ABSTRACT
The murine maternal immune activation (MIA) offspring model enables longitudinal studies to explore aberrant social behaviors similar to those observed in humans. High levels of cytokines, chemokines and cell adhesion molecules (CAM) have been found in the plasma and/or brains of psychiatric patients. We hypothesized that upregulation of the systemic or brain immune response has an augmenting effect by potentially increasing the interplay between the neuronal and immune systems during the growth of the MIA offspring. In this study, a C57BL/6j MIA female offspring model exhibiting social deficits was established. The expression of fetal interferon (IFN)-stimulated (gbp3, irgm1, ifi44), adolescent immunodevelopmental transcription factor (eg, r2, tfap2b), hormone (pomc, hcrt), adult selectin (sell, selp) and neuroligin (nlgn2) genes was altered. Systemic upregulation of endogenous IL-10 occurred at the adult stage, while both IL-1ß and IL-6 were increased and persisted in the sera throughout the growth of the MIA offspring. The cerebral IL-6 levels were endogenously upregulated, but both MCP-1 (macrophage inflammatory protein-1) and L-selectin levels were downregulated at the adolescent and/or adult stages. However, the MIA offspring were susceptible to lipopolysaccharide (LPS) stimulation. After reinjecting the MIA offspring with LPS in adulthood, a variety of sera and cerebral cytokines, chemokines and CAMs were increased. Particularly, both MCP-1 and L-selectin showed relatively high expression in the brain compared with the expression levels in phosphate-buffered saline (PBS)-treated offspring injected with LPS. Potentially, MCP-1 was attracted to the L-selectin-mediated immune cells due to augmentation of the immune response following stimulation in MIA female offspring.
Subject(s)
Brain/immunology , Chemokines/immunology , Cytokines/immunology , Selectins/immunology , Social Behavior Disorders/genetics , Social Behavior Disorders/immunology , Age Factors , Animals , Behavior, Animal/physiology , Brain/metabolism , Chemokines/biosynthesis , Chemokines/genetics , Cytokines/biosynthesis , Cytokines/genetics , Disease Models, Animal , Female , Gene Expression , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred C57BL , Pregnancy , Prenatal Exposure Delayed Effects , Selectins/biosynthesis , Selectins/genetics , Social Behavior , TranscriptomeABSTRACT
A potential role for T(H)17 cells has been suggested in a number of conditions including neurodevelopmental disorders such as autism spectrum disorders (ASD). In the current study, we investigated cellular release of IL-17 and IL-23 following an in-vitro immunological challenge of peripheral blood mononuclear cells (PBMC) from children with ASD compared to age-matched typically developing controls. Following stimulation, the concentration of IL-23, but not IL-17, was significantly reduced (p=0.021) in ASD compared to controls. Decreased cellular IL-23 production in ASD warrants further research to determine its role on the generation and survival of T(H)17 cells, a cell subset important in neuroinflammatory conditions that may include ASD.
Subject(s)
Autistic Disorder/immunology , Autistic Disorder/metabolism , Interleukin-17/metabolism , Interleukin-23/metabolism , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Autistic Disorder/physiopathology , Biomarkers/metabolism , Cells, Cultured , Child, Preschool , Down-Regulation/drug effects , Down-Regulation/immunology , Encephalitis/complications , Encephalitis/immunology , Encephalitis/physiopathology , Female , Humans , Male , Neuropsychological Tests , Phytohemagglutinins/immunology , Phytohemagglutinins/pharmacology , Social Behavior , Social Behavior Disorders/diagnosis , Social Behavior Disorders/immunology , Surveys and Questionnaires , T-Lymphocytes, Helper-Inducer/drug effects , T-Lymphocytes, Helper-Inducer/immunologyABSTRACT
Female antisocial behavior in adolescence and late childhood has been associated with low basal cortisol levels. Because low cortisol has also been correlated with T helper cell Type 1 (Th1) predominance and suppression of T helper cell Type 2 (Th2), we investigated whether adolescent antisocial girls demonstrated this immunologic profile. Using plasma levels of IgG3 and IgG4 as markers for Th1 and Th2 activity, we studied IgG 3:4 ratios in 16-year-old girls with conduct disorder (CD) (n=42) or no psychiatric disorder (normal controls (NC)) (n=35). The mean IgG 3:4 ratio was higher in the CD group; this relationship remained significant after controlling for the effects of other variables. These data indicate that immunologic abnormalities are present in adolescent antisocial girls. Future studies should measure cytokine levels and investigate the clinical implications of these findings.
