immunopsychiatry and clinical Neuroquantology warrant further promotion.

Accumulating evidence indicate a role for the immune system particularly inflammation and autoimmunity in the aetiology of major psychiatric disorders such as depression and schizophrenia. In this paper, we discuss some of the key advances in immunopsychiatry in order to highlight to psychiatrists and other health professionals how an increased understanding of this field might enhance our knowledge of illness mechanism and approaches to treatment. We present a brief overview of clinical research that link inflammation and autoimmunity with depression and psychosis, including potential role of inflammation in treatment response, current evidence for the effectiveness of immune-modulating treatment for depression and psychosis, and possible role of inflammation in common physical comorbidities for these disorders such as coronary heart disease and diabetes mellitus. Gaining a better understanding of the role of immune system could be paradigm changing for psychiatry. We need collaborations between clinicians and scientists to deliver high-quality translational research in order to fully realise the clinical potential of this exciting and rapidly expanding field.

The possibility that inflammation plays a causal role in major depression is an important claim in the emerging field of immunopsychiatry and has generated hope for new treatments. The aims of the present review are first to provide some historical background and to consider the evidence in favor of the claim that inflammation is causally involved in major depression. The second part discusses some of the possibilities allowed for by the use of broad ‘umbrella’ concepts, such as inflammation and stress, in terms of proposing new working hypotheses and potential mechanisms. The third part reviews proposed biomarkers of inflammation and depression and the final part addresses how elements discussed in the preceding sections are used in immunopsychiatry. The ‘umbrella’ concepts of inflammation and stress, as well as insufficiently-met criteria based inferences and reverse inferences are being used to some extent in immunopsychiatry. The field is therefore encouraged to specify concepts and constructs, as well as to consider potential alternative interpretations and explanations for findings obtained. The hope is that pointing out some of the potential problems will allow for a clearer picture of immunopsychiatry’s current strengths and limitations and help the field mature.

Implication des lymphocytes T régulateurs dans le trouble du spectre autistique secondaire à une activation immunitaire maternelle pendant la grossesse. Rationnel pour l'utilisation d'interleukine 2 faible dose à visée préventive et curative.Le trouble du spectre autistique (TSA) est une entité clinique hétérogène caractérisée par des troubles dans les interactions et la communication sociale et des comportements restreints et/ou stéréotypés. Son étiopathogénie repose sur l'interaction entre des facteurs de prédisposition génétique et des facteurs environnementaux. Parmi ces derniers, l'activation immunitaire maternelle durant la grossesse (MIA) augmente le risque de TSA dans la descendance. Il persiste cependant de nombreuses inconnues, à la fois fondamentales chez l'animal et cliniques chez l'Homme sur les mécanismes qui sous-tendent la persistance des symptômes autistiques. Afin de répondre à ces questions, nous avons combiné une approche épidémiologique et clinique, basée sur la cohorte de patients atteints de TSA pris en charge dans le centre d'excellence sur l'autisme et les troubles du neurodéveloppement de Robert Debré, avec une approche fondamentale sur un modèle murin de TSA en lien avec une MIA. Notre travail a mis en évidence, chez la souris, que la MIA entraine un défaut à long terme des lymphocytes T régulateurs (Tregs) dans la descendance entrainant une inflammation chronique du système nerveux central sous-tendant les symptômes autistiques. La stimulation des Tregs par de l'interleukine-2 à faible dose permet de normaliser les symptômes autistiques. Chez l'homme, nous avons également retrouvé ce défaut des Tregs et décrit que les TSA en lien avec un MIA représentent un sous-groupe homogène distinct des autres patients atteints de TSA. Nos résultats apportent un éclairage nouveau sur la physiopathologie du TSA en lien avec un MIA qui peut être considéré comme une maladie inflammatoire chronique du système nerveux central. Par ailleurs, ces patients représentent un sous-groupe identifiable dans l'hétérogénéité du TSA, ouvrant la voie au développement d'immunothérapie ciblant spécifiquement les Tregs, comme l'utilisation de l'interleukine-2 à faible dose
Implication of regulatory T cells in autism spectrum disorder secondary to maternal immune activation during pregnancy. Rationale for the use of low-dose interleukin 2 for preventive and curative treatment.Autism spectrum disorder (ASD) is a heterogeneous clinical condition characterized by impaired social interaction and communication, and restricted and/or stereotyped behavior. Its etiopathogenesis is based on the interaction between genetic predisposition and environmental factors. Among the latter, maternal immune activation during pregnancy (MIA) increases the risk of ASD in the offspring. However, there are still many unknowns, both fundamental in animals and clinical in humans, about the mechanisms underlying the persistence of autistic symptoms. To answer these questions, we have combined an epidemiological and clinical approach, based on the cohort of ASD patients cared for at the Robert Debré Center of Excellence for Autism and Neurodevelopmental Disorders, with a fundamental approach using a mouse model of ASD in association with MIA. Our work has shown that, in mice, MIA results in a long-term defect in regulatory T cells (Tregs) in the offspring, leading to chronic inflammation of the central nervous system underlying autistic symptoms. Stimulation of Tregs with low-dose interleukin-2 normalizes autistic symptoms. In humans, we have also found this Tregs defect and described that ASD related to MIA represents a homogeneous subgroup distinct from other ASD patients. Our findings shed new light on the pathophysiology of MIA-associated ASD, which can be considered a chronic inflammatory disease of the central nervous system. Furthermore, these patients represent an identifiable subgroup within the heterogeneity of ASD, paving the way for the development of immunotherapies specifically targeting Tregs, such as the use of low-dose interleukin-2

