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Background Mucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and therefore virus shedding. Parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior mucosal infection compared with injections of a parenteral vaccine in a mucosally naive subject. We investigated whether this was also the case for the BNT162b2 coronavirus disease 2019 (COVID-19) messenger RNA vaccine. Methods Twenty recovered COVID-19 subjects (RCSs) and 23 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–naive subjects were vaccinated with, respectively, 1 and 2 doses of the BNT162b2 COVID-19 vaccine. Nasal epithelial lining fluid (NELF) and plasma were collected before and after vaccination and assessed for immunoglobulin G (IgG) and IgA antibody levels to Spike and for their ability to neutralize binding of Spike to angiotensin-converting enzyme-2 receptor. Blood was analyzed 1 week after vaccination for the number of Spike-specific antibody-secreting cells (ASCs) with a mucosal tropism. Results All RCSs had both nasal and blood SARS-CoV-2–specific antibodies at least 90 days after initial diagnosis. In RCSs, a single dose of vaccine amplified preexisting Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including Delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2–naive subjects after 2 vaccine doses compared with RCSs after 1 dose. Conclusions Mucosal immune response to the SARS-CoV-2 Spike protein is higher in RCSs after a single vaccine dose compared with SARS-CoV-2–naive subjects after 2 doses.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies in adults, displaying a progressive, frequently asymmetric involvement of a typical muscles’ pattern. FSHD is associated with epigenetic derepression of the polymorphic D4Z4 repeat on chromosome 4q, leading to DUX4 retrogene toxic expression in skeletal muscles. Identifying biomarkers that correlate with disease severity would facilitate clinical management and assess potential FSHD therapeutics’ efficacy. Objectives: This study purpose was to analyze serum cytokines to identify potential biomarkers in a large cohort of adult patients with FSHD. Methods: We retrospectively measured the levels of 20 pro-inflammatory and regulatory cytokines in sera from 100 genetically confirmed adult FSHD1 patients. Associations between cytokine concentrations and various clinical scores were investigated. We then measured serum and muscle interleukin 6 (IL-6) levels in a validated FSHD-like mouse model, ranging in severity and DUX4 expression. Results: IL-6 was identified as the only cytokine with a concentration correlating with several clinical severity and functional scores, including Clinical Severity Score, Manual Muscle Testing sum score, Brooke and Vignos scores. Further, FSHD patients displayed overall IL-6 levels more than twice high as control, and patients with milder phenotypes exhibited lower IL-6 serum concentration than those with severe muscular weakness. Lastly, an FSHD-like mouse model analysis confirmed that IL-6 levels positively correlate with disease severity and DUX4 expression. Conclusions: Serum IL-6, therefore, shows promise as a serum biomarker of FSHD severity in a large cohort of FSHD1 adult patients.

Childhood internalizing disorders refer to inwardly focused negative behaviours such as anxiety, depression, and somatic complains. Interactions between psychosocial, genetic, and environmental risk factors adversely impact neurodevelopment and can contribute to internalizing disorders. While prenatal exposure to single endocrine disruptors (ED) is associated with internalizing behaviours in infants, the associations with prenatal exposure to ED in mixture remain poorly addressed. In addition, the biological mediators of ED mixture effects on internalizing behaviours remain unexplored. ED do not only interfere with endocrine function, but also with immune function and inflammatory processes. Based on this body of evidence, we hypothetised that inflammation at birth is a plausible biological pathway through which ED prenatal exposure could operate to influence offspring internalizing behaviours. Based on the EDEN birth cohort, we investigated whether ED mixture exposure increased the odds of internalizing disorders in 459 boy infants at age 3, and whether the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α measured at birth are mediators of this effect. To determine both the joint and individual associations of ED prenatal exposure with infant internalizing behaviours and the possible mediating role of cytokines, we used the counterfactual hierarchical Bayesian Kernel Machine Regression (BKMR) regression-causal mediation analysis. We show that prenatal exposure to a complex ED mixture has limited effects on internalizing behaviours in boys at age 3. We also show that IL-1β, IL-6, and TNF-α are unlikely mediators or suppressors of ED mixture effects on internalizing behaviours. Further studies on larger cohorts are warranted to refine the deleterious effects of ED mixtures on internalizing behaviours and identify possible mediating pathways.

