Allergy and the Nervous System

J. Bienenstock

• Publisher: S. Karger
• Year: 2012
• ISBN:
  9783805599856
• Topic: Psychologie
• Subtopic: Histoire et théorie en psychologie

In recent decades, it has become increasingly clear that the immune and nervous systems communicate with each other in a bidirectional way. The role of chronic stress in allergic disease and inflammation has been confirmed and raises the important question of how psychosocial factors influence the outcome of allergic conditions.This book explains the roles of the autonomic, peripheral and central nervous systems in allergy and asthma. With contributions from leading authorities - both clinicians and basic researchers - it covers a wide range of topics from psychology over epigenetics to brain imaging. The 15 invited reviews discuss topics such as the role of stress in allergy and asthma, the concept of programming in utero and in childhood and adulthood, the significance of neurotrophins, and the involvement of the nervous system in the lung in asthma and lung inflammation. The interactions between mast cells and the nervous system are examined as well as the role of the gut microbiome in regulating the hypothalamic-pituitary-adrenal axis and the stress response. Further chapters are devoted to neural and behavioral changes associated with food allergy, the role of the neuroendocrine system in the skin, and the way in which itch is processed by the brain.Unique in its field, this valuable volume is recommended reading not only for allergologists, psychologists specializing in allergy and somatic manifestations, respirologists and asthma researchers, but for anyone interested in psychoneuroimmunology.

Bienenstock J (ed): Allergy and the Nervous System.
Chem Immunol Allergy. Basel, Karger, 2012, vol 98, pp 196–221

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The Mast Cell-Nerve Functional Unit: A Key Component of Physiologic and Pathophysiologic Responses

Paul Forsythe · John Bienenstock

The Brain- Body Institute, St. Joseph’s Healthcare, Department of Medicine, McMaster University, Hamilton, Ont., Canada

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Abstract

A key characteristic of mast cells appears to be an ability to span the division between nervous and immune system. Indeed, much of our understanding of the bi-directional relationship between the nervous and immune systems has come from the study of mast cell-nerve interaction. Although differences in species have been reported, morphologic as well as functional associations between mast cell and nerves are found in most tissues in many mammalian species, including humans. These interactions are involved in the regulation of physiologic homeostatic processes as well as in disease mechanisms. Here we discuss the influence of cholinergic and sensory neurons on mast cells as well as the importance of mast cell nerve interactions at specific tissue sites, including the brain.

Copyright © 2012 S. Karger AG, Basel

Mast Cells

Mast cells are immunocytes with secretory functions that act locally to maintain tissue integrity, local hemodynamics and tissue homeostatic mechanisms. Mast cells are heterogeneous and exhibit site-specific adaptations induced by micro-environmental signals that lead to selective expression of potential mast cell characteristics. This flexibility of phenotype has important functional implications and allows these cells to adapt to organ or tissue specific roles [1].

While best known for their role in allergic inflammation through the ability of allergens to cross-link antigen-specific IgE bound to the high affinity IgE receptor (FceRI) expressed on the cell surface [2] mast cells have been identified as having diverse physiologic roles. These roles range from providing innate defense against bacteria [3] and protection from the venom of bees and snakes [4] to participating multiple aspects of adaptive immune responses such as antigen presentation [5] and lymphocyte recruitment to draining lymph nodes [6], as well as downregulation of immune responses [7]. In recent years, the pathogenic roles of mast cells have been extended to include not only allergic diseases and helminth infection, but also autoimmune diseases such as experimental allergic encephalomyelitis [8], rheumatoid arthritis [9], allograft tolerance [7], angiogenesis in tissue repair [10], and carcinogenesis [11].

A key characteristic of mast cells appears to be an ability to span the division between nervous and immune system with the cells exhibiting variably functional aspects of both systems [12]. Indeed, much of our understanding of the bi-directional relationship between the nervous and immune systems has come from the study of mast cell-nerve interaction, often considered as the archetype of neuroimmune communication. Mast cells can be activated by a range of neurotransmitters and reciprocally a variety of molecules, including histamine and serotonin, are synthesized and released by mast cells can influence neuronal activity [13] while mast cell-derived cytokines, including TNF, and growth factors, such as NGF, lower the threshold for activation of local neurons and promote nerve fiber growth [14-16].

While mast cells are distributed widely throughout the body in connective tissue and at mucosal surfaces they are concentrated at interfaces with the external environment, near blood vessels, lymphatic vessels, and nerve fibers [1]. Positioned at these strategic locations, mast cells act as sentinels of the immune system, protecting against invading microbes and signaling environmental changes or immune challenges to other cells involved in physiological and immunological responses.

