Mechanisms underlying the neuronal-based symptoms of allergy
2014; Elsevier BV; Volume: 133; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2013.11.027
ISSN1097-6825
AutoresBradley J. Undem, Thomas E. Taylor‐Clark,
Tópico(s)Vagus Nerve Stimulation Research
ResumoPersons with allergies present with symptoms that often are the result of alterations in the nervous system. Neuronally based symptoms depend on the organ in which the allergic reaction occurs but can include red itchy eyes, sneezing, nasal congestion, rhinorrhea, coughing, bronchoconstriction, airway mucus secretion, dysphagia, altered gastrointestinal motility, and itchy swollen skin. These symptoms occur because mediators released during an allergic reaction can interact with sensory nerves, change processing in the central nervous system, and alter transmission in sympathetic, parasympathetic, and enteric autonomic nerves. In addition, evidence supports the idea that in some subjects this neuromodulation is, for reasons poorly understood, upregulated such that the same degree of nerve stimulus causes a larger effect than seen in healthy subjects. There are distinctions in the mechanisms and nerve types involved in allergen-induced neuromodulation among different organ systems, but general principles have emerged. The products of activated mast cells, other inflammatory cells, and resident cells can overtly stimulate nerve endings, cause long-lasting changes in neuronal excitability, increase synaptic efficacy, and also change gene expression in nerves, resulting in phenotypically altered neurons. A better understanding of these processes might lead to novel therapeutic strategies aimed at limiting the suffering of those with allergies. Persons with allergies present with symptoms that often are the result of alterations in the nervous system. Neuronally based symptoms depend on the organ in which the allergic reaction occurs but can include red itchy eyes, sneezing, nasal congestion, rhinorrhea, coughing, bronchoconstriction, airway mucus secretion, dysphagia, altered gastrointestinal motility, and itchy swollen skin. These symptoms occur because mediators released during an allergic reaction can interact with sensory nerves, change processing in the central nervous system, and alter transmission in sympathetic, parasympathetic, and enteric autonomic nerves. In addition, evidence supports the idea that in some subjects this neuromodulation is, for reasons poorly understood, upregulated such that the same degree of nerve stimulus causes a larger effect than seen in healthy subjects. There are distinctions in the mechanisms and nerve types involved in allergen-induced neuromodulation among different organ systems, but general principles have emerged. The products of activated mast cells, other inflammatory cells, and resident cells can overtly stimulate nerve endings, cause long-lasting changes in neuronal excitability, increase synaptic efficacy, and also change gene expression in nerves, resulting in phenotypically altered neurons. A better understanding of these processes might lead to novel therapeutic strategies aimed at limiting the suffering of those with allergies. Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.GlossaryACTION POTENTIALA mammalian nerve fiber at rest is in a state of electronegativity because of concentration gradients of ions and membrane permeability for particular ions. An action potential involves brisk changes in the membrane potential that spread rapidly down the length of the nerve fiber membrane. A normal resting negative membrane potential changes suddenly (within a few 10,000ths of a second) to a positive potential (depolarization) and then back to a negative potential (repolarization). Events that cause an increase in the membrane potential from electronegativity toward the zero level trigger voltage-gated sodium channels to begin opening, causing a further increase in the membrane potential and more opening of voltage-gated sodium channels until all channels have been opened. Potassium-gated channels then begin to open and sodium channels close, leading to termination of the action potential.CYSTEINYL LEUKOTRIENE D4 (LTD4)LTD4 binds to cysteinyl leukotriene receptor (CysLT) 1 and