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Concept: Mastocytosis

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Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.Molecular Psychiatry advance online publication, 26 January 2016; doi:10.1038/mp.2015.216.

Concepts: Immune system, Asthma, Mast cell, Serotonin, Mastocytosis, Eicosanoid, Leukotriene, Beck Depression Inventory

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Diagnosis of mast cell activation disease (MCAD), i.e. systemic mastocytosis (SM) and idiopathic systemic mast cell activation syndrome (MCAS), usually requires demonstration of increased mast cell (MC) mediator release. Since only a few MC mediators are currently established as biomarkers of MCAD, the sensitivity of plasma heparin level (pHL) as an indicator of increased MC activation was compared with that of serum tryptase, chromogranin A and urinary N-methylhistamine levels in 257 MCAD patients. Basal pHL had a sensitivity of 41% in MCAS patients and 27% in SM patients. Non-pharmacologic stimulation of MC degranulation by obstruction of venous flow for 10 minutes increased the sensitivity of pHL in MCAS patients to 59% and in SM patients to 47%. In MCAS patients tryptase, chromogranin A, and N-methylhistamine levels exhibited low sensitivities (10%, 12%, and 22%, respectively), whereas sensitivities for SM were higher (73%, 63%, and 43%, respectively). Taken together, these data suggest pHL appears more sensitive than the other mediators for detecting systemic MC activity in patients with MCAS. The simple, brief venous occlusion test appears to be a useful indicator of the presence of pathologically irritable MCs, at least in the obstructed compartment of the body.

Concepts: Immune system, Cell biology, Mast cell, Vein, Heparin, Anaphylaxis, Mastocytosis, Degranulation

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IgE antibodies and mast cells play critical roles in the establishment of allergic responses to food antigens. Curcumin, the active ingredient of the curry spice turmeric, has anti-inflammatory properties, and thus may have the capacity to regulate Th2 cells and mucosal mast cell function during allergic responses. We assessed whether curcumin ingestion during oral allergen exposure can modulate the development of food allergy using a murine model of ovalbumin (OVA)-induced intestinal anaphylaxis. Herein, we demonstrate that frequent ingestion of curcumin during oral OVA exposure inhibits the development of mastocytosis and intestinal anaphylaxis in OVA-challenged allergic mice. Intragastric (i.g.) exposure to OVA in sensitized BALB/c mice induced a robust IgE-mediated response accompanied by enhanced OVA-IgE levels, intestinal mastocytosis, elevated serum mMCP-1, and acute diarrhea. In contrast, mice exposed to oral curcumin throughout the experimental regimen appeared to be normal and did not exhibit intense allergic diarrhea or a significant enhancement of OVA-IgE and intestinal mast cell expansion and activation. Furthermore, allergic diarrhea, mast cell activation and expansion, and Th2 responses were also suppressed in mice exposed to curcumin during the OVA-challenge phase alone, despite the presence of elevated levels of OVA-IgE, suggesting that curcumin may have a direct suppressive effect on intestinal mast cell activation and reverse food allergy symptoms in allergen-sensitized individuals. This was confirmed by observations that curcumin attenuated the expansion of both adoptively transferred bone marrow-derived mast cells (BMMCs), and inhibited their survival and activation during cell culture. Finally, the suppression of intestinal anaphylaxis by curcumin was directly linked with the inhibition of NF-κB activation in curcumin-treated allergic mice, and curcumin inhibited the phosphorylation of the p65 subunit of NF-κB in BMMCs. In summary, our data demonstrates a protective role for curcumin during allergic responses to food antigens, suggesting that frequent ingestion of this spice may modulate the outcome of disease in susceptible individuals.

Concepts: Immune system, Asthma, Cell biology, Immunoglobulin E, Allergy, Mast cell, Anaphylaxis, Mastocytosis

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To the Editor: Theoharides et al. (July 9 issue)(1) propose that underlying systemic mastocytosis should be considered in patients who have repeated episodes of anaphylaxis, even in the absence of clinical features of mast-cell hyperactivity. They also emphasize important triggers for anaphylaxis in such patients, including stings from insects of the order Hymenoptera. We would also suggest that systemic mastocytosis should be considered in patients in whom perioperative anaphylaxis develops, particularly in patients who have repeated episodes and who have received structurally unrelated drugs. Indeed, drug triggers are estimated to account for 5 to 25% of cases of anaphylaxis in . . .

