Date of Award

1-1-2011

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Environmental Health Sciences

Content Description

1 online resource (viii, 154 pages) : illustrations (some color)

Dissertation/Thesis Chair

David A Lawrence

Committee Members

Richard F Seegal, Jeffrey S Kennedy, David C Spink, William T Lee

Keywords

anti-brain antibody, autism spectrum disorders, autoimmunity, mercury, neuroinflammation, social behavior, Autism, Immunodeficiency, Gene expression

Subject Categories

Immunology of Infectious Disease | Toxicology

Abstract

Autism is a neurodevelopmental disorder with unknown etiology, affecting about 1 in 110 children in the US. Here, we show that developmental exposure to anti-brain Abs impaired mouse social behaviors. BTBR mice, a mouse strain with high serum anti-brain Abs and behaviors that resemble autism, have more activated splenic B cells, CD4+ T cells (Th1, Th2 and Th17 subsets), and CD4+ T cells with expression of Vb6 chains than B6 mice (the control H-2 identical strain). Elevated numbers of activated (CD25+) CD4+Vb6+ cells also were detected in thymic preparations. All of the immunological and behavioral parameters of BTBR mice were compared with those of B6 mice, which have relatively normal behaviors. The high level of IgG production by B cells was T cell-dependent. B6 offspring developed in and nursed by BTBR dams had impaired social behavior, while BTBR offspring from B6 dams had social behavior closer to that of the normal B6 strain. To assess the influence of the environmental toxicant mercury on the immunity and behavior of mice, maternal drinking water containing subclinical doses of 1.25 uM methylmercury (MeHg) or 50 uM HgCl2 were used to evaluate developmental induction of immune responses to brain Ags in A.SW mice. HgCl2, but not MeHg induced autoAbs production and elevated brain IgG deposition; the HgCl2-exposed offspring had an increased number of CD4+CD25+Vb8.3+ splenic T cells, and their anti-brain Abs were predominantly against nuclear proteins (30 and 34 kD). Inflammation responses were observed only in the cerebellum of female A.SW mice, and their responses were associated with increased levels of exploratory behavior. The developmental exposure to MeHg also induced inflammation in the cerebellum and increased exploratory behavior of the female A.SW mice, but the change did not correlate with increased IgG in the brain. An additional evaluation of HgCl2 was undertaken with more strains to assess whether HgCl2 exposure during fetal development can induce social behavioral alterations dependent on strain and sex. Developmental HgCl2-treatment increased the serum IgG levels of all of the pnd21 offspring (SFvF1, FvSF1 and B6BF1) as well as SJL/J, but not FVB or B6, dams. Serum anti-brain Abs were not increased either in HgCl2-treated pnd21 SFvF1 offspring or their dams; however, both the control and HgCl2-exposed groups had higher levels of IgG anti-brain Abs than the other strains. Serum anti-brain Abs were increased in the HgCl2-exposed pnd21 FvSF1 offspring and their dams, while there were negligible levels of serum IgG anti-brain Abs in the pnd21 B6BF1 offspring and their dams. HgCl2 elevated IgG deposition in all assayed brain regions of all of the pnd21, but not pnd70 offspring, and SFvF1 mice had the greatest amount of brain-deposited IgG. Multiple Cytokines were elevated in many brain regions of Hg-treated pnd21 SFvF1 offspring. HgCl2-treatment significantly impaired social behavior only of SFvF1 offspring, and only HgCl2-treated female SFvF1 offspring displayed autistic-like social behavior. A subtle but non-significant sociability deficit was observed with female FvSF1 offspring, and enhanced sociability was apparent with female B6BF1 offspring. The overall conclusions of the research are that genetics and environment combined to influence immunity and behavior and that autoAbs to brain Ags (spontaneously produced or Hg-induced), activated CD4+ T cells, and the related neuroinflammation are implicated in the pathogenic processes associated with impaired social behavior.

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