CysLT2. CysLT1 promotes bronchial smooth muscle contraction and regulates various aspects of the immune system. Montelukast antagonizes CysLT1.EICOSANOID FAMILYA class of lipids derived from polyunsaturated fatty acids (eg, arachidonic acid) that mediate inflammation.ENTERICA nervous system exclusive to the gastrointestinal tract. The enteric system contains approximately 100 million neurons, which is comparable to the number of neurons in the spinal cord. It contains an outer (myenteric) plexus and an inner (submucosal) plexus. Sympathetic and parasympathetic nerves connect with these 2 plexuses. Enteric nerves secrete a variety of neurotransmitters, including acetylcholine, norepinephrine, serotonin, dopamine, substance P, and vasoactive intestinal polypeptide.MECHANOSENSORSA sensory receptor that detects mechanical compression or stretching of the receptor or adjacent tissues. Respiratory muscle mechanosensors provide afferent input to neurons in the medulla, as well as the sensory cortex.MYELINATEDNerve fibers with axons surrounded by a myelin sheath. Schwann cells envelop axons and rotate around the axon many times, creating layers of membrane containing the lipid substance sphingomyelin. Sphingomyelin acts as an electrical insulator and is capable of decreasing ion flow through the membrane approximately 5000-fold. Uninsulated junctions between Schwann cells are termed the node of Ranvier. Action potentials “jump” from node to node to increase the velocity of nerve transmission in myelinated fibers.NEUROTRANSMITTERA chemical substance secreted by neurons that causes signal transmission in CNS synapses. Most synapses involved in CNS signal transmission are chemical synapses. The neurotransmitter binds to membrane receptor proteins of the next neuron to excite, inhibit, or modify the sensitivity of the neuron. There are more than 40 neurotransmitters, including acetylcholine, norepinephrine, histamine, serotonin, and gamma-aminobutyric acid.PARASYMPATHETICNerve fibers of the autonomic nervous system that leave the CNS through cranial nerves III, VII, IX, and X, as well as spinal sacral nerves. Most parasympathetic nerves are in the vagus nerves (cranial nerve X). Parasympathetic nerves also contain preganglionic and postganglionic neurons. Most parasympathetic postganglionic neurons are cholinergic.REACTIVE OXYGEN SPECIES (ROS)Substances typically generated at a low frequency during oxidative phosphorylation in the mitochondria, as well as in a variety of other cellular reactions. ROS can exert cellular damage by reacting with intracellular constituents, such as DNA and membrane lipids.SYMPATHETICNerve fibers of the autonomic nervous system that originate in the spinal cord between T1 and L2. They pass first into paravertebral chains of ganglia and then to tissues and organs. Each sympathetic nerve is composed of a preganglionic neuron and a postganglionic neuron. Preganglionic nerves can synapse in a paravertebral ganglion or a peripheral sympathetic ganglion (eg, celiac ganglion). Preganglionic nerves in both the sympathetic and parasympathetic systems are cholinergic (ie, secrete acetylcholine). Most sympathetic postganglionic neurons are adrenergic (ie, secrete norepinephrine).TACHYKININSA class of neuropeptides, which includes the sensory afferent neurotransmitter substance P.The Editors wish to acknowledge Daniel Searing, MD, for preparing this glossary.Allergy is the consequence of an IgE-driven overreaction of the immune system to what would otherwise be a relatively innocuous stimulus. Clinically, allergy is characterized by symptoms that, by in large, are secondary to an altered nervous system. The panoply of neuronal symptoms depends on the organ in which the reaction occurs but can include itchy and red eyes; rhinorrhea, nasal congestion, and sneezing; urge to cough, dyspnea, airway mucus secretion, and episodic reflex bronchospasm; dysphagia, altered gastrointestinal motility, and discomfort; and cutaneous itching and flare responses. These events are either in toto or in part secondary to changes in neuronal activity. Therefore allergy can be characterized as an immune-neuronal disorder (Fig 1).Immunologists predominate among those interested in investigating the mechanisms of