Nasal Mast Cells Research Articles

Neuroendocrinology of mast cells: Challenges and controversies.

Mast cells (MC) are hemotopoietically derived tissue immune cells that are ubiquitous in the body, including neuroendocrine organs such as the hypothalamus, pineal, pituitary, ovaries, pancreas and uterus where their action is not well understood. Mast cells have historically been associated with allergies because of their rich content of histamine and tryptase, but more recently with regulation of immunity and inflammation due to their synthesis and release of numerous cytokines and chemokines. Mast cells are located perivascularly and express numerous receptors for diverse ligands such as allergens, pathogens, neurotransmitters, neuropeptides and hormones including acetylcholine, calcitonin gene-related peptide (CGRP), corticosteroids, corticotropin-releasing hormone (CRH), β-endorphin, epinephrine, 17β-oestradiol, gonadotrophins, hemokinin-A (HKA), leptin, melatonin, neurotensin (NT), parathyroid hormone (PTH), substance P (SP) and vasoactive intestinal peptide (VIP). Moreover, MC can synthesize and release most of their neurohormonal triggers, including adrenocorticotropin hormone (ACTH), CRH, endorphins, HKA, leptin, melatonin, NT, SP and VIP. Animal experiments have shown that diencephalic MC increase in number during courting in doves, while stimulation of brain and nasal MC leads to activation of the hypothalamic-pituitary-adrenal (HPA) axis. Recent evidence indicates that MC reactivity exhibits diurnal variations, and it is interesting that melatonin appears to regulate MC secretion. However, the way MC change their phenotype or secrete specific molecules selectively at different pathophysiological settings still remains unknown. Mast cells developed over 500million years ago and may have served as the original prototype neuroimmunoendocrine cell and then evolved into a master regulator of such interactions, especially as most of the known diseases involve neuroinflammation that worsens with stress.

6 Regulation of MCTC development by SCF, especially with regard to nasal mast cells (3 マスト細胞研究の最前線)

6 Regulation of MCTC development by SCF, especially with regard to nasal mast cells (3 マスト細胞研究の最前線)

Increase of Mast Cell-Nerve Association and Neuropeptide Receptor Expression on Mast Cells in Perennial Allergic Rhinitis

Objectives: Mast cells (MCs) and nerves play an important role in allergic rhinitis (AR), but little is known about their crosstalk in AR. The aim of this study was to investigate MC-nerve interaction in the human nasal mucosa during AR. Methods: The association between MCs and nerves, the expression of neuropeptide receptors (neurokinin 1 receptor [NK1R], neurokinin 2 receptor [NK2R], calcitonin gene-related peptide receptor [CGRPR], and MrgX2) on MCs, and protease-activated receptor 2 (PAR2) and tyrosine receptor kinase A (TrkA) on nerve fibres in the human nasal mucosa were investigated with immunofluorescence and real-time PCR. Results: The association between MCs and nerves was found to be significantly increased, although the numbers of MCs and nerve fibres were unchanged during AR. MCs expressing tryptase-chymase (MC_tc) were frequently associated with nerve fibres and these contacts increased significantly in AR. Neuropeptide receptors NK1R, NK2R, and CGRPR were firstly found to be largely localised on MCs. The number of MCs expressing NK1R and NK2R, but not CGRPR, was significantly increased in AR. Interestingly, MC_tc mostly expressed these neuropeptide receptors. The newly discovered tachykinin receptor MrgX2 was not expressed on nasal MCs, but was expressed on gland cells and increased in AR. Additionally, tachykinergic nerve fibres were found to express PAR2 or TrkA as receptors for MCs. Conclusions: This study revealed for the first time an increase of MC-nerve association and neuropeptide receptor expression on MCs during AR as well as nerve fibres containing receptors for MCs. These results suggest that targeting or controlling airway sensory nerve function as a modulator of MCs may prevent allergic airway inflammation such as AR.

Genitourinary mast cells and survival.