There is anatomical evidence for mast cell associations with peripheral myelinated and unmyelinated nerves [17-19]. Close apposition of mast cells and neurons containing substance P, CGRP or both have been described in the rat and human gastrointestinal tract, the rat trachea and peripheral lung, the urinary bladder and several other tissues [20-22]. These interactions underlie the classical inflammatory axon reflex where antigen or noxious stimuli causes stimulation of sensory c-fibers that in turn, through collateral axons, provide an efferent route for the lateral spread of inflammatory signals [23].

While exocytosis is the most obvious event associated with secretion of the mediator molecules contained in granules the function of mast cells in health and disease often involves more subtle activities and these cells have been increasingly implicated in inflammatory processes in which degranulation is generally not observed. Mast cells can undergo ultrastructural alterations of their electron-dense granular core that are indicative of secretion but without degranulation, a process termed piecemeal degranulation, in which even molecules stored within the same granule can be secreted in a discriminatory pattern [24].

Mast cells in close proximity to unmyelinated nerve fibers have been observed to contain granules showing ultrastructural features of activation or piecemeal degranulation that have been associated with differential secretion. Histamine content of intestinal tissue increased flowing vagal stimulation without notable degranulation of mast cells [25, 26]. Selective secretion of IL-6 from mast cells appears to be distinct from degranulation and may contribute to the development of inflammation [27]. Serotonin can be released independently from histamine [28] and differential synthesis and release of arachidonic acid metabolites prostaglandins and leukotrienes have also been reported [29].

Mast cells are derived from progenitor cells that translocate from the bone marrow to tissue sites where they locally undergo differentiation into mature forms [30]. Studies have identified the remarkable facility of mast cell populations to respond to changes in the environment by significant alterations in multiple aspects of their phenotype, including morphology, mediator content, degranulation pattern and proliferative potential [1]. Consequently, mast cells can be divided into various subpopulations with distinct phenotypes. In rodents, mast cells are often classified broadly, based on tissue location, as mucosal mast cells (MMC) or connective-tissue type mast cells (CTMC) [31, 32]. However, mast cells possess a remarkable degree of plasticity and even apparently fully differentiated CTMC will transform their phenotype to that of MMC if transplanted into a mucosal environment [33]. Alternatively, and most often in human tissue, mast cells can be classified based on the protease content of secretory granules that differ between tissues, i.e. MCt for cells containing only tryptases and MCtc for those containing tryptase and chymase [30]. Tryptase is present in all mast cell subtypes and can activate cells through cleavage of protease-activated receptors (PAR) [34]. Proteases regulate neurons and glia in the central nervous system by cleaving PAR [35]. Furthermore, tryptase has been shown to cleave PAR2 on primary spinal afferent neurons, which causes the release of substance P, and CGRP and sensitization of co-expressed TRP channels that together cause plasma extravasation, amplification of inflammation and thermal and mechanical hyperalgesia [36]. Purified tryptase stimulates calcium mobilization in myenteric neurons [37] presumably through PAR2 because activation of PAR2 with trypsin or peptide agonists strongly desensitizes the response to tryptase. Mast cell proteases have also been demonstrated to degrade nerve products by enzymatic cleavage and thus may act to limit the effects of neurogenic signals [38]. It is proposed that IgE-mediated mast cell activation results in the release of tryptase from intracellular secretory granules, and the tryptase activates PAR2 on sensory neurons to stimulate the release of substance P and CGRP [39]. These neuro-peptides induce the further activation of mast cells as well as inflammatory response such as arteriolar vasodilation and increased blood flow.

Molecules Involved in Mast Cell Nerve Attachments

Co-culture systems of mast cells and neurons have been particularly informative regarding the molecules involved in the formation of a neuroimmune synapse.

The adhesion molecule, cell adhesion molecule 1 (CADM1) is localized on both sides of most synapses in the brain and functions as a homophilic adhesion molecule spanning the synaptic cleft in the nervous system. CADM1 was also found to mediate mast cell/fibroblasts adhesion [40] and was subsequently demonstrated to be critical to mast cell-nerve interactions [41].

CADM1 is highly localized at the contact site between mast cells and neurites and the attachment of mast cells is dose-dependently reduced in the presence of an anti-CADM1 blocking antibody. Mast cells lacking CADM1 attach poorly to neurites, while attachment is significantly enhanced with ectopic expression of this adhesion molecule [41, 42].

The neuron-induced activation of CADM1-deficient mast cells is also markedly reduced while the response rate of CADM1 + mast cel...