allergy. Over the past few decades, scientists have made tremendous progress in untangling the complex web comprising the immunologic basis of allergy. This includes both the afferent (sensitization) and efferent (inflammatory cell recruitment and activation) limbs of the response. The outcomes from these investigations are filling pharmaceutical pipelines with rational, clever, and exciting therapeutic strategies aimed at quelling the inflammation associated with the allergic reaction.However, one might argue that the immune-driven inflammation associated with allergic reactions might in some cases be trivial unless transduced into the neurogenic symptoms of suffering (eg, itch, cough, bronchospasm, motility disturbance, pain, sneeze, skin conditions). Yet although the anti-inflammatory pipeline in allergy therapeutics is teeming with activity, the antineuromodulatory pipeline is largely empty. This might be due to the less than appropriate attention given to the neuronal aspect of this immune-neuronal disorder.Here we have attempted to review literature that provides a sense of how the nervous system is affected by an allergic reaction. Space limitations preclude an exhaustive review of this literature, and therefore instead prime examples are selected to reveal some of the more fundamental principles of allergen-induced neuromodulation. We have not reviewed the clinical scientific literature that has investigated neuronal symptoms of allergy nor have we dealt with the issue of the role of higher brain centers (emotion and stress) on the allergic response. We have also largely avoided the related important aspects of mast cell–nerve interactions that occur independently of the immediate hypersensitivity response, as well as the literature that pertains to mechanisms by which the nervous system can modulate the immune response. Rather we have focused here on basic mechanistic investigations of allergy-induced neuromodulation that will give the reader a sense of the peripheral neurologic substrates of allergy.General principles of sensory-autonomic innervationSensory (afferent) nerves sense the local tissue environment.1Lynn B. Somatosensory receptors and their CNS connections.Annu Rev Physiol. 1975; 37: 105-127Crossref PubMed Scopus (19) Google Scholar Their peripheral nerve terminals are “free” and do not synapse with other nerves. Instead, these peripheral sensory terminals synapse with the local tissue environment. Peripheral sensory terminals express various receptors and ion channels that transduce environmental signals into electrical signals (ie, action potentials). In the visceral and somatosensory systems, these stimuli include touch and other mechanical perturbations, temperature, pH, osmolarity, and various types of chemical stimuli. The action potentials conduct along the axon centrally, past the cell body that resides in a specific peripheral ganglion (either dorsal root ganglia, vagal nodose ganglia, vagal jugular ganglia, or trigeminal ganglia), and into the central nervous system (CNS), where the signal is transposed into neurotransmitter release at the nerve's synapse with second-order central neurons.Sensory nerves are heterogeneous with respect to sensitivity to stimuli (ie, receptor expression), size, myelination, conduction velocity, and neuropeptide and neurotransmitter content. In general, however, sensory nerves fall into 2 main categories: those that have been specifically adapted to detect routine physiologic stimuli (eg, touch, hearing, smell, mild temperature, changes in blood pressure, and osmolarity) and those that detect noxious or potentially noxious stimuli, such as physical damage, chemical irritants, and strong changes in pH.Sherrington2Sherrington C. The integrative action of the nervous system. Yale University Press, New Haven (CT)1906Google Scholar was the first to specifically describe these latter types of nerves in his famous book, The Integrative Action of the Nervous System.2Sherrington C. The integrative action of the nervous system. Yale University Press, New Haven (CT)1906Google Scholar He noted that a large number of sensory nerves in the skin were activated only by nonphysiologic stimulation of a noxious character. He termed these specialized