Mast cells (MCs) are ubiquitous in the body, but they have historically been associated with allergies, and most recently with regulation of immunity and inflammation. However, it remains a puzzle why so many MCs are located in the diencephalon, which regulates emotions and in the genitourinary tract, including the bladder, prostate, penis, vagina and uterus that hardly ever get allergic reactions. A number of papers have reported that MCs have estrogen, gonadotropin and corticotropin-releasing hormone (CRH) receptors. Moreover, animal experiments have shown that diencephalic MCs increase in number during courting in doves. We had reported that allergic stimulation of nasal MCs leads to hypothalamic-pituitary adrenal (HPA) activation. Interestingly, anecdotal information indicates that female patients with mastocytosis or mast cell activation syndrome may have increased libido. Preliminary evidence also suggests that MCs may have olfactory receptors. MCs may, therefore, have been retained phylogenetically not only to “smell danger”, but to promote survival and procreation.

Exhaled nitric oxide and nasal tryptase are associated with wheeze, rhinitis and nasal allergy in primary school children

Rhinitis and asthma are the most common respiratory diseases in children. We assessed whether airway inflammation markers were associated with nasal allergies and self-reported symptoms of wheeze and rhinitis in 130 children 6–12 year old in an epidemiological context. Independent of sex and age, the fraction of exhaled nitric oxide (FeNO) and nasal mast cell (MC) activation (tryptase ≥ 5 ng/mL) were positively associated with wheeze, rhinitis and with nasal allergy. Nasal eosinophil cationic protein (ECP) and exhaled breath condensate (EBC) markers (pH, 8-isoprostane, interleukin-1β) were not associated with symptoms or with nasal allergy. In conclusion, FeNO and nasal tryptase reflect allergic inflammation in the respiratory system.

Non‐allergic, mastocytosis‐associated rhinitis

Systemic mastocytosis (SM) is a clonal proliferative disorder of mast cells (MC) that causes pathological accumulation of mast cells in various tissues, which results in clinical symptoms (e.g. diarrhoea, urticaria) due to MC mediator release. Previous studies have shown that up to fifty percent of rhinitis symptoms in SM patients are non-allergic and it has been assumed that these nasal complaints in SM patients are due an increased nasal mast cell burden. Nevertheless, to date there are no data supporting this hypothesis. The study aims to investigate if the presence of allergy-suggesting nasal complaints in non-allergic SM patients is correlated with objective measure of nasal mast cell burden. Eleven adult patients with systemic mastocytosis underwent a comprehensive rhinologic work-up. All patients fulfilled the clinical ARIA criteria for rhinitis. The allergologic work-up included serological allergy testing, determination of tryptase levels (serum and nasal secretion), skin prick testing, and nasal provocation testing. Ten out of eleven SM patients with clinical persistent allergic rhinitis were found to be non-allergic. In these patients, the most predominant symptoms were rhinorrhea, sneezing, and itching. All three symptoms were strongly correlated with the nasal tryptase level but not to the level of serum tryptase. Non-allergic persistent nasal complaints in systemic mastocytosis were significantly correlated with elevated nasal tryptase level as a measure of local MC burden. Furthermore, elevated nasal tryptase correlated with persistent rhinorrhea, sneezing, and itching as predominant symptoms, which seems to characterize a non-allergic mastocytosis-associated rhinitis (NAMAR) in systemic mastocytosis.

