INTEGRATIVE NEUROIMMUNOLOGY OF THE DIGESTIVE-TRACT

The epithelium of the gastrointestinal tract is continuously exposed t o the external environment containing food antigens, microbes and othe r pathogens. Immunologic and nonimmunologic mechanisms contribute to t he neutralization and elimination of these foreign antigens. The immun e system of the intestine is the most extensive in the organism and in volves diffuse populations of immune cells, lymphoid aggregates and in traepithelial lymphocytes. On the other hand, the functions of the dig estive tract contibute to the overall host defense (mucus secretion, g astric acid secretion, water and electrolyte secretion and peristaltis m). These functions are regulated by intrinsic and extrinsic nervous s ystems. It is currently recognized that the physiological and patholog ical responses of the intestine require an integrate neuroimmune netwo rk. Such neuroimmune regulation is based on anatomical and biochemical supports. Indeed, there are membrane-to-membrane contacts between axo nal varicosities and the immune cells. Specific receptors for neurotra nsmitters such as substance P, vasoactive intestinal polypeptide and s omatostatin have been identified in many immune cells. Nerve profile c hange has been described under pathological conditions such as parasit ic infections and acute phase of inflammation. In addition to supporti ng the growth and survival of several populations of nerves the classi cal nerve growth factor (NGF) has been shown to affect an immune cell population by inducing mast cell hyperplasia. Furthermore the NGF can induce mast cell degranulation, acting directly on mast cell membrane NGF receptors or indirectly by NGF-mediated release of substance P by peripheral extrinsic or intrinsic nerves. Moreover, non-immune cells s uch as epithelial and smooth muscle cells can produce immunologic mess engers under pathological conditions such as infectious diseases or in flammation. Besides the local regulation of gut functions, neuroimmune control can be exerted at extra-intestinal sites. During physiologica l and pathological conditions, gastrointestinal secretions and motor e vents are strongly regulated by the central nervous system. Moreover, infectious agents can induce cytokine and particularly interieukin-1 r elease by the brain astrocytes and microglial cells which have been sh own to play a pivotal role in fever induction and modifications of the gastrointestinal functions. Visceral afferent fibers play a pivotal r ole in 'cross-communication' between central sites and immune response . Recent studies evoke, more specifically, the role of vagus as a key modulatory participant in the close relationship between the extrainte stinal nerves and the immune system. Future work in this field will cl arify the role of the different participants in the intimate communica tion between the gastrointestinal tract, immune system and central ner vous system.