Neuroinflammation has been proposed to impact symptomatology in patients with schizophrenia spectrum disorders. While previous studies have shown equivocal effects of treatments with add-on anti-inflammatory drugs such as Aspirin, N-acetylcysteine and Celecoxib, none have used a subset of prospectively recruited patients exhibiting an inflammatory profile. The aim of the study is to evaluate the efficacy and safety as well as the cost-effectiveness of a treatment with 400 mg Celecoxib added to an ongoing antipsychotic treatment in patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. The “Add-on Celecoxib treatment in patients with schizophrenia spectrum disorders and inflammatory cytokine profile trial (TargetFlame)” is a multicentre randomized, placebo-controlled phase III investigator-initiated clinical trial with the following two arms: patients exhibiting an inflammatory profile receiving either add-on Celecoxib 400 mg/day or add-on placebo. A total of 199 patients will be assessed for eligibility by measuring blood levels of three pro-inflammatory cytokines, and 109 patients with an inflammatory profile, i.e. inflamed, will be randomized, treated for 8 weeks and followed-up for additional four months. The primary endpoint will be changes in symptom severity as assessed by total Positive and Negative Syndrome Scale (PANSS) score changes from baseline to week 8. Secondary endpoints include various other measures of psychopathology and safety. Additional health economic analyses will be performed. TargetFlame is the first study aimed at evaluating the efficacy, safety and cost-effectiveness of the antiphlogistic agent Celecoxib in a subset of patients with schizophrenia spectrum disorders exhibiting an inflammatory profile. With TargetFlame, we intended to investigate a novel precision medicine approach towards anti-inflammatory antipsychotic treatment augmentation using drug repurposing. Clinical trial registration:http://www.drks.de/DRKS00029044 and https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00029044

Omicron s escape to vaccine-induced systemic antibody responses has been shown in several studies in Omicron-infected patients and vaccine controls.In the present study we compared mucosal antibody response to Omicron to mucosal antibody response to ancestral strain and Delta variant. This was done on nasal epithelial lining fluid (NELF) prospectively collected in 84 otherwise healthy healthcare workers who had never exhibited PCR-documented COVID-19 and had received three doses of the Pfizer-BioNTech COVID-19 mRNA vaccine. NELF was collected prior to Omicron detection in the geographical area of inclusion.We show that NELF antibodies from vaccinated individuals were less efficient at inhibiting the binding of the Omicron Spike protein to ACE-2 compared to those of Delta or the ancestral strain.These findings may explain the increased risk of onward transmission of Omicron, consistent with its successful global displacement of Delta in countries with a high vaccination coverage.

Presentation of the article in video : https://vimeo.com/465124099; International audience; In an effort to reduce CO2 emissions, many countries throughout the world are initiating plans to transition to more sustainable forms of energy. Nuclear energy would appear to be a powerful contender to replace fossil fuels, or at least be an unavoidable option, from an energy-mix perspective. However, nuclear energy suffers from a poor image among certain populations, especially the young, who favor the development of renewable energies. We wanted to get a more accurate read of what was happening in France, one of the most nuclearized countries in the world, where the share of nuclear energy is greater than 70%. Since plans are underway to reduce this level to 50% by 2035, understanding popular perceptions on this matter is even more important. In order to gain a better understanding, we interviewed an “expert” population and compared the results obtained with a so-called young “non-expert” student population. The first group is composed of firefighters, about half of whom have attended training in radiological risks, and the other, a non-expert population, composed of students from Université Côte d’Azur (UCA), who are potentially influenced (for better or worse) by social media. The aim of this study is to compare and contrast any differences in perception that these two distinct populations may have on the subject of nuclear energy.

International audience; Nearly 10% of 5-year-old children experience social, emotional or behavioral problems and are at increased risk of developing mental disorders later in life. While animal and human studies have demonstrated that cytokines can regulate brain functions, it is unclear whether individual cytokines are associated with specific behavioral dimensions in population-based pediatric samples. Here, we used data and biological samples from 786 mother-child pairs participating to the French national mother-child cohort EDEN. At the age of 5, children were assessed for behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) and had their serum collected. Serum samples were analyzed for levels of well-characterized effector or regulatory cytokines. We then used a penalized logistic regression method (Elastic Net), to investigate associations between serum levels of cytokines and each of the five SDQ-assessed behavioral dimensions after adjustment for relevant covariates and confounders, including psychosocial variables. We found that interleukin (IL)-6, IL-7, and IL-15 were associated with increased odds of problems in prosocial behavior, emotions, and peer relationships, respectively. In contrast , eight cytokines were associated with decreased odds of problems in one dimension: IL-8, IL-10, and IL-17A with emotional problems, Tumor Necrosis Factor (TNF)-α with conduct problems, CC motif chemokine Ligand (CCL)2 with hyperactivity/inattention, C-X-C motif chemokine Ligand (CXCL)10 with peer problems, and CCL3 and IL-16 with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines regulate brain functions and behavior and provide a rationale for launching longitudinal studies.