sensory nerves “nociceptors” and suggested “…that under selective adaptation, they attach to the skin a so-to-say specific sense of its own injuries.”2Sherrington C. The integrative action of the nervous system. Yale University Press, New Haven (CT)1906Google Scholar Generally, nociceptors are small-diameter, unmyelinated, slowly conducting nerves referred to as C-fibers (A- and B-fibers are myelinated, faster-conducting nerves). It is now known that sensory nerves in visceral organs also comprise C-fibers that fit Sherrington's definition of nociceptors.The signals (action potentials) arising from these primary afferent nerves are integrated in the CNS, where the ultimate consequence can be either conscious perception (eg, pain, cramping, itch, dyspnea, or urge to cough or sneeze) or a subconscious activation of preganglionic autonomic neurons, thereby initiating sympathetic, parasympathetic, and enteric reflexes. In the skin nociceptor activation leads to itching and pain. In the respiratory tract activation of nociceptors leads to sneezing, coughing, dyspnea, and reflex bronchospasm and secretions. In the gut nociceptor activation can lead to secretion, diarrhea, gastric discomfort, and visceral pain.1Lynn B. Somatosensory receptors and their CNS connections.Annu Rev Physiol. 1975; 37: 105-127Crossref PubMed Scopus (19) Google Scholar, 3Coleridge J.C. Coleridge H.M. Afferent vagal C fibre innervation of the lungs and airways and its functional significance.Rev Physiol Biochem Pharmacol. 1984; 99: 1-110Crossref PubMed Google Scholar, 4Wood J.D. Enteric neuroimmunophysiology and pathophysiology.Gastroenterology. 2004; 127: 635-657Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar, 5Blackshaw L.A. Brookes S.J. Grundy D. Schemann M. Sensory transmission in the gastrointestinal tract.Neurogastroenterol Motil. 2007; 19: 1-19Crossref PubMed Google Scholar, 6Wood J.D. Nonruminant nutrition symposium: neurogastroenterology and food allergies.J Anim Sci. 2012; 90: 1213-1223Crossref PubMed Scopus (16) Google Scholar In other words activation of these nerves leads to strong sensations and/or reflexes aimed at avoidance of the stimulus. As we discuss in more detail below, nociceptors are the subtype of afferent nerve most susceptible to stimulation secondary to an acute allergic reaction.The autonomic and enteric nervous system depends on synaptic communication between presynaptic and postsynaptic elements situated in the sympathetic, parasympathetic, and enteric ganglia. In most organs the efferent neural regulation is driven by presynaptic neurons arising from the CNS. The preganglionic nerve is stimulated within the CNS, and action potentials conduct along the preganglionic axon that ultimately form synapses with neurons in the autonomic ganglia. It should be kept in mind that these ganglia are not simple relay stations but sites where filtering and integration of the CNS input occurs. This might be relevant in allergy because mast cells are commonly associated with sympathetic, parasympathetic, and enteric ganglia (as we will discuss further below). In the gut, in particular, there is also autonomous efferent control that is independent of the CNS neural processing. In this case a sensory nerve that detects a stimulus in the local environment can transmit this information directly to nearby efferent enteric neurons through local afferent-efferent synapses. This is referred to as a local “peripheral reflex.” The enteric ganglion neurons communicate through intraganglionic transmission. Peripheral reflexes can occur in other visceral organs, such as the airways and gall bladder, as well, although not to the extent seen in the gastrointestinal tract.7Myers A.C. Undem B.J. Electrophysiological effects of tachykinins and capsaicin on guinea-pig bronchial parasympathetic ganglion neurones.J Physiol. 1993; 470: 665-679PubMed Google Scholar, 8Mawe G.M. Tachykinins as mediators of slow EPSPs in guinea-pig gall-bladder ganglia: involvement of neurokinin-3 receptors.J Physiol. 