Lack Of Mast Cells Research Articles

Myeloproliferative Hypereosinophilic Syndrome with Concomitant Ischemic Events

▪Background:Eosinophils are versatile reactionary cells that play a key role in the inflammatory response. Excessive proliferation and aggregation of eosinophils have been implicated in the pathogenesis of ischemic neurologic and cardiac events. We present a rare case of hypereosinophilic syndrome (HES) in a patient hospitalized for simultaneous acute cerebrovascular accident (CVA) and acute coronary syndrome.Case:A 53-year-old male with past medical history of hypertension and diabetes mellitus presented with new onset bifrontal headache, right arm numbness and apraxia, and concurrent typical angina. On physical examination, he had small non-tender raised nodules on the bilateral upper and lower limbs. MRI of the brain demonstrated multifocal infarcts in a watershed distribution. Biochemical investigation revealed rising troponins. Splenomegaly of 16.4 cm was found on CT imaging. He was admitted for management of acute CVA and non-ST segment elevation myocardial infarction (NSTEMI). Complete blood count (CBC) revealed leukocytosis (34.4 K/mcL) with an eosinophilia of 85% and an absolute eosinophil count (AEC) of 29.2 x 10 3 eosinophils/µL. Serum tryptase was 29.2 µg/L. The patient was started on a high dose steroid with subsequent resolution of his neurologic and cardiac symptoms. Due to high suspicion for HES, FISH panel and bone marrow biopsy were performed. A small focus of marrow on his biopsy showed abundant eosinophils and bland spindle cells (>15 mast cells in aggregate). FISH panel was positive for 4q12 rearrangement, consistent with a FIP1L1/PDGFRA fusion mutation. Skin biopsy of his lesions demonstrated superficial and deep inflammation with eosinophils. He was diagnosed with myeloproliferative HES with features of mastocytosis and started on imatinib.Discussion:The defining features of HES consist of eosinophilia greater than 1500/µL for greater than 6 months with evidence of eosinophil induced tissue infiltration and injury. The ability of eosinophils to induce pathologic outcomes is influenced by a variety of parameters, including the number of eosinophils present, their location, and the degree of activation. Published data suggests that neurologic and cardiac ischemic events occur in HES patients with a higher leukocyte count and AEC than what we present with in this case. Our patient meets the main lab criteria of HES and our case highlights that simultaneous clinical manifestations can occur in the absence of markedly elevated peripheral eosinophilia. As with most cases involving unexplained hypereosinophilia, a wide range of diagnostic testing was necessary. The presence of a PDGFRA fusion mutation established a clonal disorder, supporting the diagnosis of myeloproliferative HES variant. The presence of eosinophils and the lack of mast cells on skin biopsy further supports myeloproliferative HES variant rather than a true systemic mastocytosis. Despite recent advances in molecular and immunologic therapies, treatment for HES remains challenging due to the wide variety of etiological classifications necessitating targeted treatments. At the time of submission, KIT mutation analysis is pending. Identification of a KIT D816V mutation would support use of midostaurin or the recently approved avapritinib for treatment of overlap syndrome. DisclosuresNo relevant conflicts of interest to declare.

Mast cell-derived serotonin enhances methacholine-induced airway hyperresponsiveness in house dust mite-induced experimental asthma.

Airway hyperresponsiveness (AHR) is a feature of asthma in which airways are hyperreactive to stimuli causing extensive airway narrowing. Methacholine provocations assess AHR in asthma patients mainly by direct stimulation of smooth muscle cells. Using in vivo mouse models, mast cells have been implicated in AHR, but the mechanism behind has remained unknown. Cpa3Cre/+ mice, which lack mast cells, were used to assess the role of mast cells in house dust mite (HDM)-induced experimental asthma. Effects of methacholine in presence or absence of ketanserin were assessed on lung function and in lung mast cells in vitro. Airway inflammation, mast cell accumulation and activation, smooth muscle proliferation, and HDM-induced bronchoconstriction were evaluated. Repeated intranasal HDM sensitization induced allergic airway inflammation associated with accumulation and activation of lung mast cells. Lack of mast cells, absence of activating Fc-receptors, or antagonizing serotonin (5-HT)2A receptors abolished HDM-induced trachea contractions. HDM-sensitized mice lacking mast cells had diminished lung-associated 5-HT levels, reduced AHR and methacholine-induced airway contraction, while blocking 5-HT2A receptors in wild types eliminated AHR, implying that mast cells contribute to AHR by releasing 5-HT. Primary mouse and human lung mast cells express muscarinic M3 receptors. Mouse lung mast cells store 5-HT intracellularly, and methacholine induces release of 5-HT from lung-derived mouse mast cells and Ca2+ flux in human LAD-2 mast cells. Methacholine activates mast cells to release 5-HT, which by acting on 5-HT2A receptors enhances bronchoconstriction and AHR. Thus, M3-directed asthma treatments like tiotropium may also act by targeting mast cells.