Cell therapy with autologous donor-specific regulatory T cells (Tregs) is a promising strategy to minimize immunosuppression in transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate donor-specific Tregs and overcome the limitations of enrichment protocols based on repetitive stimulations with alloantigens. However, the ability of CAR-Treg therapy to control alloreactivity in immunocompetent recipients is unknown. We first analyzed the effect of donor-specific CAR Tregs on alloreactivity in naive, immunocompetent mice receiving skin allografts. Tregs expressing an irrelevant or anti-HLA-A2-specific CAR were administered to Bl/6 mice at the time of transplanting an HLA-A2+ Bl/6 skin graft. Donor-specific CAR-Tregs, but not irrelevant-CAR Tregs, significantly delayed skin rejection and diminished donor-specific antibodies (DSAs) and frequencies of DSA-secreting B cells. Donor-specific CAR-Treg-treated mice also had a weaker recall DSA response, but normal responses to an irrelevant antigen, demonstrating antigen-specific suppression. When donor-specific CAR Tregs were tested in HLA-A2-sensitized mice, they were unable to delay allograft rejection or diminish DSAs. The finding that donor-specific CAR-Tregs restrain de novo but not memory alloreactivity has important implications for their use as an adoptive cell therapy in transplantation.

Background Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and the most commonly identified monogenic cause of autism. Recent studies have shown that long-term pathological consequences of FXS are not solely confined to the central nervous system (CNS) but rather extend to other physiological dysfunctions in peripheral organs. To gain insights into possible immune dysfunctions in FXS, we profiled a large panel of immune-related biomarkers in the serum of FXS patients and healthy controls. Methods We have used a sensitive and robust Electro Chemi Luminescence (ECL)-based immunoassay to measure the levels of 52 cytokines in the serum of n = 25 FXS patients and n = 29 healthy controls. We then used univariate statistics and multivariate analysis, as well as an advanced unsupervised clustering method, to identify combinations of immune-related biomarkers that could discriminate FXS patients from healthy individuals. Results While the majority of the tested cytokines were present at similar levels in FXS patients and healthy individuals, nine chemokines, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26 and CXCL10, were present at much lower levels in FXS patients. Using robust regression, we show that six of these biomarkers (CCL2, CCL3, CCL11, CCL22, CCL26 and CXCL10) were negatively associated with FXS diagnosis. Finally, applying the K-sparse unsupervised clustering method to the biomarker dataset allowed for the identification of two subsets of individuals, which essentially matched the FXS and healthy control categories. Conclusions Our data show that FXS patients exhibit reduced serum levels of several chemokines and may therefore exhibit impaired immune responses. The present study also highlights the power of unsupervised clustering methods to identify combinations of biomarkers for diagnosis and prognosis in medicine.

International audience; Inflammation appears as a cardinal mediator of the deleterious effect of early life stress exposure on neurodevelopment. More generally, immune activation during the perinatal period, and most importantly elevations of pro-inflammatory cytokines levels could contribute to psychopathology and neurological deficits later in life. Cytokines are also required for normal brain function in homeostatic conditions and play a role in neurodevelopmental processes. Despite these latter studies, whether pro-inflammatory cytokines such as Tumor Necrosis Factor (TNF) impact neurodevelopmental trajectories and behavior during the immediate postnatal period remains to be elucidated. To address this issue, we have injected mouse pups daily with recombinant TNF from postnatal day (P)1 to P5. This yielded a robust increase in peripheral and central TNF at P5, and also an increase of additional pro-inflammatory cytokines. Compared to control pups injected with saline, mice injected with TNF acquired the righting and the acoustic startle reflexes more rapidly and exhibited increased locomotor activity 2 weeks after birth. Our results extend previous work restricted to adult behaviors and support the notion that cytokines, and notably TNF, modulate early neurodevelopmental trajectories.