Age-related Reduction Of S100A8/A9 In Chronic Rhinosinusitis Is Associated With Increased Production Of Soluble gp130

S A T U R D A Y 163 Mast Cells with a Unique Phenotype Are Highly Elevated in Chronic Rhinosinusitis with Nasal Polyps T. Takabayashi, A. Kato, A. T. Peter, L. A. Suh, R. Carter, J. Norton, L. C. Grammer, B. K. Tan, R. K. Chandra, D. B. Conley, R. C. Kern, S. Fujieda, R. P. Schleimer; The Division of Allergy and Immunology Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, The Division of Otorhinolaryngology Head and Neck Surgery, Department of Sensory and Locomotor Medicine, University of Fukui, Fukui, JAPAN, Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by Th2 inflammation, the role of mast cells is poorly understood. The objective of this study was to investigate the presence, localization and phenotype of mast cells in affected tissues from patients with chronic rhinosinusitis (CRS). METHODS: We collected nasal tissue and nasal lavage fluid from patients with CRS and control subjects. We analyzed mRNA for the mast cell proteases tryptase, chymase and carboxypeptidase A3 (CPA3), using real-time PCR, and assessed the presence of mast cell proteases using ELISA and immunohistochemistry. We also performed immunofluorescence to observe the pattern of colocalization of the mast cell proteases. RESULTS: Tryptase mRNA and protein were significantly increased in nasal polyps frompatientswithCRSwNPcomparedwith uncinate tissue from patients with CRS or healthy subjects. We made the striking observation that therewere abundantmast cells localizedwithinglands of nasalpolyps and that these mast cells expressed all three proteases. We also observed increased numbers of mast cells in epithelium but not elsewhere within the lamina propria in nasal polyps. The mast cells detected in epithelium in nasal polyps were characterized by expression of tryptase and CPA3 but not chymase. CONCLUSIONS: Herein we demonstrate increased mast cells in epithelium and glands of nasal polyp tissue, and show that nasal polyp mast cells have unique phenotypes that vary by tissue location. These diverse subsets of mast cells may contribute to the pathogenesis of CRSwNP.

Evidence for the involvement of free light chain immunoglobulins in allergic and nonallergic rhinitis

Allergic rhinitis is characterized by mast cell degranulation induced by antigen cross-linking of IgE. It has been proposed that some patients with rhinitis show nasal allergy in the absence of systemic markers of atopy, termed entopy. Recent murine studies suggest the existence of an IgE-independent hypersensitivity response involving antigen-induced mast cell activation, mediated by immunoglobulin free light chains (FLCs). To determine whether FLC is associated with mast cell-mediated nasal hypersensitivity and its relationship with eosinophilic activity in allergic and nonatopic rhinitis. Patients with allergy and nonallergic rhinitis with eosinophilia syndrome (NARES) had levels of soluble FLC measured in nasal secretions and serum. In addition, levels of the nasal inflammatory mediators mast cell tryptase and eosinophil cationic protein were quantified. Cellular expression of kappa and lambda FLC was characterized in the nasal mucosa of allergic and nonatopic idiopathic rhinitis and control subjects by using immunohistochemistry. Immunopositive cells were phenotyped by using laser microdissection and PCR. Free light chain was significantly increased in nasal secretions of subjects with allergy and NARES, and in serum of patients with NARES. Nonatopic patients with allergy showed significantly increased nasal mast cell tryptase and eosinophil cationic protein. FLC-positive cells were significantly increased in allergic and nonatopic mucosa, and were shown to be mast cells and plasma cells. Nasal FLC is significantly increased in allergic and nonatopic rhinitis nasal mucosa, suggesting a role in nasal hypersensitivity. Further studies are needed to identify which allergens trigger FLC-mediated responses in nonatopic rhinitis.

Upper airways reactions to cold air

Cold air-induced rhinitis is a common complaint of individuals with chronic allergic or nonallergic rhinitis and those with no chronic nasal disease. It is characterized by rhinorrhea, nasal congestion, and nasal burning that appear within minutes of exposure to cold air and dissipate soon after exposure is terminated. The symptoms of cold-air rhinitis are reproduced experimentally with nasal cold-air provocation. This procedure has shown that nasal mast cell activation and sensory nerve stimulation are associated with the development of nasal symptoms. Sensory nerve activation generates a cholinergic reflex that leads to rhinorrhea; therefore, anticholinergic agents are highly effective in treating cold-air rhinitis. Experimental data suggest that individuals with nasal cold-air sensitivity may have reduced ability to compensate for the water loss that occurs during exposure to cold air. Therefore, the symptoms of cold air-induced rhinitis may reflect the activation of compensatory mechanisms to restore mucosal homeostasis.