1995; 485: 513-524PubMed Google ScholarIn some organs neuropeptide-containing afferent C-fibers can directly regulate organ function independently of either the CNS or efferent autonomic or enteric neurons through local “axon reflexes.”9Baluk P. Neurogenic inflammation in skin and airways.J Investig Dermatol Symp Proc. 1997; 2: 76-81Abstract Full Text PDF PubMed Scopus (78) Google Scholar In this case the action potential arising in a peripheral sensory nerve terminal is conducted centrally until it reaches a bifurcation, and then it antidromically conducts back to other peripheral terminals of the same nerve, where it evokes the release of sensory neuropeptides, such as substance P, neurokinin A, and calcitonin gene–related peptide (CGRP). The released peptides can lead to edema, vasodilation, smooth muscle contractions and relaxations, and immune cell recruitment and activation. The overall consequence of axon reflexes is often referred to as “neurogenic inflammation.”9Baluk P. Neurogenic inflammation in skin and airways.J Investig Dermatol Symp Proc. 1997; 2: 76-81Abstract Full Text PDF PubMed Scopus (78) Google Scholar The extent to which neurogenic inflammation occurs is species and organ dependent. For example, in human subjects the evidence is stronger for neurogenic inflammation in the skin and nasal mucosa than in the lower airways.10Sanico A.M. Atsuta S. Proud D. Togias A. Dose-dependent effects of capsaicin nasal challenge: in vivo evidence of human airway neurogenic inflammation.J Allergy Clin Immunol. 1997; 100: 632-641Abstract Full Text Full Text PDF PubMed Scopus (67) Google ScholarBasic mechanisms of allergen-induced neuromodulationThe allergic response comprises changes at all 3 levels of the neural arc: sensory nerve function, CNS integration, and autonomic/enteric neuroeffector cell function (Fig 1). These changes can be subdivided into acute changes (overt activation of nerves that lasts only as long as the stimulus is present), longer-lasting changes in neuroexcitability that can outlast the stimulus by hours or days, and the even more persistent phenotypic changes that can last for weeks and perhaps, when one considers the idea of developmental “critical periods,” for years.Morphologic considerationsThe allergic reaction seems particularly adept at altering neuronal function in the skin and visceral tissues. This is likely due to the close association between nerve fibers and mast cells (Fig 2).11Schemann M. Camilleri M. Functions and imaging of mast cell and neural axis of the gut.Gastroenterology. 2013; 144: 698-704.e4Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 12Silver R.B. Reid A.C. Mackins C.J. Askwith T. Schaefer U. Herzlinger D. et al.Mast cells: a unique source of renin.Proc Natl Acad Sci U S A. 2004; 101: 13607-13612Crossref PubMed Scopus (158) Google Scholar Mast cells have been anatomically associated with nerves in virtually all organ systems in laboratory animals and human subjects.11Schemann M. Camilleri M. Functions and imaging of mast cell and neural axis of the gut.Gastroenterology. 2013; 144: 698-704.e4Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 13Arizono N. Matsuda S. Hattori T. Kojima Y. Maeda T. Galli S.J. Anatomical variation in mast cell nerve associations in the rat small intestine, heart, lung, and skin. Similarities of distances between neural processes and mast cells, eosinophils, or plasma cells in the jejunal lamina propria.Lab Invest. 1990; 62: 626-634PubMed Google Scholar, 14Alving K. Sundstrom C. Matran R. Panula P. Hokfelt T. Lundberg J.M. Association between histamine-containing mast cells and sensory nerves in the skin and airways of control and capsaicin-treated pigs.Cell Tissue Res. 1991; 264: 529-538Crossref PubMed Scopus (73) Google Scholar, 15Forsythe P. Bienenstock J. The mast cell-nerve functional unit: a key component of physiologic and pathophysiologic responses.Chem Immunol Allergy. 2012; 98: 196-221Crossref PubMed Scopus (9) Google Scholar, 16Keith I.M. Jin J. Saban R. Nerve-mast cell interaction in normal guinea pig urinary bladder.J Comp Neurol. 1995; 363: 28-36Crossref PubMed Scopus (58) Google Scholar, 17Van Nassauw L. Adriaensen D. Timmermans J.P. The bidirectional communication between neurons and mast cells within the gastrointestinal tract.Auton Neurosci. 