Immuno-metabolic profile of patients with psychotic disorders and metabolic syndrome. Results from the FACE-SZ cohort

Background: Metabolic syndrome (MetS) is a highly prevalent and harmful medical disorder often comorbid with psychosis where it can contribute to cardiovascular complications. As immune dysfunction is a key shared component of both MetS and schizophrenia (SZ), this study investigated the relationship between immune alterations and MetS in patients with SZ, whilst controlling the impact of confounding clinical characteristics including psychiatric symptoms and comorbidities, history of childhood maltreatment and psychotropic treatments. Method: A total of 310 patients meeting DSM-IV criteria for SZ or schizoaffective disorders (SZA), with or without MetS, were systematically assessed and included in the FondaMental Advanced Centers of Expertise for Schizophrenia (FACE-SZ) cohort. Detailed clinical characteristics of patients, including psychotic symptomatology, psychiatric comorbidities and history of childhood maltreatment were recorded and the serum levels of 18 cytokines were measured. A penalized regression method was performed to analyze associations between inflammation and MetS, whilst controlling for confounding factors. Results: Of the total sample, 25% of patients had MetS. Eight cytokines were above the lower limit of detection (LLOD) in more than 90% of the samples and retained in downstream analysis. Using a conservative Variable Inclusion Probability (VIP) of 75%, we found that elevated levels of interleukin (IL)-6, IL-7, IL-12/23 p40 and IL-16 and lower levels of tumor necrosis factor (TNF)-α were associated with MetS. As for clinical variables, age, sex, body mass index (BMI), diagnosis of SZ (not SZA), age at the first episode of psychosis (FEP), alcohol abuse, current tobacco smoking, and treatment with antidepressants and anxiolytics were all associated with MetS. Conclusion: We have identified five cytokines associated with MetS in SZ suggesting that patients with psychotic disorders and MetS are characterized by a specific “immuno-metabolic” profile. This may help to design tailored treatments for this subgroup of patients with both psychotic disorders and MetS, taking one more step towards precision medicine in psychiatry. © 2022 The AuthorsImmuno-Génétique, Inflammation, retro-Virus, Environnement : de l'étiopathogénie des troubles psychotiques aux modèles animauxRéseau d'Innovation sur les Voies de Signalisation en Sciences de la Vi

Le microbiote intestinal : un rôle potentiel dans les troubles psychiatriques majeurs

International audienceThe gut microbiota is increasingly considered as a symbiotic partner in the maintenance of good health. Metagenomic approaches could help to discover how the complex gut microbial ecosystem participates in the control of the host's brain development and function, and could be relevant for future therapeutic developments, such as probiotics, prebiotics and nutritional approaches for psychiatric disorders. Previous reviews focused on the effects of microbiota on the central nervous system in in vitro and animal studies. The aim of the present review is to synthetize the current data on the association between microbiota dysbiosis and onset and/or maintenance of major psychiatric disorders, and to explore potential therapeutic opportunities targeting microbiota dysbiosis in psychiatric patients.Le microbiote intestinal est considéré de plus en plus comme un partenaire symbiotique contribuant au bon état de santé général de l’organisme. Les approches métagénomiques, en pleine expansion, permettent de mieux en mieux appréhender la complexité de l’écosystème intestinal et de son impact sur le développement et le fonctionnement du système nerveux central de son hôte. Elles pourraient permettre à l’avenir le développement de thérapeutiques spécifiques ciblant le microbiote intestinal, comme les probiotiques, les prébiotiques et les approches nutritionnelles chez les patients souffrant de troubles mentaux. Ces traitements existent déjà dans le traitement de certaines pathologies intestinales, mais l’efficacité, le type de souches, la quantité et la durée administrée restent à déterminer chez l’humain, alors que les résultats animaux sont très prometteurs dans les modèles de troubles anxieux et de stress chronique. Le but de la présente revue est de synthétiser les données actuelles, d’une part, sur l’association entre la dysbiose du microbiote intestinal et le déclenchement ou l’entretien de troubles psychiatriques, et d’autre part, d’explorer les thérapeutiques potentielles qui pourraient être proposées aux patients souffrant de troubles psychiatriques associés à une dysbiose intestinale

T-cell subset phenotypes in patients with bipolar disorder or schizophrenia with history of childhood maltreatment