Background: The immunogenicity of a two-dose mRNA COVID-19 vaccine regimen is low in kidney transplant (KT) recipients. Here, we provide a thorough assessment of the immunogenicity of a three-dose COVID-19 vaccine regimen in this population. Methods: We performed a prospective longitudinal study in sixty-one KT recipients given three doses of the BNT162b2 COVID-19 vaccine. We performed semi-structured pharmacovigilance interviews and monitored donor-specific antibodies and kidney function. We compared levels of anti-spike IgG, pseudo-neutralization activity against vaccine homologous and heterologous variants, frequency of spike-specific interferon (IFN)-γ-secreting cells, and antigen-induced cytokine production 28 days after the second and third doses. Findings: Reactions to vaccine were mild. One patient developed donor-specific anti-HLA antibodies after the second dose which could be explained by non-adherence to immunosuppressive therapy. Spike-specific IgG seroconversion raised from 44·3% (n=27) after the second dose to 62·3% (n=38) after the third dose (p

Most researchers working in the field of immunopsychiatry would agree with the statement that "severe psychiatric disorders are associated with inflammation and more broadly with changes in immune variables". However, as many other fields in biology and medicine, immunopsychiatry suffers from a replication crisis characterized by lack of reproducibility. In this paper, we will comment on four types of immune variables which have been studied in psychiatric disorders: Acute Phase Proteins (AAPs), cytokines, lipid mediators of inflammation and immune cell parameters, and discuss the rationale for looking at them in blood. We will briefly describe the analytical methods that are currently used to measure the levels of these biomarkers and comment on overlooked analytical and statistical methodological issues that may explain some of the conflicting data reported in the literature. Lastly, we will briefly summarize what cross-sectional, longitudinal and mendelian randomization studies have brought to our understanding of schizophrenia (SZ).

Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Results Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

Background: Others and we have shown that T cells have an important role in hippocampal synaptic plasticity, including neurogenesis in the dentate gyrus, spinogenesis, and glutamatergic synaptic function in the CA of the hippocampus. Hippocampus plasticity is particularly involved in the brain effects of the enriched environment (EE), and interestingly CD4+ and CD8+ T cells play essential and differential roles in these effects. However, the precise mechanisms by which they act on the brain remain elusive. Objectives: We searched for a putative mechanism of action by which CD4+ T cells could influence brain plasticity and hypothesized that they could regulate protein transport at the level of the blood-CSF barrier in the choroid plexus. Method: We compared mice housed in EE and deprived of CD4+ T cells using a depleting antibody with a control group injected with the control isotype. We analyzed in the hippocampus the gene expression profiles using the Agilent system, and the expression of target proteins in plasma, CSF, and the choroid plexus using ELISA. Results: We show that CD4+ T cells may influence EE-induced hippocampus plasticity via thyroid hormone signaling by regulating in the choroid plexus the expression of transthyretin, the major transporter of thyroxine (T4) to the brain parenchyma. Conclusions: Our study highlights the contribution of close interactions between the immune and neuroendocrine systems in brain plasticity and function.

International audience; Bipolar disorder (BD) diagnosis currently relies on assessment of clinical symptoms, mainly retrospective and subject to memory bias. BD is often misdiagnosed as Major Depressive Disorder (MDD) resulting in ineffective treatment and worsened clinical outcome. The primary purpose of this study was to identify blood biomarkers that discriminate MDD from BD patients when in a depressed state. We have used clinical data and serum samples from two independent naturalistic cohorts of patients with a Major Depressive Episode (MDE) who fulfilled the criteria of either BD or MDD at inclusion. The discovery and replication cohorts consisted of 462 and 133 patients respectively. Patients were clinically assessed using standard diagnostic interviews, and clinical variables including current treatments were recorded. Blood was collected and serum assessed for levels of 31 cytokines using a sensitive multiplex assay. A penalized logistic regression model combined with nonparametric bootstrap was subsequently used to identify cytokines associated with BD. Interleukin (IL)-6, IL-10, IL-15, IL-27 and C-X-C ligand chemokine (CXCL)-10 were positively associated with BD in the discovery cohort. Of the five cytokines identified as discriminant features in the discovery cohort, IL-10, IL-15 and IL-27 were also positively associated with BD in the replication cohort therefore providing an external validation to our finding. Should our results be validated in a prospective cohort, they could provide new insights into the pathophysiological mechanisms of mood disorders.