Mast Cell Stabilizers in the Treatment of Allergic Rhinitis

Allergic rhinitis (AR) is caused by an immediate type hypersensitivity reaction in sensitized subjects after exposure to airborn allergens. The interaction of the allergen with a specific IgE antibody attached to the nasal mast cells leads to the local release of vasoactive and inflammatory mediators such as histamine, leukotriene C4 and prostaglandin D2. These mediators cause the nasal allergic symptoms complex of rhinorrhea, nasal obstruction, nasal itching and sneezing, which improve spontaneously or with treatment. Cromolyn sodium and nedocromil sodium are often termed ‘antiallergic drugs’, which are defined here as drugs capable of inhibiting both the early-phase response to challenge and chronic allergic inflammation. They act at the cell membrane levels. Intranasal and ocular formulations of cromones, such as cromoglycate, are available without medical prescription in many countries. Sodium cromoglycate or nedocromil have a good safety profile. They reduce the symptoms of AR, and should be used profilactically, but limited efficacy and the need for frequent dosing are disadvantages.

Nasal provocation of patients with allergic rhinitis and the hypothalamic-pituitary-adrenal axis

Allergic rhinitis is a common problem involving activation of nasal mast cells and irritability. The hypothalamic-pituitary-adrenal (HPA) axis is stimulated in cases of emotional or environmental stress, and mast cells have been implicated in stress-induced immune responses. To investigate whether intranasal challenge of patients allergic to a single antigen would stimulate the HPA axis. Plasma corticotropin and cortisol levels were measured 20, 40, 60, 80, 100, and 120 minutes after intranasal antigen administration in healthy volunteers (n=3) and in patients with rhinitis who are allergic to Parietaria (n=10). Mean +/- SD corticotropin levels were 24.43 +/- 14.38 pg/mL in patients compared with 8.83 + 5.02 pg/mL in controls, and this increase was statistically significant (P = .049). Patient cortisol levels also increased to a mean +/- SD of 8.87 +/- 4.90 pg/mL (at 40 minutes) compared with 4.36 +/- 1.72 pg/mL in controls (P = .11 due to 1 outlier). Compared with individual patient prechallenge levels, corticotropin levels increased in 7 patients and cortisol levels increased in 5 at 40 minutes. These results suggest that allergic rhinitis may activate the HPA axis. A larger study with additional controls is required for definitive conclusions.

Inhibition of nasal polyp mast cell and eosinophil activation by desloratadine

Nasal polyp tissue which contains mast cells and eosinophils is similar to the inflamed airway mucosa in cellular composition and mediator content. This investigation assessed the effect of desloratadine (DL), on activation of cells in nasal polyp tissue. Polyps were obtained from 22 patients with chronic rhinosinusitis [nine aspirin acetylosalitic acid (ASA)-sensitive and 13 ASA-tolerant]. Polyp tissue was dispersed by digestion, and preincubated with DL and incubated with anti-immunoglobulin E (IgE) or calcium ionophore. LTC4, eosinophil cationic protein (ECP) and tryptase concentrations in supernatants were measured by immunoassays. Desloratadine (1, 10 and 50 microM) inhibited calcium ionophore-induced LTC4 release by a mean of 29%, 50% and 63% respectively, and anti-IgE-induced LTC4 release by a mean of 27%, 35% and 39% respectively. Calcium ionophore-induced tryptase release was inhibited 60% and 69% by 10 and 50 microM of DL, respectively, and anti-IgE-induced tryptase release was inhibited 33%, 47% and 66% for 1, 10 and 50 microM of DL. Desloratadine 10 microM and 50 microM inhibited ECP release by and 45% and 48% respectively. Polyp tissue from ASA-sensitive patients when compared with ASA-tolerant patients released at baseline significantly more ECP (medians 120.0 microg/ml, range: 69.0-182.0 vs 63.4 microg/ml, range: 3.7-172.0; P <0.05), but similar amounts of tryptase and LTC4. This study demonstrated that DL inhibits activation of both eosinophils and mast cells derived from a site of airway mucosal inflammation.

