Neural and Behavioral Responses to Systemic Immunologic Stimuli: A Consideration of Bacterial T Cell Superantigens

Alexander   W.   Kusnecov; Yael      Goldfarb

Abstract

Immune responses represent a source of sytemic stress which impacts the brain and modifies various neuroendocrine and behavioral functions. Therefore, the immune system has been conceived of as a potential contributor to stress-related behavioral abnormalities, such as depression. Much of this knowledge has been gained through research focused largely on the administration of cytokines and/or bacterial endotoxin (eg., LPS), which targets innate immune cells, such as macrophages. However, fewer studies have addressed the effects of T cell activation on central nervous sytem (CNS) function. The discovery and characterization of bacterial superantigens (SAgs) has introduced an important opportunity for studying how T cell activation influences CNS function. Superantigens target unique variable regions of the beta chain of the mouse and human T cell receptor. This is restricted by the class II molecule of the major histocompatibility complex (MHC), and results in the production of a cytokine cascade that includes interleukin-2 (IL-2), interferon-gamma (IFNγ), tumor necrosis factor (TNF) and many other cytokines, including IL-6. The best studied SAgs are the staphylococcal enterotoxins, of which staphylococcal enteroxins A and B (SEA and SEB), have been shown to produce significant changes in behavior and activation of the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, a T cell requirement was necessary to produce these changes. Furthermore, the anorexic or hypophagic effects of SAg challenge in mice appears to be related to anxiety-like processes, since challenge with both SEA or SEB reduces consumption of mainly novel food or food presented in a novel context. In the present paper, these studies are reviewed and related to known alterations in both anxiogenic and anxiolytic neuropeptides. It is suggested that immunologicallyinduced changes in the brain activate both categories of neuropeptides, thereby sustaining an adaptive state of arousal that promotes appropriate behavioral adjustments during infectious illness.

Keywords: autonomic nervous system (ANS) pathways, immune system, sensations, cytokines, viral inoculation, immunization, keyhole limpet hemocyanin, superantigens