2007; 133: 91-103Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar The percentage of mast cells making meaningful associations with nerves depends on the distance that one considers meaningful. In the bladder, for example, it has been argued that greater than 75% of mast cells are close enough to nerve fibers for meaningful bidirectional communication,18D'Andrea M.R. Saban M.R. Gerard N.P. Wershil B.K. Saban R. Lack of neurokinin-1 receptor expression affects tissue mast cell numbers but not their spatial relationship with nerves.Am J Physiol Regul Integr Comp Physiol. 2005; 288: R491-R500Crossref PubMed Scopus (18) Google Scholar and in the human gastrointestinal tract 50% to 70% of mast cells were considered to be in close apposition to neurites.19Stead R.H. Dixon M.F. Bramwell N.H. Riddell R.H. Bienenstock J. Mast cells are closely apposed to nerves in the human gastrointestinal mucosa.Gastroenterology. 1989; 97: 575-585Abstract PubMed Scopus (375) Google Scholar There is good evidence that mast cells actually make synaptic-like contacts with nerves, but this holds true for only a small subset of mast cells.20Stead R.H. Tomioka M. Quinonez G. Simon G.T. Felten S.Y. Bienenstock J. Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves.Proc Natl Acad Sci U S A. 1987; 84: 2975-2979Crossref PubMed Scopus (491) Google Scholar, 21Williams R.M. Berthoud H.R. Stead R.H. Vagal afferent nerve fibres contact mast cells in rat small intestinal mucosa.Neuroimmunomodulation. 1997; 4: 266-270PubMed Google Scholar The intimate synaptic-like nerve–mast cell contacts can be induced or enhanced by specific adhesion molecules, such as cell adhesion molecule 1.22Hagiyama M. Furuno T. Hosokawa Y. Iino T. Ito T. Inoue T. et al.Enhanced nerve-mast cell interaction by a neuronal short isoform of cell adhesion molecule-1.J Immunol. 2011; 186: 5983-5992Crossref PubMed Scopus (45) Google Scholar In experimental systems of mast cell–sensory nerve contacts, nerve–mast cell communication was inhibited by blocking the heterophilic binding between mast cell–expressed cell adhesion molecule 1 and nectin 3 localized to the nerve.23Furuno T. Hagiyama M. Sekimura M. Okamoto K. Suzuki R. Ito A. et al.Cell adhesion molecule 1 (CADM1) on mast cells promotes interaction with dorsal root ganglion neurites by heterophilic binding to nectin-3.J Neuroimmunol. 2012; 250: 50-58Abstract Full Text Full Text PDF PubMed Scopus (17) Google ScholarFig 2Mast cells are found in close proximity to nerves in virtually all organs. A, Mast cell tryptase–positive cells (red) near PGP9.5-positive nerves (green) in human intestinal submucosal plexus.11Schemann M. Camilleri M. Functions and imaging of mast cell and neural axis of the gut.Gastroenterology. 2013; 144: 698-704.e4Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar B, Mast cells (red) near synapsin-positive neurons (green) in rat cardiac ventricle.12Silver R.B. Reid A.C. Mackins C.J. Askwith T. Schaefer U. Herzlinger D. et al.Mast cells: a unique source of renin.Proc Natl Acad Sci U S A. 2004; 101: 13607-13612Crossref PubMed Scopus (158) Google Scholar C, Mast cells (purple) near MrgA3 expressing “afferent itch nerves” (orange) in mouse skin (personal observation).View Large Image Figure ViewerDownload Hi-res image Download (PPT)More often, mast cells are situated close to nerves without forming true contacts. The anatomic association between mast cells and nerves becomes even more prevalent at sites of inflammation.20Stead R.H. Tomioka M. Quinonez G. Simon G.T. Felten S.Y. Bienenstock J. Intestinal mucosal mast cells in normal and nematode-infected rat intestines are in intimate contact with peptidergic nerves.Proc Natl Acad Sci U S A. 1987; 84: 2975-2979Crossref PubMed Scopus (491) Google Scholar, 24Barbara G. Wang B. Stanghellini V. de Giorgio R. Cremon C. Di Nardo G. et al.Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome.Gastroenterology. 2007; 132: 26-37Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar, 25Moon T.C. St Laurent C.D. Morris K.E. Marcet C. Yoshimura T. Sekar Y. et al.Advances in mast cell biology: new understanding of heterogeneity and function.Mucosal Immunol. 2010; 3: 111-128Crossref PubMed Scopus (208) Google Scholar Mechanisms have been proposed to explain the propensity for mast cell–nerve associations, including the release of neurotrophic factors and cytokines by mast cells that promote nerve elongation into the vicinity of mast cells.26Kakurai M. Monteforte R. Suto H. Tsai M. Nakae S. Galli S.J. Mast cell-derived tumor necrosis factor can promote nerve fiber elongation in the skin during contact hypersensitivity in mice.Am J Pathol. 