In contrast to other fields of medicine, and despite extensive research to identify neuroimaging, electroencephalography, or blood-based biomarkers, neither trait nor state biomarkers are currently available in psychiatry. Would such biomarkers be available, they could help clinicians to answer some of the simplest questions to which they are faced in their daily practice. Previous studies have shown that most severe mental disorders are associated with altered blood levels of cytokines, a group of small soluble proteins that are mainly produced by immune cells. Because cytokine levels can be measured using sensitive and cost-effective analytical methods, many authors have investigated whether they could be useful biomarkers in psychiatry. Despite hundreds of papers in this field, no single cytokine, or combination of cytokines, has emerged as a biomarker that would be robust enough to be used in clinical settings. Here, we will argue that this failure may have been due at least in part to overlooked methodological issues not only for preparation, storage, and analysis of the biological samples but also for statistical analysis of the datasets. We will also propose some guidelines for future studies and advocate for the adoption of common Standard Operating Procedures.

Background: The immunogenicity of a two-dose mRNA COVID-19 vaccine regimen is low in kidney transplant (KT) recipients. We report the first complete assessment of safety and cross-variant immunogenicity of a three-dose vaccine regimen in KT recipients. Methods: We performed a prospective longitudinal study in sixty-one KT recipients given three doses of the BNT162b2 COVID-19 vaccine. We performed semi-structured pharmacovigilance interviews and monitored donor-specific antibodies and kidney function. We compared geometric mean titers (GMT) of anti-spike IgG, pseudo-neutralization activity against vaccine homologous and heterologous variants, frequency of spike-specific interferon (IFN)-γ-secreting cells, and antigen-induced cytokine production 28 days after the second and third doses. The immunoassays were also performed in non-transplanted individuals 28 days after the second dose to obtain reference values. Findings: Reactions to vaccine were mild. One patient developed donor-specific anti-HLA antibodies after the second dose which could be explained by non-adherence to immunosuppressive therapy. Spike-specific IgG seroconversion raised from 44·3% (n=27) after the second dose to 62·3% (n=38) after the third dose (p

Background Patients with a First-Episode of Psychosis (FEP) exhibit low-grade inflammation as demonstrated by elevated levels of C reactive protein (CRP) and pro-inflammatory cytokines. Aims The primary goal of this study was to investigate the association between pro-inflammatory biomarkers and clinical outcomes in unmedicated FEP patients. Method We used clinical data and biological samples from 289 FEP patients participating to the Optimization of Treatment and Management of Schizophrenia in Europe (OPTIMISE) clinical trial. Patients were assessed at baseline and 4-5 weeks after treatment with amisulpride. Baseline serum levels of interleukin (IL)-6, IL-8, Tumor Necrosis Factor (TNF)-α and CRP were measured. We first used multivariable regression to investigate the association between each of the four tested biomarkers and the following clinical outcomes: Positive And Negative Syndrome Scale (PANSS), Calgary Depression Score for Schizophrenia (CDSS), remission according to Andreasen’s criteria and Serious Adverse Events (SAEs). As a complementary approach, we used an unsupervised clustering method to stratify patients into an “inflamed” or a “non-inflamed” biotype based on baseline levels of IL-6, IL-8 and TNF-α. We then used linear and logistic regressions to investigate the association between the patient biotype and clinical outcomes. Results After adjusting for covariates and confounders, we did not find any association between IL-6, IL-8, TNF-α, CRP or the patient biotype and clinical outcomes. Implications Our results do not support the existence of an association between baseline levels of CRP and proinflammatory cytokines and early response to amisulpride in unmedicated FEP patients.

BackgroundMucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and hence virus shedding. Preclinical and clinical studies have shown that a parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior infection compared to two injections of a parenteral vaccine. We investigated whether this was also the case for a COVID-19 mRNA vaccine.MethodsTwenty-three COVID-19 convalescent patients and 20 SARS-CoV-2-naive subjects were vaccinated with respectively one and two doses of the Pfizer-BioNTech COVID-19 RNA vaccine. Nasal Epithelial Lining Fluid (NELF) and plasma were collected before and after vaccination and assessed for Immunoglobulin (Ig)G and IgA to Spike and for their ability to inhibit the binding of Spike to its ACE-2 receptor. Blood was analyzed one week after vaccination for the number of Spike-specific Antibody Secreting Cells (ASCs) with a mucosal tropism.ResultsIn COVID-19 convalescent patients, a single dose of vaccine amplified pre-existing Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2-naive subjects after two vaccine dosesConclusionThis study showed that a parenteral booster injection of a COVID-19 RNA vaccine promoted stronger mucosal immune responses in COVID-19 convalescent patients compared to SARS-CoV-2 naive subjects who had received a first vaccine dose.