Introduction: History of Childhood Maltreatment (CM) has repeatedly been associated with an increased risk of developing bipolar disorders (BD) or schizophrenia (SZ). The impact of severe stress induced by CM is thought to be mediated by increased inflammation reflected by deregulated levels of circulating pro- and anti-inflammatory cytokines. However, little is known about the potential impact of exposition to CM on lymphocyte subpopulations or the role of pre-existing infections on the impact of CM. We thus explored the role of CM and the impact of past exposure to infections on lymphocyte subpopulation.as these could be important avenues to better understand the impact of severe stress in major mood and psychotic disorders. Patients and Methods: 118 adult patients with SZ and 152 with BD were included in the analysis. History of CM was assessed using the Childhood Trauma Questionnaire (CTQ), current and past psychiatric symptomatology were evaluated. Circulating lymphocytes subsets were analyzed using flow cytometry-based analysis. Past exposure to common infectious stigma including toxoplasma, Cytomegalovirus (CMV) and Ebstein-Barr Virus (EBV) were measured by solid phase-enzyme microplate and ELISA immunoassays. Relationship between CM, biological phenotypes and clinical phenotypes were analyzed using univariate and multivariate analyses. Results: We found that patients with BD and CM, as compared to those without, had higher levels of CD3+CD8+ cytotoxic T cells and CMV antibodies along decreased levels of CD45RA+CCR7+CD8+ naïve CD8 T cells, and a more severe clinical profile. We also observed that levels of CMV antibodies were inversely associated with the CD3+CD8+ lymphocyte subset level.Patients with SZ and CM have decreased levels of CD14+ monocytes. Accumulation of types of maltreatment is associated with increased Body Mass Index and CMV autoantibodies as well as decreased levels of CD14+ monocytes. Conclusion: We observed that adult patients with BD or SZ having been exposed to CM exhibit specific immune cell subset profiles, clinical features and stigma of past infections. Altogether, our findings, especially in the context of BD, allows us to suggest a possible interplay between CM and CMV infectious events possibly inducing premature aging and cellular senescence, two events already known to be associated with psychiatric conditions. Longitudinal studies of patients exposed to maltreatment are warranted to replicate, predict and anticipate the specific needs of these patients

NKp30 isoforms and NKp46 transcripts in metastatic melanoma patients: Unique NKp30 pattern in rare melanoma patients with favorable evolution.

Given the NK cell-based immunosurveillance of melanoma, we investigated the prognostic value of NKp46 transcript and NKp30 isoform (NKp30A, NKp30B and NKp30C) profiling in blood of 187 melanoma patients including 13 long survivors (LS), metastatic patients that have controlled the disease. Compared to healthy volunteers (HV), patients had reduced amounts of transcripts of the three NKp30 isoforms (NKp30 A, B and C) but similar ratios between NKp30 isoforms (ΔAB, ΔAC, ΔBC). Stratification of patients according to disease stage showed higher NKp30C and lower NKp46 transcripts in stage IV patients. Furthermore, patients with previous history of conventional chemotherapy displayed reduced NKp30A transcripts. The expression levels of NKp30 isoforms failed to predict survival from sampling of patients, while NKp46 expression predicted melanoma outcome. LS patients displayed elevated NKp30A levels, accordingly high ΔAB and ΔBC ratios, and a unique pattern of rare allelic variants of NKp30 SNPs. Moreover, NK cells from LS displayed correlated NKp30/NKp46 membrane expression, high spontaneous and NKp30- or NKp46-triggered degranulation. These data outline the impact of NKp30 and NKp46 transcripts on melanoma evolution and identify unique genetic features of NKp30 associated with higher NK activation in rare LS melanoma patients that control a metastatic disease

Minimizing the risk of allo-sensitization to optimize the benefit of allogeneic cardiac-derived stem/progenitor cells

Allogeneic human cardiac-derived stem/progenitor cells (hCPC) are currently under clinical investigation for cardiac repair. While cellular immune response against allogeneic hCPC could be part of their beneficial-paracrine effects, their humoral immune response remains largely unexplored. Donor-specific HLA antibodies (DSA-HLA-I/DSA-HLA-II), primary elements of antibody-mediated allograft injury, might present an unidentified risk to allogeneic hCPC therapy. Here we established that the binding strength of anti-HLA monoclonal antibodies delineates hCPC proneness to antibody-mediated injury. In vitro modeling of clinical setting demonstrated that specific DSA-HLA-I of high/intermediate binding strength are harmful for hCPC whereas DSA-HLA-II are benign. Furthermore, the Luminex-based solid-phase assays are suitable to predict the DSA-HLA risk to therapeutic hCPC. Our data indicate that screening patient sera for the presence of HLA antibodies is important to provide an immune-educated choice of allogeneic therapeutic cells, minimize the risk of precipitous elimination and promote the allogeneic reparative effects