HIV infection not only causes abnormalities of immune cells, but also of neurons of the central nervous system (CNS) and the enteric nervous system (ENS). Psychological factors (via the CNS) can influence the course and symptoms of immune diseases. We have shown that interactions of nerves with certain immune cells affect physiology. Therefore, immunophysiology is subject to modification by Pavlovian conditioning. Our long-term obiectives are to characterize changes in mucosal immunophysiology affected by conditioning in normal and in infectious/inflammatory states, Mucosal mast cells (MHC) are immunocompetent cells present in mucosal tissues which require T lymphocyte growth factors. MMC are in close contact with nerves and can be stimulated by neurotransmitters such as substance P. Activated MMC release mediators such as histamine which causes increased sensitivity of nerves and spontaneous discharge of action potentials. Both MMC mediators and neurotransmitters alter epithelial function in the gut and lung. Preliminary studies have shown that following conditioning, sensitized rats demonstrated activation of MMC and physiological changes in response to an audiovisual (AV) cue previously associated with antigen injection.
The specific aims of this proposal are to examine the mechanisms by which Pavlovian conditioning affects mast cells and conseguent physiological changes. Our hypothesis is that nerve/mast cell/epithelial cell interactions mediate changes in mucosal function. We will examine conditional activation of MMC and changes in epithelial function (ion transport) in the small intestine and trachea. Rats will be sensitized to an antigen (egg albumin, EA) and trained to associate injection of EA with an AV cue. Rats will then be challenged with EA plus AV or AV alone. Controls will be rats trained with EA injection 24 h after AV, then challenged with AV. Blood and tissue segments will be obtained 60 min after in vivo challenge. MMC activation will be indicated by the presence of a MMC specific protease in serum. Ion transport will be assessed in tissues by measurement of flux of radioactive tracers (22Na, 36C1) and short-circuit current. Surgical (nerve section or crush) or pharmacological manipulations will be employed to investigate the pathways and biochemical mediators involved. Finally, we will attempt to attenuate responses using extinction techniques. Future experiments will examine responses in models of infection/inflammation. In AIDS, abnormalities of nerves and/or mast cells may cause gastrointestinal symptoms which may be modified by psychological factore.