Disruption of neurodevelopmental trajectories can alter brain circuitry and increase the risk of psychopathology later in life. While preclinical studies have demonstrated that the immune system and cytokines influence neurodevelopment, whether immune activity and in particular which cytokines at birth are associated with psychopathology remains poorly explored in children. We used data and biological samples from 869 mother-child pairs participating in the French mother-child cohort EDEN. As proxies for immune activity at birth, we measured the levels of 27 cytokines in umbilical cord blood sera (CBS). We then explored the association between CBS cytokine levels and five psychopathological dimensions assessed in 5-year-old children using the Strengths and Difficulties Questionnaire (SDQ). Five cytokines were positively associated with psychopathology: C-X-C motif chemokine Ligand (CXCL)10, interleukin (IL)-10 and IL-12p40 with emotional symptoms, C–C motif chemokine Ligand (CCL)11 with conduct problems, and CCL11, and IL-17A with peer relationships problems. In contrast, seven cytokines were negatively associated with psychopathology: IL-7, IL-15 and Tumor Necrosis Factor (TNF)-β with emotional symptoms, CCL4 and IL-6 with conduct problems, CCL26 and IL-15 with peer relationships problems, and CCL26, IL-7, IL-15, and TNF-α with abnormal prosocial behavior. Without implying causation, these associations support the notion that cytokines influence neurodevelopment in humans and the risk of psychopathology later in life., Highlights • Twelve cytokines at birth are associated with psychopathology in 5-year-old children. • IL-7, IL-10, IL-12p40, IL-15, TNF-β and CXCL10 are associated with emotional symptoms. • IL-6, CCL4 and CCL11 are associated with conduct problems. • IL-15, IL-17A, CCL11 and CCL26 are associated with peer relationship problems. • IL-7, IL-15, TNF-α and CCL26 are associated with prosocial behavior.

Background Recent research suggests that immune dysregulation in pregnancy could be a risk factor for anxiety and depression symptoms in offspring. Whereas animal studies have demonstrated the importance of the link between perinatal cytokines and abnormal behaviors in offspring, human epidemiological studies in this area remain limited. The objectives of the study were to describe the network of cord serum cytokines at birth and test whether they are associated with subsequent anxiety and depression symptom trajectories in offspring. Methods We used data and biological samples from 871 mother–child pairs followed up from pregnancy to 8 years of age and participating in the French mother–child cohort EDEN (a study on the pre- and early postnatal determinants of child health and development). Cord serum cytokines were measured at birth. Children’s symptoms of anxiety and depression were assessed with the emotional difficulties subscore of the Strength and Difficulties Questionnaire at ages 3, 5, and 8 years, from which trajectories of anxiety-depression symptoms were derived. Results Results showed a significant association between cord serum interleukin-7 at birth and the trajectories of children’s anxiety-depression symptoms between ages 3 to 8 years (adjusted odds ratio, 0.73; 95% confidence interval, 0.57–0.93). The associations considered relevant confounders, including prenatal maternal depressive symptoms. Conclusions Early immune changes may contribute to subsequent anxiety and depression symptoms in childhood. Beyond the understanding of mechanisms underlying the occurrence of emotional difficulties in children, our findings open avenues for future research in human and animals.

International audience; Maternal immune activation (MIA) during pregnancy induces a cytokine storm that alters neurodevelopment and behavior in the progeny. In humans, MIA increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD). In mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C)) to pregnant dams. Although the murine model of MIA has been extensively studied, it is not clear whether MIA results in cytokine changes in the progeny at early postnatal stages. Further , the murine model of MIA suffers from a lack of reproducibility and high inter-individual variability. Multivariable (MV) statistical analysis is widely used in human studies to control for confounders and covariates such as sex, age and exposure to environmental factors. We therefore reasoned that animal studies in general and studies on the MIA model in particular could benefit from MV analyses to account for complex phenotype interactions and high inter-individual variability. Here, we used MV statistical analysis to identify cytokines associated with MIA after adjustment for covariates. Besides confirming the association between previously described variables and MIA, we identified new cytokines that could play a role in behavioural alterations in the progeny during the early postnatal period.

