STRESS & IMMUNITY--BEHAVIORAL & PHYSIOLOGICAL MECHANISMS

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DESCRIPTION (Adapted from applicant's abstract): Despite the growing body of research concerning interactions between stress and immunity, there is relatively little understanding of the neural, endocrine, and immunologic mechanisms by which an environmental stressor ultimately alters some measure of immune function. Stressors do not have a pathway directly to immune cells and organs. Rather, they alter neural activity, which in turn regulates neuronendocrine and autonomic processes, which in turn impact on organs andcells of the immune system. During the previous grant period the research has indicated that a variety of stressors interfere with the generation of antibody to an antigen (Ag). The research further suggested a hypothesis to explain these findings. The hypothesis is that stressors can induce IL-1b in brain which both downregulates Type I glucocorticoid receptor function in the hippocampus and in addition leads to an outflow of products from brain that activate a classic acute phase response in the periphery. Thus macrophages became activated, the liver shifts towards the production of acute phase proteins (positive reactants) and away from albumin and carrier proteins (negative reactants), etc. The downregulation of Type I glucocorticoid receptors in the hippocampus elevates basal levels of plasma corticosteroids. This effect, in combination with the reduced corticosteroid binding globulin (a carrier protin) production by the liver, leads to large increases in free corticosterone for a 2-3 day period following IS, which in turn produces a reduction in the Th1-like "subpopulation" of T-helper cell during the time period in which Ag-specific T abd B cells develop (4 days after Ag and IS). The activated macrophage also is seen as suppressing T cell function. Thus developing T and B-cells receive insufficient Th cytokines to develop adequately, and this is hypothesized to be the ultimate cause of the eventual reduction in Ig to Ag. The proposed research is designed to test each step of this hypothesis.