Regulation of mast cell migration into the allergic nasal epithelium by RANTES and not SCF

Rationale Mast cells are increased in the nasal epithelium of patients with allergic rhinitis (AR). Yet, the precise mechanism is unclear. We reported that nasal mast cells (NMC) express CCR3 and exhibit increased chemotaxis to RANTES suggesting a role for RANTES in mast cell migration. To further confirm this, we examined the levels of RANTES, eotaxin and SCF in the epithelium and lamina propria (LP) of patients with AR and the change in RANTES+, tryptase+, and CCR3+ cells after nasal allergen challenge (NAC). Methods By ELISA, we examined the levels of RANTES, eotaxin and SCF in homogenized nasal scrapings and LP of AR patients. In AR patients, we performed NAC with house dust mite, took biopsies at 30 min, 6 hrs, and 12 hrs and by immunohistochemistry, we examined the number of tryptase+ RANTES+, eotaxin+ and CCR3+ cells as compared to control. Results The levels of RANTES, but not Eotaxin and SCF was greater in the epithelium than in the LP. At 30 minutes after NAC, tryptase+, RANTES+ and CCR3+ cells were increased in the epithelium. At six hours, tryptase+ cells and RANTES+ cells were still increased in the epithelium but at 12 hrs only an increase in tryptase+ cells was detected. Conclusions Migration of the mast cells in the epithelium occurred as early as 30 min and was paralleled by an increase in CCR3+ and RANTES+ cells. These results further confirm that RANTES may be the critical factor regulating mast migration into the allergic nasal epithelium.

Revisiting the roles of mast cells in allergic rhinitis and its relation to local IgE synthesis.

Mast cells are important effector cells in the immediate-phase allergic reaction. However, in recent years much evidence has accumulated on the versatile role of mast cells in allergic inflammation. The present article is an overview of the roles of mast cells in allergic inflammation, especially in light of the local production of IgE and the IgE-IgE receptor network. Although both nasal mast cells (NMC) and T cells in allergic rhinitics are important sources of Th2-type cytokines like IL-4 and IL-13, and can induce IgE synthesis, we report here that antigen-activated NMC can secrete greater levels of IL-4/IL-13 and induce increased levels of IgE synthesis than antigen-activated nasal T cells. Furthermore, IgE production can occur locally in the nasal mucosa (target organ) and IgE itself can enhance the Fc epsilon RI expression and subsequent mediator release from NMC, thus contributing to the perpetuation of on-going allergic inflammation. Again, mast cells can contribute to the late-phase allergic reaction not only via the upregulation of adhesion molecules like VCAM-1, but also through the interactions of NMC with the extracellular matrix proteins, and interaction of NMC with nasal epithelial cells (NEC). Thus, it is increasingly evident that mast cells are not only important for the genesis of the allergic reaction, but also contribute to the late-phase allergic reaction and on-going allergic inflammation.

Localization of interleukin (IL) ‐4 but not IL‐5 to human mast cell secretory granules by immunoelectron microscopy

