immune activation

Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism

February 1, 2020
Brown, A. S.
Developmental Neurobiology 2012, 72: 1272 - 1276

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In this review, we provide a synopsis of work on the epidemiologic evidence for prenatal infection in the etiology of schizophrenia and autism. In birth cohort studies conducted by our group and others, in utero exposure to infectious agents, prospectively obtained after biomarker assays of archived maternal sera and by obstetric records was related to an increased risk of schizophrenia. Thus far, it has been demonstrated that prenatal exposure to influenza, increased toxoplasma antibody, genitalreproductive infections, rubella, and other pathogens are associated with schizophrenia. Anomalies of the immune system, including enhanced maternal cytokine levels, are also related to schizophrenia. Some evidence also suggests that maternal infection and immune dysfunction may be associated with autism. Although replication is required, these findings suggest that public health interventions targeting infectious exposures have the potential for preventing cases of schizophrenia and autism. Moreover, this work has stimulated translational research on the neurobiological and genetic determinants of these conditions.

Tagged: adult schizophrenia, association, birth cohort, Epidemiology, herpes-simplex-virus, immune activation, infection, influenza, maternal exposure, pregnancy, reproductive infections, Schizophrenia, spectrum disorders, toxoplasmosis

Mental health

Toxoplasma gondii: Biological parameters of the connection to schizophrenia

February 12, 2018
Xiao, J. C. ,Prandovszky, E. , Kannan,G., Pletnikov, M. V. Dickerson, ,F. , Severance , E. G., Yolken, R. H.
Schizophrenia Bulletin 2018; 44: 983-992

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It is increasingly evident that the brain is not truly an immune privileged site and that cells of the central nervous system are sensitive to the inflammation generated when the brain is fighting off infection. Among the many microorganisms that have access to the brain, the apicomplexan protozoan Toxoplasma gondii has been one of the most studied. This parasite has been associated with many neuropsychiatric disorders including schizophrenia. This article provides a comprehensive review of the status of Toxoplasma research in schizophrenia. Areas of interest include (1) the limitations and improvements of immune-based assays to detect these infections in humans, (2) recent discoveries concerning the schizophrenia-Toxoplasma association, (3) findings of Toxoplasma neuropathology in animal models related to schizophrenia pathogenesis, (4) interactions of Toxoplasma with the host genome, (5) gastrointestinal effects of Toxoplasma infections, and (6) therapeutic intervention of Toxoplasma infections.

Tagged: attempts, bipolar disorder, complement c1q, congenital toxoplasmosis, immune activation, infection, microorganism, molecular-mechanisms, murine toxoplasmosis, pathogenesis, psychiatric-disorders, risk factors, suicide, tissue cyst formation

Mental health

Pathogen-mediated NMDA receptor autoimmunity and cellular barrier dysfunction in schizophrenia

May 9, 2017
Kannan, G., Gressitt, K.L., Yang, S., Stallings, C.R., Katsafanas, E., Schweinfurth, L.A., Savage, C.L.G., Adamos, M.B., Sweeney, K.M., Origoni, A.E., Khushalani, S., Bahn, S., Leweke, F.M., Dickerson, F.B., Yolken, R.H., Pletnikov, M.V., Severance, E.G.
Translational Psychiatry 2017; 7: 10.1038/tp.2017.162

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Autoantibodies that bind the N-methyl-D-aspartate receptor (NMDAR) may underlie glutamate receptor hypofunction and related cognitive impairment found in schizophrenia. Exposure to neurotropic pathogens can foster an autoimmune-prone environment and drive systemic inflammation leading to endothelial barrier defects. In mouse model cohorts, we demonstrate that infection with the protozoan parasite, Toxoplasma gondii, caused sustained elevations of IgG class antibodies to the NMDAR in conjunction with compromised blood-gut and blood-brain barriers. In human cohorts, NMDAR IgG and markers of barrier permeability were significantly associated with T. gondii exposure in schizophrenia compared with controls and independently of antipsychotic medication. Combined T. gondii and NMDAR antibody seropositivity in schizophrenia resulted in higher degrees of cognitive impairment as measured by tests of delayed memory. These data underscore the necessity of disentangling the heterogeneous pathophysiology of schizophrenia so that relevant subsets eligible for NMDAR-related treatment can be identified. Our data aid to reconcile conflicting reports regarding a role of pathological NMDAR autoantibodies in this disorder.

Tagged: bipolar disorder, celiac-disease, glutamate-receptor, human-behavior, immune activation, increased prevalence, latent toxoplasmosis, lupus autoantibodies, S100B protein, Toxoplasma gondii

Behavior Mental health

Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis

January 4, 2016
Jiang, H. Y., Xu, L. L., Shao, L., Xia, R. M., Yu, Z. H., Ling, Z. X., Yang, F., Deng, M., Ruan, B.
Brain Behavior and Immunity 2016; 58: 165-172

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Conflicting evidence exists with regard to the relationship between maternal infection during pregnancy and the risk of autism spectrum disorder (ASD) in offspring. The aim of this meta-analysis was to systematically assess this relationship. To identify relevant studies, we conducted systematic searches in PubMed and Embase of scientific articles published through March 2016. Random-effects models were adopted to estimate overall relative risk. A total of 15 studies (2 cohort and 13 case-control studies) involving more than 40,000 ASD cases were included in our meta-analysis. Our results showed that maternal infection during pregnancy was associated with an increased risk of ASD in offspring (OR = 1.13, 95% confidence interval (CI): 1.03-1.23), particularly among those requiring hospitalization (OR = 1.30, 95% CI: 1.14-1.50). Subgroup analyses suggested that risk may be modulated by the type of infectious agent, time of infectious exposure, and site of infection. These findings indicate that maternal infection during pregnancy increases the risk of ASD in offspring. Possible mechanisms may include direct effects of pathogens and, more indirectly, the effects of inflammatory responses on the developing brain. (C) 2016 Elsevier Inc. All rights reserved.