Les troubles du spectre autistique (TSA) sont un ensemble de pathologies neurodéveloppementales dont la prévalence est en constante augmentation. Ils sont caractérisés par des déficits de la communication et des interactions sociales, et par des comportements répétitifs et stéréotypés. A l’origine d’un handicap sévère, ces troubles se manifestent dès la petite enfance et persistent chez l’adulte. Cette entité recouvre des profils cliniques très hétérogènes, tant par le spectre de sévérité des symptômes que par la variété des comorbidités psychiatriques et somatiques associées sous tendues, en partie, par des dysfonctionnements immunitaires. Dans ce contexte, nous nous sommes de ce fait intéressés à l’identification et à la caractérisation de biomarqueurs à valence immunogénétique et immunologique afin d’en étudier l’implication physiopathologique et d’en déterminer les corrélats cliniques.De manière plus précise, nous avons évalué l’implication de la diversité génétique de molécules intervenant dans l’immunité innée (PRR, CLR, Dectin-1) et l’immunité adaptative (système HLA) dans le but d’apprécier le poids du terrain immunogénétique sur le développement de ces troubles. Puis, nous avons analysé les caractéristiques phénotypiques et fonctionnelles des cellules Natural Killer de patients atteints de TSA afin d’en déterminer l’influence potentielle sur l’état inflammatoire permanent rapporté chez certains patients TSA.Sur le plan immunogénétique, nous avons montré que la diversité génétique de Dectin-1 (CLEC7A), candidat sélectionné en raison de son implication dans la modulation de pathologies microbiennes intestinales, était associé à une forme particulière de TSA, le syndrome d’Asperger. Nous avons observé que le génotype CLEC7A rs2078178 GG ainsi que l’haplotype rs2078178/rs16910631 GG/GG étaient non seulement plus fréquents chez les Asperger mais aussi associées aux scores de quotient intellectuel (QI). Dans le cadre de l’analyse de la diversité génétique du système HLA, nous avons identifié un haplotype à risque (HLA-DRB1 *11-DQB1*07) et un haplotype de protection (HLA-DRB1 *17-DQB1*02). L’haplotype à risque étant également associé avec la sévérité de la maladie, reflétée par des scores défavorables dans les échelles cliniques psychiatriques testées.Dans la seconde partie de cette thèse nous avons exploré les modifications phénotypiques et fonctionnelles des cellules NK CD3- CD56+ chez les patients atteints d’autisme de haut niveau. Nous avons observé un état d’activation cellulaire permanent concomitant avec une capacité de dégranulation spontanée, une production soutenue d’IFN-?, et un état hypofonctionnel/épuisement cellulaire après stimulation in vitro. De plus, nous avons identifié un cluster spécifique de cellules NK, basé sur les paramètres HLA-DR, NKG2C, et KIR2DL1, et nous avons observé une augmentation inattendue des cellules NK NKG2C+ chez les sujets TSA en dehors de toute piste infectieuse connue. Enfin, nous avons observé que l’expression de KIR2DL1 et de HLA-DR était respectivement corrélée aux scores de QI et à ceux évaluant les CCA-LS et SAWR.Pris dans leur ensemble, ces données pourraient permettre de contribuer à une meilleure connaissance des mécanismes physiopathologiques associés au système immunitaire dans les TSA et par conséquent à une meilleure catégorisation des groupes de patients susceptibles de bénéficier de stratégies thérapeutiques immunologiques ciblées
Autism spectrum disorders (ASD) are severe neurodevelopmental conditions characterized by deficits in communication and social interactions, and by repetitive and stereotyped behaviors and exhibiting a constant increase in terms of prevalence. Affecting ages ranging from the early post-natal period to adulthood, ASD are clinically heterogeneous and often associated with psychiatric and somatic comorbidities underlying, in part, by immune dysfunctions. In this context, we thus focused our attention on the analysis of immunogenetic and immunological characteristics potentially implicated in the disease risk and/or in the modulation their clinical phenotype. More precisely, we evaluated the potential implication of the genetic diversity of molecules involved in innate (PRR, CLR, Dectin-1) and adaptive (HLA) immune responses in disease risk. We then analyzed the phenotypic and functional characteristics of Natural Killer cells in patients with ASD, investigating their influence on the permanent inflammatory state often reported in ASD settings.On the immunogenetic point of view, we found that the genetic diversity of Dectin-1 (CLEC7A), a candidate selected because of its involvement in the modulation of intestinal microbial disorders, was associated with Asperger syndrome, a clinical form of ASD. We observed that the CLEC7A genotype rs2078178 GG and the rs2078178 / rs16910631 GG /GG haplotype were not only more frequent in Asperger but also associated with IQ scores.In terms of HLA diversity, we identified a risk haplotype (HLA-DRB1 * 11-DQB1 * 07) and a protective haplotype (HLA-DRB1 * 17-DQB1 * 02). The risk haplotype was also found to be associated with disease’s severity as reflected by unfavorable scores in the psychiatric clinical scales tested.In the second part of this thesis, we explored the phenotypic and functional modifications of CD3-CD56 + NK cells in patients with high-functioning autism. We observed a permanent cell activation state concomitant with spontaneous degranulation capacity, sustained IFN-? production and cellular hypofunction /exhaustion after in vitro stimulation. In addition, we identified a specific cluster of NK cells, based on the HLA-DR, NKG2C, and KIR2DL1 parameters, and we observed an unexpected increase of NK NKG2C + cells in ASD subjects independent of CMV infection. Finally, we observed that the expression of KIR2DL1 and HLA-DR were respectively correlated with the scores of IQ and those evaluating the CCA-LS and SAWR scales.Taken together, these data could contribute to a better knowledge of the pathophysiological mechanisms associated with the immune system in ASD and consequently to a better categorization of the groups of patients likely to benefit from targeted immunological therapeutic strategies

