Interactions of mast cells with the nervous system —Recent advances

This article reviews recent advances in the understanding of mast cell-nervous system interactions. It is drawn largely from work published within the last ten years, and discusses the anatomical and biochemical evidence of a functional connection between mast cells and the nervous system, and the implications that such a relationship may have for normal and abnormal physiological functioning. Mast cells are found at varying levels of association with the nervous system; in CNS parenchyma (mainly thalamus), in connective tissue coverings (e.g. meninges, endonerium), and in close apposition to peripheral nerve endings in a variety of tissues. There is, as yet, no clearly defined role for mast cells in nervous system function, or vice-versa, and it seems most likely that their interactions fulfil mutually modulatory roles. By extension, pathological situations where one of the partners in this relationship is overly stimulated may lead to a dysregulation of the other, and contribute to disease symptomatology.Abbreviations ACh acetylcholine - BMMC bone marrow-derived mast cells - CGRP calcitonin gene-related peptide - EAE experimental allergic encephalomyelitis - EAN experimental allergic neuritis - 5-HT serotonin - IgE immunoglobulin E - IL-3 interleukin-3 - MS multiple sclerosis - NA noradrenaline - NF neurofibromatosis - NGF nerve growth factor - VIP Vasoactive intestinal polypeptide Special issue dedicated to Dr. Alan N. Davison.     

Role of nonsynaptic communication in regulating the immune response

The discovery of nonsynaptic communication in the 1960s and 1970s was an important milestone in investigating the function of the nervous system, and it revolutionized our view about information transmission between neurons. In addition, nonsynaptic communication has a practical importance not only within the nervous system, but in the communication between the peripheral nervous system and other organ systems. Nonsynaptic communication takes place in different immune organs, which are innervated by sympathetic nerve terminals. In addition, the function of microglia, one of the immunocompetent cell types of the brain, can also be affected by neurotransmitters released from axon varicosities. The various functions of immune cells are modulated by released neurotransmitters without any direct synaptic contact between nerve endings and targeted immune cells requiring only functional neurotransmitter receptors on immune cells. Here, we briefly overview the role of the various receptor subtypes mediating nonsynaptic modulation of the function of immunocompetent cells both in the periphery and in the central nervous system.     

Immunocytochemical demonstration of neuropeptides in the fish-gill parasite, Diclidophora merlangi (Monogenoidea)

Using the indirect immunofluorescence technique, immunoreactivity (IR) to three mammalian and one invertebrate regulatory peptide has been demonstrated in the nervous system of the monogenean gill parasite Diclidophora merlangi. IR to pancreatic polypeptide (PP), peptide tyrosine tyrosine (PYY) and FMRFamide was evident throughout central and peripheral nervous tissues, whereas vasoactive intestinal polypeptide (VIP)-IR was confined to a portion of the longitudinal ventral nerve cords. Staining patterns revealed the orthogonal arrangement of the nervous system consisting of paired cerebral ganglia, connecting post-pharyngeal commissure, three pairs of longitudinal nerve cords and associated neurones. PP-IR, PYY-IR and FMRFamide-IR were intense throughout the central nervous system of the worm. A small plexus of nerve fibres and somata in each peduncle was immunoreactive for FMRFamide and provided innervation to each of the eight posterior clamps. In the peripheral nervous system, PP-IR, PYY-IR and FMRFamide-IR occurred in an extensive nerve-net with fine, possibly sensory nerve endings in the tegument. PP-IR was also present in nerve fibres in the walls of the ootype, seminal vesicle and uterus. PYY- and FMRFamide-IRs, while evident in nerve fibres of the ootype wall, were also present in a distinct population of cells that encircles the ootype, and which are linked to it by fine cytoplasmic connectives. The majority of these somata were bipolar or multipolar. PYY-IR and FMRFamide-IR were also associated with nerve fibres and bipolar cells in the wall of the vitelline reservoir. Regulatory peptides would appear to play an integral role in neuronal functioning and egg development in D. merlangi.     

