PROJECT 2: Immunological Susceptibility in AutismEPA Grant Number: R833292C002
Subproject: this is subproject number 002 , established and managed by the Center Director under grant R833292
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: UC Davis Center for Children’s Environmental Health
Center Director: Pessah, Isaac N.
Title: PROJECT 2: Immunological Susceptibility in Autism
Investigators: Van de Water, Judith
Institution: University of California - Davis
EPA Project Officer: Louie, Nica
Project Period: November 1, 2006 through October 31, 2011 (Extended to October 31, 2013)
RFA: Centers for Children’s Environmental Health and Disease Prevention Research (2005) RFA Text | Recipients Lists
Research Category: Health , Children's Health , Health Effects
Project 2 of the UC Davis Center for Children’s Environmental Health will address the cellular basis and possible mechanisms contributing to alteration aspects of immune function associated with autism.
The overall hypothesis of Project 2 is that patients with autism have a fundamental defect at the cellular level that ultimately leads to abnormalities in immune function and heightened susceptibility to environmental triggers. The specific objectives of Project 2 are to (1) examine longitudinally the serologic profile of children with ASD to ascertain whether the various immune changes noted in our first studies are maintained and/or deteriorating further; (2) determine which immune cell population(s) plays a critical role in the immune dysfunction seen in patients with autism; and (3) fully characterize the autoantibody response in a subpopulation of children with ASD and some mothers of children with ASD.
First, longitudinal serologic analyses will examine plasma from patients with autism and our control populations for changes in IgG, IgM, IgA and IgE, basal cytokine profile; and leptin levels. This will allow us to verify the differences noted at the earlier time point as well as determine the profile of the developing immune system in the disease population. Second, we will analyze the patterns of peripheral blood cell surface marker expression following stimulation/activation. By studying these markers, the level and extent of activation following stimulation can be determined. Cell surface marker expression and cytokine production in stimulated and unstimulated cells will be studied following culture with recall vaccine antigens and mitogens. In addition, culture supernatants will be analyzed by Luminex multiplex analysis for evidence of differential cytokine production. The cellular source of any differentially expressed cytokines will be confirmed by intracellular cytokine staining. These analyses will be performed by multi-color flow cytometry. Third, we will investigate if there is a defect in B cell function in autism. B cells from patients with autism and controls will be analyzed following incubation with Fab anti-IgM, with and without CD40L followed by microarray analysis. Fourth, the differential functional response of peripheral blood cells from autistic children in the presence of low levels of organic mercury, PBDE, or PCB challenge will be measured. PBMC will be analyzed for proliferative responses, cytokine production, and transcriptional signatures in stimulated cultures with and without exposure to xenobiotics of concern to immune health and known to influence aspects of development. Fifth, we will identify the brain proteins that are targets of autoanti-bodies we have identified in a sub-population of children with autism.
We expect to identify how the immune system from autistic children differs from that of the general population. Importantly these studies will elucidate how the immunological differences seen in autism influence the sensitivity and pattern of responses to environmental chemicals. The identity of the antigens recognized by autoantibody may be crucial to understanding both the etiology and the pathology of autism.
Supplemental Keywords:autism, genes, environment, mercury, PCBs, PBDEs, immune, autoimmune, neurodevelopment, developmental neurotoxicity, persistent organic pollutants, CHARGE, MARBLES,, Health, Scientific Discipline, Genetics, Health Risk Assessment, Epidemiology, Risk Assessments, Biochemistry, developmental neurotoxicology, children's health, ecotoxicogenomics, developmental effects, genetic analysis, susceptibility
Progress and Final Reports:
Main Center Abstract and Reports:R833292 UC Davis Center for Children’s Environmental Health
Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R833292C001 PROJECT 1: Environmental Epidemiology of Autism
R833292C002 PROJECT 2: Immunological Susceptibility in Autism
R833292C003 PROJECT 3: Models of Neurosusceptibility