Decreased Presence of Mast Cells in the Bursa Premacularis of Proliferative Diabetic Retinopathy

Introduction: We previously reported that the intravitreal activities of chymase and tryptase were more increased in the patients with macular hole (MH) and epiretinal membrane (ERM) than in those with proliferative diabetic retinopathy (PDR) and that the source of these serine proteases might be mast cells in the bursa premacularis (BPM). The purpose of this study was to compare the density of mast cells in BPM samples obtained from MH, ERM, and PDR patients. Methods: BPM and vitreous core samples were first collected during vitrectomy from eyes afflicted with vitreoretinal diseases (MH: 6 eyes, ERM: 3 eyes, and PDR: 9 eyes), and then were stained with hematoxylin, toluidine blue, antibodies against chymase and tryptase, and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay kit. Results: Hematoxylin nuclear staining showed fewer positive-staining cells in the BPM samples obtained from PDR patients than in those obtained from MH and ERM patients. Toluidine blue staining of the BPM revealed metachromasia in the mast cells of the patients with MH and ERM, but not those of the patients with PDR. In addition, immunostaining using anti-chymase and anti-tryptase antibodies showed that the BPM samples were more intensely stained than the vitreous core samples from the patients with MH and ERM and that both tissue samples were poorly stained in the patients with PDR. The apoptotic cells were more frequently observed in the BPM samples from patients with MH than in those from patients with PDR. Conclusions: These findings indicated that lower activities of chymase and tryptase in the vitreous of PDR patients appeared to be attributable to the decreased presence of mast cells in the BPM. The lack of mast cells in the BPM might be related to the pathogenesis of PDR.

No Role for Mast Cells in Obesity-Related Metabolic Dysregulation.

Obesity-related adipose tissue (AT) inflammation that promotes metabolic dysregulation is associated with increased AT mast cell numbers. Mast cells are potent inducers of inflammatory responses and could potentially contribute to obesity-induced AT inflammation and metabolic dysregulation. Conflicting findings were reported on obesity-related metabolic dysfunction in mast cell-deficient mice, thus creating a controversy that has not been resolved to date. Whereas traditional Kit hypomorphic mast cell-deficient strains featured reduced diet-induced obesity and diabetes, a Kit-independent model of mast cell deficiency, Cpa3Cre/+ mice, displayed no alterations in obesity and insulin sensitivity. Herein, we analyzed diet-induced obesity in Mcpt5-Cre R-DTA mice, in which the lack of mast cells is caused by a principle different from mast cell deficiency in Cpa3Cre/+ mice or Kit mutations. We observed no difference between mast cell-deficient and -proficient mice in diet-induced obesity with regards to weight gain, glucose tolerance, insulin resistance, metabolic parameters, hepatic steatosis, and AT or liver inflammation. We conclude that mast cells play no essential role in obesity and related pathologies.

Hematopoietic Kit Deficiency, rather than Lack of Mast Cells, Protects Mice from Obesity and Insulin Resistance

Obesity, insulin resistance, and related pathologies are associated with immune-mediated chronic inflammation. Kit mutant mice are protected from diet-induced obesity and associated co-morbidities, and this phenotype has previously been attributed to their lack of mast cells. We performed a comprehensive metabolic analysis of Kit-dependent Kit(W/Wv) andKit-independent Cpa3(Cre/+) mast-cell-deficient mouse strains, employing diet-induced or genetic (Lep(Ob/Ob) background) models of obesity. Our results show that mast cell deficiency, in the absence of Kit mutations, plays no role in the regulation of weight gain or insulin resistance. Moreover, we provide evidence that the metabolic phenotype observed in Kit mutant mice, while independent of mast cells, is immune regulated. Our data underscore the value of definitive mast cell deficiency models to conclusively test the involvement of this enigmatic cell in immune-mediated pathologies and identify Kit as a key hematopoietic factor in the pathogenesis of metabolic syndrome.