Action of Thymoxamine on Mydriasis induced by Levodopa and Dopamine

Eye-drops of levodopa and dopamine induce pupillary dilatation which is inhibited by thymoxamine, an alpha-adrenergic blocking drug. This indicates that the mydriatic action of levodopa and dopamine involves excitation of alpha-adrenergic receptors of the dilator pupillae muscle. Such a conclusion is in accord with the previously expressed suggestion that levodopa is rapidly converted to dopamine, which displaces noradrenaline from adrenergic nerve endings.The findings that dopamine exerts alpha-adrenergic effects at the periphery may be construed as evidence in support of the view that the hypotensive action of levodopa is mediated via the central nervous system.     

Ultrastructure of the nodes of Ranvier and their surrounding structures in the central nervous system

Summary The nodes of Ranvier and their surrounding structures have been studied by means of serial and single ultrathin sections of the frog's optic tract and diencephalon.The following aspects of the ultrastructure of the myelin sheath at the nodes are described: (a) the site and manner of termination of the compact myelin and glia-satellite cytoplasm; (b) the reflection of the glia-satellite cytoplasm at the node; (c) the formation of compact myelin during development; (d) the involvement of the glia-satellite cell in the metabolism and impulse conduction of the fiber.The nodes are surrounded by a considerable extension of the extracellular space — the perinodal extracellular space or perinodal matrix. The ground substance of the perinodal matrix consists of ill defined granules arranged in patches or in fibrillar or vacuolar manner. Microvilli-like protuberances of the glia and nervous processes emerge into the perinodal matrix. The shape and the volume of the perinodal extracellular space is determined using a reconstruction method from a series of sections through the node in diencephalon.In the diencephalon nerve endings show close contact with the node and its surroundings. These nerve endings contain synaptic vesicles, mitochondria and small opaque particles. Small opaque particles, up to the present not recognized as components of synapses, have been observed in a number of nerve endings in the diencephalon. The possibility is considered that such nervous configurations at the node could be involved in subliminal interactions between different neurons.Based on the ultrastructural data the concept of nodal apparatus is introduced as a working hypothesis. The nodal apparatus consists of the node, terminal compartments of the glia-satellite cell, the perinodal matrix, and the surrounding glia and nervous structures, which may be involved in the nodal activities. The structural pattern of such a nodal apparatus may vary in different parts of the central nervous system indicating the possibility of variation in the functioning of the corresponding nodes.This investigation was supported by a grant from the Medical Research Council, Canada (MA-1247).The author is very much indebted to Mrs. H. Rushforth for excellent technical assistance, to Mr. H. R. A. Meiborg, Groningen, for very skilful printing of the photographs and to Mr. Hoekstra, Groningen, who made the drawing of Fig. 8.     

Transcriptional profile of the human peripheral nervous system by serial analysis of gene expression

The peripheral nerve contains both nonmyelinating and myelinating Schwann cells. The interactions between axons, surrounding myelin, and Schwann cells are thought to be important for the correct functioning of the nervous system. To get insight into the genes involved in human myelination and maintenance of the myelin sheath and nerve, we performed a serial analysis of gene expression of human sciatic nerve and cultured Schwann cells. In the sciatic nerve library, we found high expression of genes encoding proteins related to lipid metabolism, the complement system, and the cell cycle, while cultured Schwann cells showed mainly high expression of genes encoding extracellular matrix proteins. The results of our study will assist in the identification of genes involved in maintenance of myelin and peripheral nerve and of genes involved in inherited peripheral neuropathies.     

