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.

Sympathetic noradrenergic nerve fibers, stained with antiserum for tyrosine hydroxylase (TH), richly innervate the splenic white pulp. These fibers distribute with the vascular and trabecular systems, and associate mainly with the central artery and its branches, the periarteriolar lymphatic sheath (PALS), the marginal sinus, and the parafollicular zone, with occasional delicate fibers also present in the follicles. Simultaneous staining of TH-positive nerve fibers and markers for specific lymphoid cells has shown several regions of contact between nerves and lymphocytes or macrophages. The TH-positive nerve fibers in the plexuses around the central arterial system and in the PALS are present among T lymphocytes (OX-19-positive cells) including both T helper and T suppressor cells, and interdigitating cells. At the marginal sinus, TH-positive fibers run adjacent to macrophages (ED3-positive cells), B lymphocytes (IgM-positive), and intensely fluorescent IgM-positive cells. Along the parafollicular zone, TH-positive nerve fibers run adjacent to T lymphocytes, peripheral follicular B lymphocytes, and intensely fluorescent IgM-positive cells. Within some follicles, delicate fibers end adjacent to both T and B lymphocytes. These relationships suggest a direct interaction between norepinephrine release from the TH-positive nerve terminals and the lymphocytes and macrophages closely associated with them, and focuses attention on the potential neural modulation of related functions such as T and B lymphocyte entry into the spleen and antigen capture (marginal zone), antigen presentation and T cell activation (PALS), B cell activation (parafollicular zone and marginal zone), and lymphocyte egress (outer marginal zone).

Background. We have shown previously that norepinephrine (NE) uptake activity is reduced in the failing right ventricle of animals with right heart failure (RHF) produced by tricuspid avulsion and progressive pulmonary constriction. However, it is unknown whether this defect in neuronal NE uptake is related to reduction of noradrenergic nerve terminals or whether these changes also occur in animals with left heart failure (LHIF). It is also unknown whether increased NE release in heart failure contributes to the noradrenergic nerve abnormalities.Methods and Results. We measured myocardial NE content, NE uptake function, and noradrenergic nerve profiles in dogs with either RHF or LHF induced by rapid ventricular pacing. NE uptake activity was

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