Type 1 diabetes in NOD mice unaffected by mast cell deficiency.

Mast cells have been invoked as important players in immune responses associated with autoimmune diseases. Based on in vitro studies, or in vivo through the use of Kit mutant mice, mast cells have been suggested to play immunological roles in direct antigen presentation to both CD4(+) and CD8(+) T cells, in the regulation of T-cell and dendritic cell migration to lymph nodes, and in Th1 versus Th2 polarization, all of which could significantly impact the immune response against self-antigens in autoimmune disease, including type 1 diabetes (T1D). Until now, the role of mast cells in the onset and incidence of T1D has only been indirectly tested through the use of low-specificity mast cell inhibitors and activators, and published studies reported contrasting results. Our three laboratories have generated independently two strains of mast cell-deficient nonobese diabetic (NOD) mice, NOD.Cpa3(Cre/+) (Heidelberg) and NOD.Kit(W-sh/W-sh) (Leuven and Boston), to address the effects of mast cell deficiency on the development of T1D in the NOD strain. Our collective data demonstrate that both incidence and progression of T1D in NOD mice are independent of mast cells. Moreover, analysis of pancreatic lymph node cells indicated that lack of mast cells has no discernible effect on the autoimmune response, which involves both innate and adaptive immune components. Our results demonstrate that mast cells are not involved in T1D in the NOD strain, making their role in this process nonessential and excluding them as potential therapeutic targets.

Erratum

Journal of Fish DiseasesVolume 34, Issue 4 p. 331-331 Free Access Erratum This article corrects the following: Host response to the chondracanthid copepod Chondracanthus goldsmidi, a gill parasite of the striped trumpeter, Latris lineata (Forster), in Tasmania M Andrews, S Battaglene, J Cobcroft, M Adams, E Noga, B Nowak, Volume 33Issue 3Journal of Fish Diseases pages: 211-220 First Published online: November 12, 2009 First published: 08 March 2011 https://doi.org/10.1111/j.1365-2761.2011.01240.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Host response to the chondracanthid copepod Chondracanthus goldsmidi, a gill parasite of the striped trumpeter, Latris lineata (Forster), in Tasmania M Andrews, S Battaglene, J Cobcroft, E Noga, B Nowak This article was published despite containing errors. Paragraph 2 on page 218 should have appeared as below. ‘Given the lack of mast cells in healthy tissue, their abundance in damaged tissue (such as the PLL), and expression of piscidin in the mast cells, strongly suggests that these cells are an important component of the host defence against this parasite in striped trumpeter. The staining methods used identified the expression of piscidin-positive mast cells in the affected area with none identified in unaffected areas. To find unstained mast cells in unaffected areas is unexpected as these cells would not be responding to a stimulus (e.g. disruption caused by an attached parasite).’ Only mast cells were positive for piscidin. The authors sincerely apologize for these errors. We would like to thank Dr Bahram Defzuli for alerting us to these errors. Reference Andrews M., Battaglene S., Cobcroft J., Noga E. & Nowak B. (2010) Host response to the chondracanthid copepod Chondracanthus goldsmidi, a gill parasite of the striped trumpeter, Latris lineata (Forster), in Tasmania. Journal of Fish Diseases 33, 211– 220. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Volume34, Issue4April 2011Pages 331-331 ReferencesRelatedInformation

Lack of c-kit receptor promotes mammary tumors in N-nitrosomethylurea-treated Ws/Ws rats

Backgroundc-kit is expressed in various cell types during development and it has been linked to the promotion of cellular migration, proliferation and/or survival of melanoblasts, hematopoietic progenitors and primordial germ cells. Several reports have proposed a role for the c-kit gene on carcinogenesis. Gain-of-function mutations are associated with diseases such as mastocytosis and gastrointestinal stromal tumors among others. However, very little is known about pathologies associated with loss-of-function mutations. Regarding breast cancer, c-kit protein and mRNA are highly expressed in normal breast but their expression decreases or is absent in the presence of breast cancer. We studied the role of c-kit in mammary carcinogenesis in the Ws/Ws rats carrying spontaneous lack-of-function mutation in the c-kit gene. Fifty day-old virgin female Ws/Ws rats and their wild type counterparts were injected with either 50 mg/kg body weight of the chemical carcinogen N-nitrosomethylurea or with vehicle. The animals were followed-up for 6 months. Fisher 344 rats were used as positive controls for tumor development.ResultsEleven weeks after treatment, palpable tumors were detected in the Ws/Ws rats. The tumor incidence was 80% in Ws/Ws rats, while no tumors were observed in the wild type rats (p = 0.006). Our data show that the lack of c-kit is permissive for the development of mammary tumor in Ws/Ws rats treated with carcinogen.ConclusionWe conclude that the lack of c-kit may contribute to an imbalanced homeostatic state in the mammary gland either by affecting signaling between stroma and epithelium, or through the lack of mast cells.

IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells

Constitutive expression of IL9 in the lungs of transgenic (Tg) mice resulted in an asthma-like phenotype consisting of lymphocytic and eosinophilic lung inflammation, mucus hypersecretion and mast cell hyperplasia. Several T(h)2 cytokines including IL4, IL5 and IL13 were expressed in the lung in response to Tg IL9. IL13 was absolutely necessary for the development of lung pathology. To understand how IL9 induces IL13-dependent lung inflammation and mucus production, we sought the IL13-producing cells. Surprisingly, we found that the absence of T cells and B cells in recombinase-activating gene 1 (RAG1)-deficient IL9 Tg mice enhanced lung inflammation and dramatically enhanced IL13 production. In addition, the lack of mast cells or eosinophils in IL9 Tg mice did not affect IL13 levels in the lung. In situ hybridization for IL13 on lung sections from RAG1-/- IL9 Tg mice revealed that airway epithelial cells were the major IL13-producing cell type. Our results implicate the lung epithelium as a potentially important source of inflammatory cytokines in asthma.

An essential role of mast cells in the development of airway hyperresponsiveness in a murine asthma model.

Immunization of BALB/c mice with alum-adsorbed OVA, followed by three bronchoprovocations with aerosolized OVA, resulted in the development of airway hyperresponsiveness (AHR) and allergic inflammation in the lung accompanied by severe infiltration of eosinophils into airways. In this murine asthma model, administration of monoclonal anti-IL-5 Ab before each Ag challenge markedly inhibited airway eosinophilia, but the treatment did not affect the development of AHR. Immunization and aerosol challenges with OVA following the same protocol failed to induce AHR in the mast cell-deficient W/Wv mice, but induced AHR in their congenic littermates, i.e., WBB6F1 (+/+) mice. No significant difference was found between the W/Wv mice and +/+ mice with respect to the IgE and IgG1 anti-OVA Ab responses and to the airway eosinophilia after Ag provocations. It was also found that reconstitution of W/Wv mice with bone marrow-derived mast cells cultured from normal littermates restored the capacity of developing Ag-induced AHR, indicating that lack of mast cells was responsible for the failure of W/Wv mice to develop Ag-induced AHR under the experimental conditions. However, the OVA-immunized W/Wv mice developed AHR by increasing the frequency and Ag dose of bronchoprovocations. The results suggested that AHR could be developed by two distinct cellular mechanisms. One would go through mast cell activation and the other is IgE/mast cell independent but an eosinophil/IL-5-dependent mechanism.

Decreased Production of Mast Cells in S1/S1dAnemic Mice

AbstractProduction of tissue mast cells was evaluated in genetically anemic mice of S1/S1dgenotype. In the skin of adult S1/S1d mice the numbers of mast cells per centimeter were less than 1 % of the numbers observed in congenic + /+ mice, as reported for adult W/Wv mice. Any mast cells were scarcely detected in other tissues in both S1/S1d and W/Wv mice. Since bone marrow cell transplantation from S1/S1d mice increases the numbers of mast cells in the skin, stomach, and mesentery of W/Wv mice, the bone marrow of S1/S1d mice would seem to contain precursors of mast cells. These precursor cells may arrive at peripheral tissues, as is suggested by the observation that the numbers of mast cells increase in the skin of W/Wv mice grafted to S1/S1drecipients. The lack of mast cells in the S1/S1d mice seems to be due to a tissue defect that locally induces the differentiation of mast cells, as is indicated by the observation that bone marrow transplantation from + /+ donors does not increase the numbers of mast cells in the skin, stomach, and mesentery of S1/S1d mice and the observation that mast cells do not develop in skin of S1/S1d mice grafted to + /+ recipients.