Maternal immune activation (MIA) during pregnancy increases the odds of developing neuropsychiatric disorders such as autism spectrum disorder (ASD) later in life. In pregnant mice, MIA can be induced by injecting the viral mimic polyinosinic:polycytidylic acid (poly(I:C) to pregnant dams resulting in altered fetal neurodevelopmental and behavioral changes in their progeny. Although the murine MIA model has been extensively studied worldwide, the underlying mechanisms have only been partially elucidated. Furthermore, the murine MIA model suffers from lack of reproducibility, at least in part because it is highly influenced by subtle changes in environmental conditions. In human studies, multivariable (MV) statistical analysis is widely used to control for covariates including sex, age, exposure to environmental factors and many others. We reasoned that animal studies in general, and studies on the MIA model in particular, could therefore benefit from MV analyzes to account for complex phenotype interactions and high inter-individual variability. Here, we used a dataset consisting of 26 variables collected on 67 male pups during the course of several independent experiments on the MIA model. We then analyzed this dataset using penalized regression to identify variables associated with in utero exposure to MIA. In addition to confirming the association between some previously described biological variables and MIA, we identified new variables that could play a role in neurodevelopment alterations. Aside from providing new insights into variable interactions in the MIA model, this study highlights the importance of extending the use of MV statistics to animal studies.

Background: Leptin is potentially involved in the correction of early postnatal growth of infants having deviated from their genetic trajectory in utero. Aim: To analyse the potential mediating role of cord blood leptin level in the association between neonatal anthropometry and early postnatal growth in the mother–child EDEN cohort. Subjects and methods: We included term newborns with information on leptin, birth weight and length, and weight and length SD-score changes over the first 2 months. The Baron and Kenny method was used to quantify the mediation contribution of leptin in the association between neonatal anthropometry and postnatal growth, considering several confounders. Analyses were stratified to consider sexual dimorphism. Results: A 1 SD higher birth weight was associated with a lower 2-months weight variation of 0.27 (0.18; 0.36) SD and a 0.16 (0.06; 0.26) SD, in boys and girls, respectively. Leptin explained 20% and 25% of these associations, respectively. Leptin did not mediate the association between birth length and birth-to-2 months length variation. Conclusion: Our results suggest that cord blood leptin may not be involved in the negative association between birth length and postnatal length growth but may play a modest mediating role in early postnatal catch-up or catch-down in weight.

The original Article did not feature the list of collaborators. This has now been corrected in the PDF and HTML versions of this Article.

Background: Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and the most commonly identified monogenic cause of autism. Recent studies have shown that long-term pathological consequences of FXS are not solely confined to the central nervous system (CNS) but rather extend to other physiological dysfunctions in peripheral organs. To gain insights into possible immune dysfunctions in FXS, we profiled a large panel of immune-related biomarkers in the serum of FXS patients and healthy controls. Methods: We have used a sensitive and robust ElectroChemiLuminescence (ECL)-based immunoassay to measure the levels of 52 cytokines in the serum of n=25 FXS patients and n=29 healthy controls. We then used univariate statistics and multivariate analysis, as well as an advanced unsupervised clustering method, to identify combinations of immune-related biomarkers that could discriminate FXS patients from healthy individuals. Results: While the majority of the tested cytokines were present at similar levels in FXS patients and healthy individuals, nine chemokines, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26 and CXCL10, were present at much lower levels in FXS patients. Applying the K-sparse unsupervised clustering method to the biomarker dataset allowed for the identification of two subsets of individuals, which essentially matched the FXS and healthy control categories. Conclusions: Our data suggest that FXS patients exhibit reduced serum levels of several chemokines and may therefore exhibit impaired immune responses. The present study also highlights the power of unsupervised clustering methods to identify combinations of biomarkers for diagnosis and prognosis in medicine.

BACKGROUND: Early response to first-line antipsychotics is associated with positive long-term symptomatic outcome in psychosis. Unfortunately, attempts to identify reliable predictors of treatment response in first-episode psychosis (FEP) patients have not yet been successful. One reason for this could be that FEP patients are heterogeneous in terms of symptoms and underlying disease biological mechanisms, thereby impeding the identification of one-size-fits-all predictors of treatment response. METHODS: We have used a two-step hierarchical clustering approach to stratify 325 FEP patients into four subtypes, termed C1A, C1B, C2A and C2B, based on their symptoms assessed using the Positive and Negative Syndrome Scale. After validating our clustering approach on external measures, we then used a regularized logistic regression method to identify biological and clinical variables associated with increased odds of being non-remitters within each subtype. RESULTS: Compared to those from the other subtypes, C1A patients exhibited higher serum levels of several pro-inflammatory cytokines and were the most at risk of being non-remitters when treated with a second-generation antipsychotic drug. In C1A patients, but not in others, lower serum levels of interleukin-15, higher levels of C-X-C motif chemokine 12, previous exposure to cytomegalovirus, use of recreational drugs and a younger age were all associated with higher odds of being non-remitters 4 weeks after treatment. The predictive value of this model was 73%, and its specificity and sensitivity were 45% and 83% respectively. CONCLUSIONS: Serum levels of two cytokines combined with three clinical variables predict remission in a subtype of FEP patients.