Uteroglobin and other proteins in rabbit blastocyst fluid after development in vivo and in vitro

Summary The taste bud of the human fungiform papilla was examined by electron microscopy. Typical type I, type II, and type III cells were found along with contact sites with nerve endings. Vesicles in nerve fibers contacting type I and type II cells suggest that these cells may receive efferent impulses, whereas vesicles and granules in type III cells adjacent to (afferent) nerve fibers support the view that type III cells are sensory receptors. All of these features are virtually indistinguishable from those previously reported in fungiform taste buds of other mammals.Supported by fellowship from Campbell Institute for Food Research.     

The antidystrophic effect of the action of beta-adrenoblockaders in local damage to the nervous system]

It has been established that the lesion of the sciatic nerve, accompanied by a disturbance of normal neurotrophic provision of a kidney as a result of coming to the organ of the perverted nervous stimuli (by the neuro-conductive path through sympathetic nerves and by participation of the hypothalamus--hypophysis--peripheral glands system), leads to disturbance of functioning of mineral-corticoid receptors of kidneys. It has been also established that simultaneous pharmacological blockade of neuro-conductive and humoral pathways of transmission to the kidney of pathological stimuli from the central stump of the cut sciatic nerve prevents the development of trophic organ disturbances, tested by the state of the kidney mineral-corticoid receptor apparatus, while pharmacological stimulation of sympathetic nervous system leads to the greater disturbance of aldosterone reception by the cells of kidney channels. A valid conclusion can be made that propranolol is a substance, which may weaken possible non-adequate reactions of peripheral tissues to the action of physiologically active substances during the development of the consequences of the lesion of the nervous system and thus to prevent the development of neurogenic dystrophies.     

Role of the "little brain" in the gut in water and electrolyte homeostasis

The enteric nervous system plays a key role in maintenance of body fluid homeostasis by regulating the transport of ions by the intestinal epithelium. The epithelial cells normally absorb large volumes of fluid and ions daily, but tonically active submucosal neurons continuously suppress ion transport and limit the absorptive capacity of the intestine. Specialized nerve endings detect chemical, osmotic, or thermal alterations of the luminal contents or mechanical activity of the gut wall and encode this information as action potentials that propagate along nerve processes to the ganglia. Information transfer within the ganglia occurs at nicotinic cholinergic or other synapses. Ion transport is altered when neurotransmitters released from motor neurons interact with receptors on epithelial cells to initiate stimulus-response coupling. The signals that transduce changes in epithelial ion transport are largely unknown, except for acetylcholine, but may include vasoactive intestinal peptide or other peptides. These trigger changes in intracellular messengers that influence the state of ionic channels in the epithelial cells and thereby inhibit absorptive processes or stimulate secretory mechanisms. When conservation of salt and water is necessary, command signals from the central nervous system, and perhaps from the myenteric ganglia, will shut down the synaptic circuits in the submucosal ganglia and enhance the absorptive capacity of the bowel.     

THE ULTRASTRUCTURE AND DISPOSITION OF VESICULATED NERVE PROCESSES IN SMOOTH MUSCLE

The walls of the gastrointestinal tract and urinary bladder of rats were fixed in osmium tetroxide, embedded in methacrylate, and sectioned for electron microscopy. The examination of sections of smooth muscle tissue with the electron microscope reveals the presence of bundles of unmyelinated nerve fibers within the intercellular spaces. In addition, vesiculated nerve processes, bounded on their outer surfaces by delicate plasma membranes and typically containing varying quantities of synaptic vesicles and mitochondria, make intimate contact with the surface of smooth muscle cells. These nerve processes are similar in structure and disposition to nerve endings previously described in skeletal muscle, in the central nervous system, in peripheral ganglia, in receptors, and in glands. It is concluded that the relationships existing between vesiculated nerve processes and the surface of smooth muscle cells constitute neuromuscular junctions. Profiles of protrusions of smooth muscle cells are often seen protruding into the intercellular spaces. Here they occur singly or in groups, originating from one or more cells. Because of the plane of section the protrusions may sometimes appear as individual entities between the muscle cells. In such cases care must be exercised in their identification because they have characteristics similar to sectioned nerve processes which also occur in the intercellular spaces.     