In recent years, great attention has been devoted to the understanding of the immune dysfunction that is associated with major psychiatric disorders. In the context of the reconceptualization of the immune system as a homeostatic system, immune cells, molecules and mechanisms are highly promising as new diagnostic and therapeutic targets to reduce the burden of mental/psychiatric disorders. In this regard, immune cells, molecules and mechanisms are highly promising. The literature on immunology of psychiatric disorders is still disperse, and only very few attempts have been done so far to consolidate the current knowledge in this expanding and exciting area. Each chapter will present the available data on the immune/inflammatory dysfunction in psychiatric disorders, indicating the potential use of novel immunological biomarkers or therapeutic targets, as well as discussing the challenges ahead to incorporate this knowledge into the clinical practice.

This chapter presents an overview of the immune system, presenting its organization, major cellular and molecular components, as well as functional responses. The main objective of this chapter is to provide the reader the basic information necessary to understand the immunological terms in the following chapters. More in-depth information can be found in several excellent basic immunology books. In addition to the well-known roles in generating immunity against infections, cells of the immune system are also involved in regulating non-immune physiological processes, including tissue remodeling and brain functions. The generation of sterile inflammation and the role of T-lymphocyte subsets are important hallmarks discussed here.

This chapter presents an overview of the current literature on the pathophysiological mechanisms of inflammatory mediators in neuroimmune modulation, as well as pharmacological strategies in inflammatory signaling pathways in the central nervous system (CNS). Increasing attention has been paid to the importance of brain–immune interaction for the maintenance of brain homeostasis. If immune activation persists, inflammatory mediators and their signaling pathways can influence neurons/neuronal circuits, leading to mood, cognitive, and behavioral impairment. Therefore, immune dysregulation can play a role in the pathophysiology of psychiatric disorders through its direct and indirect ability to alter the synthesis, reuptake, and release of multiple neurotransmitters, and to induce oxidative stress, mitochondrial dysfunction, cytoskeletal disruption, and cytotoxic lipid peroxidation, among other effects. In this sense, inflammatory mediators and their signaling pathway are currently regarded as attractive targets for promising therapeutic and preventative therapeutic strategies in clinical psychiatry, especially for patients who are resistant to treatment and exhibit inflammatory phenotypes. The efficacy and precision of anti-inflammatory treatments can be further tuned, and they depend on the methodologically rigorous design of future clinical trials.

This chapter presents an overview of the immune mechanisms affecting the functioning of the central nervous system (CNS). The cross-talk between the immune system and the CNS is established by three independent pathways: the humoral, neural, and cellular (leukocyte) routes. Of note, increased circulating pro-inflammatory cytokines and concomitant activation of brain-resident microglia can lead to impaired cognition and depressive behavioral symptoms. The activated microglia phenotype has been associated with neuroinflammation reported in neurodegenerative and psychiatric disorders. This chapter also reviews novel physiological roles for adaptive immunity (especially T cells) during health and disease. T cells support hippocampal neurogenesis, cognition, mood, resilience to stress, and are protective against the development of psychiatric disorders.

