Inflammatory or allergic conditions, as well as situations where healing and repair processes occur, are characterized by the presence of increased numbers of mast cells. Previous work on the effect of neuropeptides on mast cell mediator release showed that only substance P caused such release from intestinal mucosal mast cells [Shanahan, F., Denburg, J. A., Fox, J., Bienenstock, J. & Befus, A. D. (1985) J. Immunol. 135, 1331Immunol. 135, -1337. Accordingly, we investigated the microanatomical relationship between mast cells and enteric nerves in normal rat intestine and parasite-infected rat intestine, in which mucosal mast cell hyperplasia occurs. Combined immunohistochemistry for neuron-specific enolase and staining with alcian blue at pH 0.5 was employed on paraffinembedded sections of normal and Nippostrongylus brasiliensisinfected rat jejunum. Sixty-seven percent of intestinal mucosal mast cells were touching subepithelial nerves, and an additional 20% were within 2 ,im of nerves. Assessment of the proportion of the lamina propria occupied by mast cells (12.5%), the average mast cell area (121 ± 28 MAm2), and the density of enteric nerves (one per 788 ± 151 ,um2) suggested that the association was 5 times greater than would be expected by chance alone (P < 0.0001). In consecutive sections, the nerves in contact with mast cells were also shown to contain substance P and/or calcitonin-gene-related peptide. Electron microscopy confirmed this association: 8% of the mast cells in infected rats exhibited membrane-membrane contact with unmyelinated axons containing 70-to 170-nm dense-core vesicles, and an additional 31% were situated less than 250 nm from nerves. Other mast cells appeared to embrace nerve bundles through the projection of lamellopodia. These data provide systematic quantitative evidence that a structural foundation for communication between the immune and nervous systems exists in the rat gastrointestinal tract.The histochemical and functional heterogeneity of mast cells is well described and accepted, especially in the rat (1, 2). Major functional differences have been shown between mast cells obtained from the peritoneal cavity (PMCs) and intestinal mucosal mast cells (IMMCs) isolated from the normal lamina propria as well as from rats infected with the nematode Nippostrongylus brasiliensis, which promotes intestinal mast cell hyperplasia (3, 4). Many secretagogues that affect PMCs have no effect on IMMCs, and similar differential effects are seen with many anti-allergic compounds (5). Indeed, previous reports (J.B. and coworkers, refs. 6 and 7) showed that whereas both endorphins and neuropeptides caused degranulation of PMCs in vitro, only substance P promoted histamine release from IMMCs (6, 7).These in vitro observations are in keeping with in vivo experiments that strongly suggest that mast cells and nerves may communicate directly, presumably through soluble mediators. Kiernan (8) and Lembeck and Holzer (9) suggested that mast cells may be involved in the axon reflex responsible...

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Immunocytochemistry was used to demonstrate tyrosine hydroxylase (TH)-positive profiles in the spleen of the adult Fischer 344 rat. At the light microscopic level, numerous varicose nerve profiles were seen in the white pulp, particularly surrounding the central arteries and their arteriole branches. At the electron microscopic level, varicosities were seen in close proximity to smooth muscle cells of the arteries, and directly abutting lymphocytes (presumable T-lymphocytes) of the nearby periarteriolar lymphatic sheath. There were no intervening cell processes between the TH-positive terminals and the lymphocyte. The opposing membranes were smooth and evenly spaced approximately 6 nm apart. Additional TH-positive nerve profiles were seen in the inner marginal zone and within trabeculae. The correlation between this immunocytochemical staining and previously demonstrated histofluorescence for norepinephrine leads to the conclusion that lymphocytes in the splenic white pulp have direct associations with noradrenergic fibers of the sympathetic nervous system. This association provides a route by which the autonomic nervous system could directly influence specific immune system effector cells.