Localization of neuropeptide Y in human sympathetic ganglia: Correlation with met-enkephalin, tyrosine hydroxylase and acetylcholinesterase

Summary The relationships of immunoreactive neuropeptide Y, enkephalin and tyrosine hydroxylase, on the one hand, and acetylcholinesterase histochemical activity, on the other, were studied in human lumbar sympathetic ganglia. Two thirds of the ganglion cells contained immunoreactive neuropeptide Y. Electron microscopically the immunoreaction was localized in the Golgi apparatus and in large dense-cored vesicles in the nerve endings. Most of the neuropeptide-containing neurons and nerve fibres were also reactive for tyrosine hydroxylase. Nerve fibres reactive for neuropeptide Y were found around ganglion cells regardless of their transmitter contents, whereas enkephalin-reactive nerve terminals surrounded only acetylcholinesterase-containing neurons. The results demonstrate that neuropeptide Y is colocalized with noradrenaline in most of the human sympathetic neurons and that the nerve fibres may innervate selectively the noradrenergic and cholinergic subpopulations of ganglion cells depending on the transmitters of the nerves.     

Development of the neural and tissue components of the excretory ducts of the liver, pancreas and Odd's sphincter in human embryogeny]

The development of pancreatic, hepatic, cystic, common bile ducts, the Oddi's sphincter and their nervous apparatus were studied during prenatal human ontogenesis of fetuses and newborns. The process of formation of the nervous apparatus corresponds to the development of tissue structures of the ducts and the sphincter. The distinctions in the organization of nervous elements which are noted in adult humans are laid in the process of embryogenesis. These distinctions are especially pronounced in the structure of nervous plexuses and receptory endings. The nervous apparatus of the Oddi's sphincter region has a complex arrangement. This is the site of concentration of nerve nodules and receptory endings as well as abundant nervous connections between plexuses of the pancreatic head, duodenum and orifice zones of the both ducts. The receptors in nerve nodules and pericellular apparatuses on the bodies of ganglionic neurons were revealed.     

Neurogenesis: is the adult stem cell young or old?

Stem cell biology is one of the most exciting, controversial, and debated fields in science today. It has been suggested that neuronal replacement therapy using stem cell transplants may be one possible answer to a host of neuropathological disorders including spinal cord injury, stroke, and neurodegenerative diseases. Important sources for stem cells include the developing embryo and adult central nervous system, but will these populations of cells exhibit similar behavior and responses to stimuli? This review will discuss some important similarities and differences between the embryonic and adult stem cell, as well as the basis for developing therapeutic approaches for stem cell replacement.     

Osteotropic effects by the neuropeptides calcitonin gene-related peptide, substance P and vasoactive intestinal peptide

Immunohistochemical phenotypic characterization of skeletal nerve fibers has demonstrated the expression of a restricted number of neuropeptides, including calcitonin gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP). According to the neuro-osteological hypothesis, such neuropeptides can be released and exert paracrine biological effects on bone cells present close to the nerve endings expressing these signaling molecules. The existence of such interplay is most convincingly shown by the hypothalamic control of bone formation, in the case of leptin stimulation of hypothalamic nuclei mediated by the sympathetic nervous system and inhibitory beta-adrenergic receptors on osteoblasts. In addition to these receptors, osteoblasts and osteoclasts express functional receptors for CGRP, SP and VIP, which can regulate both bone formation and bone resorption. The evidence for these observations is summarized in the present paper.     

Hypotension Caused by L-Dopa

In 20 patients with idiopathic Parkinsonism maximum tolerated doses of L-dopa were found to induce a mean reduction in blood pressure (erect systolic) of 19·3 mm.Hg, without any significant change in pulse rate. This hypotension may be due to dopamine, acting on adrenergic nerve endings or on the central nervous system itself.     