2006; 169: 1713-1721Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar With respect to allergic inflammation, the infiltrating eosinophil is also often associated with nerves.27Thornton M.A. Akasheh N. Walsh M.T. Moloney M. Sheahan P.O. Smyth C.M. et al.Eosinophil recruitment to nasal nerves after allergen challenge in allergic rhinitis.Clin Immunol. 2013; 147: 50-57Crossref PubMed Scopus (21) Google Scholar In the airways eosinophils might be attracted to autonomic cholinergic neurons as a consequence of neuronal vascular cell adhesion protein 1 and intercellular adhesion molecule 1 expression.28Sawatzky D.A. Kingham P.J. Court E. Kumaravel B. Fryer A.D. Jacoby D.B. et al.Eosinophil adhesion to cholinergic nerves via ICAM-1 and VCAM-1 and associated eosinophil degranulation.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L1279-L1288PubMed Google Scholar On the other hand, a careful morphometric analysis revealed that fine nerve axons and terminals in various tissues are also commonly associated not just with mast cells and eosinophils but also with other bone marrow–derived cells, such as plasma cells, and these “associations” do not appear to favor one cell type over the other.13Arizono N. Matsuda S. Hattori T. Kojima Y. Maeda T. Galli S.J. Anatomical variation in mast cell nerve associations in the rat small intestine, heart, lung, and skin. Similarities of distances between neural processes and mast cells, eosinophils, or plasma cells in the jejunal lamina propria.Lab Invest. 1990; 62: 626-634PubMed Google Scholar This type of analysis leads to the conclusion that fine nerve branches, mast cells, and other bone marrow–derived cells are often concentrated in the same tissue region, making it all but certain they will, in a sense, “colocalize” by random chance. Mast cells, along with autonomic and sensory nerves, are frequently found in close proximity of the microvasculature, in the mucosa and submucosa of visceral tissues, near smooth muscle, and throughout the dermis.Regardless of the mechanisms, anatomic investigations, especially when evaluating whole mounts of tissue, often reveal a spectacular display of mast cells residing along afferent, autonomic, and enteric nerve branches (Fig 2). These images leave little doubt that many, if not most, nerve fibers in tissues are within the sphere of influence of mediators released from mast cells. Just what this influence might be is discussed below.Allergen-induced neuromodulation of afferent (sensory) nervesAction potential dischargeAllergen challenge is often associated with the overt activation of afferent nerve terminals leading to action potential discharge (Fig 3).29Omori Y. Andoh T. Shirakawa H. Ishida H. Hachiga T. Kuraishi Y. Itch-related responses of dorsal horn neurons to cutaneous allergic stimulation in mice.Neuroreport. 2009; 20: 478-481Crossref PubMed Scopus (10) Google Scholar, 30Potenzieri C. Meeker S. Undem B.J. Activation of mouse bronchopulmonary C-fibers by serotonin and allergen-ovalbumin challenge.J Physiol. 2012; 590: 5449-5459Crossref PubMed Scopus (35) Google Scholar Generally, it is thought that the types of sensory nerves most susceptible to direct activation through allergic mediators are polymodal C-fibers. This is because afferent C-fibers are known to express receptors for many chemical mediators present in the allergically inflamed tissue. Often, these nerves can be accurately categorized as nociceptors.Fig 3Allergen challenge overtly activates afferent C-fibers. Top, Hypothetical effect of allergenic activation of mast cells on afferent nerve terminal action potential discharge. Bottom, Examples of allergen-induced activation of afferent nociceptors: left, allergen (ovalbumin) evokes strong activation of vagal jugular C-fiber innervating the lung (action potentials recorded in vagal sensory ganglion)30Potenzieri C. Meeker S. Undem B.J. Activation of mouse bronchopulmonary C-fibers by serotonin and allergen-ovalbumin challenge
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