Human mast cells synthesize and secrete many cytokines of relevance to the pathogenesis of allergic diseases such as asthma and rhinitis. In particular, interleukin (IL) -4 and IL-5 are likely to play key roles in the development of the inflammatory response that characterizes these diseases. Immunohistochemical studies on human nasal and bronchial mucosal biopsies suggest that IL-4 and IL-5 may be stored preformed in mast cells. To identify whether IL-4 and IL-5 are stored within mast cell secretory granules. We used immunogold electron microscopic analysis on bronchial mucosa and lung parenchyma from resected lung specimens, and a nasal mucosal biopsy from a patient with active allergic rhinitis. Samples were fixed in 4% paraformaldehyde plus 0.5% glutaraldehyde and processed into Lowicryl K4M resin by the 'Progressive Lowering of Temperature' technique. Ultrathin sections were stained immunohistochemically by an indirect immunogold method. Immunoreactivity for IL-4, but not IL-5, was localized to the granules of mast cells in all tissue samples. IL-5 was localized to the matrix of eosinophil granules in these samples, but neither cytokine was detected in T cells. IL-4 immunoreactivity increased in the granules of mast cells 24 h after immunoglobulin (Ig) E-dependent activation (mean 17.5 +/- 1.4 gold particles per granule) compared with nonactivated mast cells (mean 6.8 +/- 0.8 gold particles per granule, P < 0.001), suggesting replenishment of stores by newly generated protein. Immunoreactive IL-5 remained undetectable in mast cells 24 h after activation, a time point at which they are known to secrete large quantities of this cytokine. Human mast cells store IL-4 within the matrix of their granules. Very few, if any, lung or nasal mast cells store IL-5. A store of preformed IL-4 within mast cell granules is likely to have an important influence during the initiation and maintenance of the allergic immunological response.

Toxicity of drugs used for treatment of rhinitis: a reminder to the otorhinolaryngologist.

We retrospectively studied files on toxicity of drugs used for treatment of rhinitis (nasal antihistamines, oral antihistamines, nasal vasoconstrictors, oral decongestants, nasal corticosteroids, nasal anticholinergic agent, nasal mast cell stabilizer, and respiratory antigen preparations for oral use) that occurred in São Paulo, Brazil, from 1 July 1996 to 30 June 1998. There were 823 cases of toxicity by these agents, with a predominance of oral decongestants (in combination with antihistamines) (53.4%). There was a significant incidence of toxicity within children aged 1 to 4 years (P < 0.05) and a preponderance among males aged 5-9 years and females aged 10-39 years. Accidental intake of medicines accounted for the majority of toxicity cases (57.2%).

206 Influence of stem cell factor on the distribution and phenotypes of nasal mast cells

206 Influence of stem cell factor on the distribution and phenotypes of nasal mast cells

134 Nasal mast cells in perennial allergic rhinitics express increased levels of β1 integrins

134 Nasal mast cells in perennial allergic rhinitics express increased levels of β1 integrins

444 Increased expression of FcεRI, IL-4, and IL-13 in nasal mast cells of seasonal allergic rhinitics.

444 Increased expression of FcεRI, IL-4, and IL-13 in nasal mast cells of seasonal allergic rhinitics.

Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the Fc epsilonRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells.

Cross-linking of allergen specific IgE bound to the high affinity IgE receptor (FC epsilonRI) on the surface of mast cells with multivalent allergens results in the release of both pre-formed and newly generated mediators, and in the manifestation of allergic symptoms. The expression of Fc epsilonRI, and the synthesis of IgE are therefore critical for the development of allergic diseases. In this study, we report that nasal mast cells (NMC) from patients with perennial allergic rhinitis (PAR) expressed significantly greater levels of the Fc epsilonRI, CD40L, IL-4, and IL-13 as compared to NMC from patients with chronic infective rhinitis (CIR). The level of Fc epsilonRI expression in NMC of PAR patients strongly correlated with the levels of serum total (r = 0.8, P < 0.003) and specific IgE (r = 0.89, P < 0.0004) antibodies. In addition, stimulation of NMC with IL-4, upregulated the Fc epsilonRIalpha chain expression both at the protein and mRNA levels, as detected by flow cytometry and reverse transcriptase-polymerase chain reaction. Furthermore, NMC from PAR, but not CIR, patients induced IgE synthesis by purified B cells in the presence of Der fII (mite antigen). These results suggest novel and critical roles for mast cells in promoting the allergic reaction through the increased expression of Fc epsilonRI and by enhancing and amplifying the IgE production, within the local microenvironment.