The infracerebral gland--a possible neuroendocrine complex in Nereis

The infracerebral gland of Nereis consists of an epithelium covering the ventral surface of the posterior region of the brain. The thickness of the epithelium varies greatly in different species, and it appears especially well developed in Nereis limnicola. Cells of the most numerous type are in direct contact with the base of the brain. Their apical surfaces bound a coelomic sinus, below which is a blood plexus. Other cells are fuchsinophilic and contain many inclusions resembling elementary neurosecretory granules. A third type is rare and resembles glial elements. A number of nerve tracts run from the neuropil to the base of the brain in the region of the gland. Where they impinge upon the capsule they form swellings containing elementary granules and small vesicles. Some axons do not end on the capsule but pass through the capsule and then ramify among the cells of the gland. The swollen endings of other fibers, probably nervous in character, are packed with mitochondria and are scattered over the inner surface of the capsule in the region of the gland. The features described are suggestive of a neuroendocrine complex, and the relation between the brain and the infracerebral gland is in need of experimental analysis in view of the important endocrine functions presently ascribed to the brain in nereids.     

Intraepidermal free nerve fiber endings in the hairless skin of the rat as revealed by the zinc iodide-osmium tetroxide technique

The nerve fiber distribution in the epidermis of the hairless rat skin was studied light microscopically by means of zinc iodide-osmium tetroxide staining. Two different morphological types of free nerve fiber endings could be detected: clusters of relatively thick nerve fibers stretched up through the spinous layer up to the granular layer sending off terminal branches. In addition, many solitary thin varicose nerve fibers were seen within the epidermis. The observed discrepancies in nerve fiber diameters appeared to be larger than those reported for human intraepidermal nerve fibers in recent immunohistochemical studies. Moreover, dendritic cells, most probably representing Langerhans cells, could be selectively stained. These cells appeared to be in a close location to thin varicose nerve fibers. Both types of demonstrated free nerve endings have to be functionally connected with different sensoric functions. Possibly, a subpopulation of the thin nerve fibers might possess primarily a nociceptive task, whereas the thick ones have most probably to be regarded as mechanoreceptive. The nerve fibers innervating dendritic cells appear to be identical to the peptidergic ones which may regulate the antigen-presenting capacity of these cells. Due to its selectivity for intraepidermal nerve fibers, the used method might supplement immunohistochemical procedures in a helpful manner.     

The distribution of carboxylic esterases in the area postrema of the guinea pig

Summary Detailed studies were made on the distribution of carboxylic esterases in the area postrema (AP) of the guinea pig. In this species the nerve cells of the AP show intense acetylcholinesterase activity which greatly enhances a morphological study of these elements. The two main types of nerve cells arebipolar cells andmultipolar cells. The bipolar cells often send their peripheral processes to the wall of a capillary, while the other processes go towards the nervous tissues outside of the organ. A similar behavior of the processes could be observed in the case of the multipolar cells. A special multipolar cell having bulb-like endings in the neuropilema of the organ has been discussed. On the basis of these findings it is conjectured that these neural elements, as well as the AChE positive nerve fibers located along the walls of the capillaries, function as parts of a chemoreceptor system, the existence of which has been postulated by former authors. The non-specific esterase activity of the organ is rather diffuse. B esterases have been described in the glial cells and in several nerve cells and in the pericytes and endothelial cells of the perivascular space. The localization of A and C esterases appeared diffuse, but only the AP showed intense C esterase activity in the caudal medullary area.     

Axon terminals with unusual vesicles in the brain of the polychaete,Ophryotrocha puerilis

Summary In the brain of Ophryotrocha puerilis swollen nerve endings filled with electron-lucent vesicles and aggregates of vesicles were observed. The vesicles do not resemble elementary neurosecretory granules. Tests for biogenic amines were negative; no dense-core vesicles were found. The vesicle type described here cannot be related to any of the types thus far found in nerve cells.Supported by Deutsche Forschungsgemeinschaft Pf116/3