Multiple factors and mechanisms may influence the healthy development of the embryo and fetus during the gestational period. Inflammation is a physiological response that mediates the clearance of cellular debris and release of neurotrophic factors. Inflammation also eludes or minimizes threats. The same developmental mechanisms that promote plastic changes may expose the organism to adverse outcomes. Several mechanisms related to the immune system, including the release of cytokines and activation of T cells, may contribute to neuroinflammation. An exacerbated inflammatory response has been associated with the occurrence of central nervous system (CNS) injuries that may determine, in the short term and/or long term, structural and functional consequences for CNS development. Evidence suggests that immune dysfunction may affect brain development and may play a role in several neurodevelopmental/psychiatric disorders.

This chapter deals with the capacity of the immune system to sense the intrusion of external challenges and modifications of self-components, and to provide information to the brain about these disturbances. These properties allow us to classify the immune system as a classical sensory organ. Besides its intrinsic function directed at the elimination of dangerous stimuli, the activation of the immune system also affects the functioning of other homeostatic systems, such as the endocrine and the nervous systems. We also discuss our view of how immune-derived information could be processed by the brain and integrated with other inputs that it permanently receives, leading to a resetting of regulatory adaptive systems. Due to the high energetic cost of immunity, we discuss how brain-borne cytokines, in particular IL-1, could affect glucose homeostasis. Deregulation of these immune-neuroendocrine interactions can affect brain mechanisms that include behavior, cognition, mood, and personality.

It is well known that the influence of the gut microbiota extends beyond their intestinal limits. A growing body of preclinical and clinical evidence suggests that the changes in the composition of the gut microbiota may regulate brain function and behavior through different gut-to-brain pathways, including immune modulation. Interestingly, studies have suggested that few commensal intestinal bacteria play a significant role in in the physiology of neuropsychiatric disorders. Here, we summarize recent discoveries on the potential role of the microbiota-gut-brain communication in the origins and development of anxiety, depression, neurodegenerative disorders, and autism-spectrum diseases. The investigation of the microbiota from the point of host–microbiota interaction can lead to the design of therapeutic interventions targeting gut microbial composition with clinical relevance for neuropsychiatric conditions.

Among potential biomarkers in psychiatry, immune markers have been regarded as very promising due to the role played by the immune system in the physiopathology of psychiatric disorders and the relatively easy access to them. The most studied immune markers are C-reactive protein (CRP), the cytokines TNF-α‎, interleukin 1 beta (IL-1β‎), IL-6, IL-8, IL-10, and the neutrophil:lymphocyte ratio. These markers lack specificity; therefore, they are not useful as diagnostic markers. Overlapping inflammatory markers across psychiatric disorders point to a likely common and/or shared immune dysfunction. Regarding diagnosis, anti-NMDA antibodies seem to be promising, being able to identify a group of patients experiencing an acute neuropsychiatric syndrome marked by psychosis and motor signs. Beyond psychiatric diagnoses, immune markers have been evaluated as risk, subgroup, and treatment-response markers.

Immune dysfunction plays an important etiological role in several psychiatric disorders, thus appearing as a transnosological feature potentially associated with worse clinical outcomes such as early onset, severity of symptoms, treatment resistance, and suicide, as well as with the development of other metabolic and autoimmune comorbidities. In this chapter, evidence for the existence of a chronic low-grade inflammation and oxidative and nitrosative stress in major psychiatric disorders is documented. In addition, elements likely to be the consequence of this immune dysfunction and suggesting that psychiatric disorders should be considered as multisystem disorders are discussed, such as the comorbidity with metabolic and autoimmune disorders, alterations of gut permeability and microbiota, and the reactivation of human endogenous retroviruses. In this context, potential constitutive (genetic) and environmental determinants (childhood stress and early-life infection) of immune dysfunction are discussed.

As in other psychiatric disorders, the role of the immune system is gathering increasing attention as an important mechanism in substance use disorders. Addiction is a complex condition in which a person engages in drug-seeking and drug-taking behaviors to accentuate the reward processes in the brain and avoid negative withdrawal states. Due in part to the activation of stress responses during drug withdrawal, high levels of peripheral pro-inflammatory cytokines are observed in this phase, and these immune changes might contribute to the behavioral negative reinforcing effects of the drug. This and other observations suggest that the immune system might play a role in the development of substance use disorders, also representing a potential target for biomarker and therapeutic strategy development (e.g., vaccines).