Background:Vagus nerve (VN) stimulation has shown the potential to improve the disease development in animal models of arthritis and in patients with RA. However, the VN can affect respiratory, cardiovascular, endocrine and gastro-intestinal physiology. The splenic nerve (SpN) has been confirmed to be the principal effector nerve for the VN-mediated immune control. Previous studies have shown that stimulating the splenic nerve resulted in an increase of norephiniphrine in the spleen, as well as a significant reduction in LPS-induced TNF (1).Objectives:To test the therapeutic efficiency of splenic nerve stimulation (SNS) in collagen-induced arthritis (CIA) in mice alone or in combination with anti-TNF treatment.Methods:CIA was induced in DBA1/J mice by immunization with bovine type II collagen at days 0 and 21. At day 11, mice were implanted with micro-cuff electrode (CorTec) onto the SpN or VN. From day 16 to day 45, SNS were applied as rectangular charged-balanced biphasic pulses with 650 μA pulse amplitude, 200 µs pulse width at 10 Hz frequency for 2 min 1 or 6 times a day using a Plexon stimulator. In order to investigatedthe mechanism of action in more detail, propranolol, a beta-adrenergic receptor (β-AR) antagonist, was added to the drinking water of mice receiving SNS. In addition, a control group was treated with anti-TNF (etanercept, 3 times/week; 10mg/kg i.p.). In curative settings, SNS and/or anti-TNF treatment was applied starting when mice scored positive for 3 consecutive days. Clinical arthritis was determined by visual examination of swelling and redness of the paws and measurement of paw thickness. Sham mice were undergoing the same procedure but did not receive stimulation.Results:In CIA in mice all sham animals developed arthritis, compared to only 14% following six times per day SNS (p Conclusion:These studies demonstrate that SNS suppresses pro-inflammatory cytokine production, and reduces clinical symptoms in mice with CIA which is at least partially mediated by the β-AR. The additive effect of anti-TNF in reducing the clinical scores demonstrates that that mechanism of action of SNS is not primarilys mediated by reducing TNF levels. Moreover, anti-TNF potentiating the inhibitory effect of SNS is supporting a combined use of these treatments, or even a combination of SNS with other biologicals, to treat RA, potentially getting more patients closer to remission. In conclusion, the data is providing compelling scientific rationale and pre-clinical evidence that splenic neuromodulation might be a new treatment modality for RA.References:[1] Guyot M et al, Brain Behav Immun. 2019;80:238.Disclosure of Interests:Thomas Simon Grant/research support from: research grant from Galvani Bioelectronics, Clara Panzolini Grant/research support from: Working on research grant Galvani bioelectronics, Julien Lavergne Grant/research support from: working on research grant Galvani Bioelectrocnics, Nicolas Hypolite Grant/research support from: Working on research grant Galvani Bioelectronics, Nicolas Glaichenhaus: None declared, Margriet Vervoordeldonk Employee of: I am an employee of Galvani Bioelectronics, Philippe Blancou Grant/research support from: Received research grant from Galvani Bioelectronics

Others and we have shown that T cells have an important role in hippocampal synaptic plasticity, including neurogenesis in the dentate gyrus, spinogenesis, and glutamatergic synaptic function in the CA of the hippocampus. Hippocampus plasticity is particularly involved in the brain effects of the enriched environment (EE), and interestingly CD4+ and CD8+ T cells play essential and differential roles in these effects. However, the precise mechanisms by which they act on the brain remain elusive.We searched for a putative mechanism of action by which CD4+ T cells could influence brain plasticity and hypothesized that they could regulate protein transport at the level of the blood-CSF barrier in the choroid plexus.We compared mice housed in EE and deprived of CD4+ T cells using a depleting antibody with a control group injected with the control isotype. We analyzed in the hippocampus the gene expression profiles using the Agilent system, and the expression of target proteins in plasma, CSF, and the choroid plexus using ELISA.We show that CD4+ T cells may influence EE-induced hippocampus plasticity via thyroid hormone signaling by regulating in the choroid plexus the expression of transthyretin, the major transporter of thyroxine (T4) to the brain parenchyma.Our study highlights the contribution of close interactions between the immune and neuroendocrine systems in brain plasticity and function.