Tagged: autism, brain-development, childhood, children, cytokines, Epidemiology, exposure, hospitalization, immune activation, infectious, prenatal, prenatal infection, prevalence, viral-infection

Mental health

Association between prenatal exposure to maternal infection and offspring mood disorders: A review of the literature

May 25, 2015
Simanek, A. M., Meier, H. C. S.
Current Problems in Pediatric and Adolescent Health Care 2015; 45: 325-364

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The purpose of this article is to provide a systematic review of studies that have examined the association between prenatal exposure to maternal infection and development of mood disorders across the life course. Drawing from both human- and animal-based studies, we give an overview of hypothesized biological mechanisms by which exposure to maternal infection during critical periods of gestation may contribute to fetal programming of mood disorders in offspring. We discuss studies examining the association between prenatal exposure to maternal infection with pathogens including influenza as well as other respiratory viruses, herpesviruses, hepatitis viruses, and Toxoplasma gondii and mood disorders in human populations. Moreover, we outline strengths and limitations of the current body of evidence and make recommendations for future research. We also discuss findings in the context of well-documented gender and socioeconomic disparities in the prevalence and severity of mood disorders, particularly major depression, and the role that early exposure to infection may play in explaining the perpetuation of such disparities across generations. Overall, this review of the current knowledge on this topic has important implications for determining future research directions, designing interventions as well as prenatal care guidelines targeted at prevention or treatment of infection during pregnancy, and clinical practice for the identification of individuals that may be at increased risk for mood disorders beginning early in life. Importantly, such efforts may not only lower the overall burden of mood disorders but also serve to address social disparities in these adverse mental health conditions in the U.S.

Tagged: bipolar disorder, comorbidity survey replication, depression-related behaviors, gray-matter volume, herpes-simplex-virus, immune activation, major affective-disorder, nervous system, toxoplasma gondii infection, united-states

Mental health Reproduction Reviews

Inflammatory molecular signature associated with infectious agents in psychosis

October 9, 2014
Hayes, L. N., Severance, E. G., Leek, J. T., Gressitt, K. L., Rohleder, C., Coughlin, J. M., Leweke, F. M., Yolken, R. H., Sawa, A.
Schizophrenia Bulletin 2014; 40: 963-972

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Schizophrenia (SZ) is a devastating mental condition with onset in young adulthood. The identification of molecular biomarkers that reflect illness pathology is crucial. Recent evidence suggested immune and inflammatory cascades in conjunction with infection may play a role in the pathology. To address this question, we investigated molecular changes in cerebrospinal fluid (CSF) from antipsychoticnaive patients with SZ and at risk mental status for psychosis (ARMS), in comparison with healthy controls (HCs). We measured 90 analytes using a broad multiplex platform focusing on immune and inflammatory cascades then selected 35 with our quality reporting criteria for further analysis. We also examined Toxoplasma gondii (TG) and herpes simplex virus 1 antibody levels in CSF. We report that expression of 15 molecules was significantly altered in the patient groups (SZ and ARMS) compared with HCs. The majority of these molecular changes (alpha-2-macroglobulin [alpha 2M], fibrinogen, interleukin-6 receptor [IL-6R], stem cell factor [SCF], transforming growth factor alpha [TGF alpha], tumor necrosis factor receptor 2 [TNFR2], IL-8, monocyte chemotactic protein 2 [MCP-2/CCL8], testosterone [for males], angiotensin converting enzyme [ACE], and epidermal growth factor receptor) were consistent between SZ and ARMS patients, suggesting these may represent trait changes associated with psychotic conditions in general. Interestingly, many of these analytes (alpha 2M, fibrinogen, IL-6R, SCF, TGF alpha, TNFR2, IL-8, MCP-2/CCL8, and testosterone [for males]) were exacerbated in subjects with ARMS compared with subjects with SZ. Although further studies are needed, we optimistically propose that these molecules may be good candidates for predictive markers for psychosis from an early stage. Lastly, reduction of IL-6R, TGF alpha, and ACE was correlated with positivity of TG antibody in the CSF, suggesting possible involvement of TG infection in the pathology.

Tagged: antibodies, at risk mental status, biomarker, cerebrospinal fluid, exposure, immune activation, inflammation, metaanalysis, pathways, prenatal infection, recent-onset schizophrenia, risk factors, Schizophrenia, simplex-virus 1, Toxoplasma gondii

Mental health

Increased body mass index in Toxoplasma gondii positive patients with schizophrenia

October 12, 2012
Mazaheri, S., Okusaga, O., Reeves, G., Giegling, I., Hartmann, A. M., Konte, B., Friedl, M., Rujescu, D., Postolache, T. T.
Biological Psychiatry 2012; 71: 280S-280S

Tagged: bmi, immune activation, Schizophrenia, Toxoplasma gondii

Mental health Morphology

Toxoplasma gondii & Human Phenotype

Compendium of Known Effects and Ongoing Research

immune activation

Epidemiologic studies of exposure to prenatal infection and risk of schizophrenia and autism

Toxoplasma gondii: Biological parameters of the connection to schizophrenia

Pathogen-mediated NMDA receptor autoimmunity and cellular barrier dysfunction in schizophrenia

Maternal infection during pregnancy and risk of autism spectrum disorders: A systematic review and meta-analysis

Inflammatory molecular signature associated with infectious agents in psychosis

Increased body mass index in Toxoplasma gondii positive patients with schizophrenia