Concepts: Immune system, Pharmacology, Drug, Mast cell, Illness, Anaphylaxis, Mastocytosis, Hymenoptera

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Counting mast cells in gastrointestinal (GI) mucosal biopsies is becoming an increasingly common practice. The primary reason for this exercise is to evaluate for possible involvement by systemic mastocytosis (SM). However, the features of mastocytosis in GI biopsies are not well described. In addition, recent studies have suggested that increased mast cells may be involved in the pathogenesis of some cases of diarrhea-predominant irritable bowel syndrome (IBS); the term “mastocytic enterocolitis” has been proposed for such cases. As the baseline mast cell density in colonic biopsies from normal patients has not been established in large cohorts, there is no widely accepted threshold for what constitutes increased mucosal mast cells. The aims of this study were (1) to determine the utility of GI biopsies for the diagnosis of SM, (2) to characterize the clinical, histologic, and immunohistochemical features of mastocytosis in the GI tract, (3) to determine mast cell density in normal colonic mucosa from a large cohort of asymptomatic patients, and (4) to compare these findings with those from patients with diarrhea-predominant IBS. Twenty-four patients with SM involving the GI tract, 100 asymptomatic patients, and 100 patients with IBS (the latter 2 groups with histologically normal colonic biopsies) were included. For the mastocytosis group, 107 biopsies (70 involved by mastocytosis; 67 mucosal, 3 liver) from 20 women and 4 men were evaluated (median age 59 y). The most commonly involved site was the colon (19 patients, 95%), followed by ileum (86%), duodenum (80%), and stomach (54%). In 16 cases (67%), the first diagnosis of SM was made on the basis of GI biopsies. Seventeen patients had documented cutaneous mastocytosis. Fifteen of 17 patients who underwent bone marrow biopsy had marrow involvement by SM. Eighteen patients had indolent disease, and 6 had aggressive disease (including all 3 with liver involvement). The most common GI symptom was diarrhea, followed by abdominal pain, nausea, weight loss, bloating, vomiting, or reflux. Liver disease presented with hepatomegaly and ascites. Endoscopic abnormalities (observed in 62%) included erythema, granularity, and nodules. Histologically, involved biopsies were characterized by infiltrates of ovoid to spindle-shaped mast cells in aggregates or sheets in the lamina propria, sometimes forming a confluent band underneath the surface epithelium; 25% of biopsies had only focal involvement (single aggregate). Prominent eosinophils were seen in 44% of involved colonic/ileal biopsies and 16% of duodenal biopsies. Mast cells were highlighted by diffuse membranous staining for KIT and CD25. In the nonmastocytosis groups, all biopsies contained singly dispersed mast cells with no aggregates. The mean highest mast cell counts (in a single high-power field) for asymptomatic patients and IBS patients were 26 (range, 11 to 55) and 30 (range, 13 to 59), respectively. In summary, GI (especially colonic) biopsies can establish a diagnosis of SM in patients with GI symptoms. GI involvement is usually subtle and is often associated with prominent eosinophils, which may obscure the mast cell infiltrate. KIT and CD25 are invaluable markers for the diagnosis. Mast cell density in colonic mucosa from asymptomatic patients is highly variable. Although patients with diarrhea-predominant IBS on average have mildly increased mast cells, the overlap in range with that of control patients is too great for this difference to be clinically useful. These findings argue against the utility of counting GI mucosal mast cell in patients with chronic diarrhea.

Concepts: Immune system, White blood cell, Digestive system, Mast cell, Gastroenterology, Irritable bowel syndrome, Digestion, Mastocytosis

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Activation of mast cells (MCs) can be achieved by the high-affinity receptor for IgE (FcepsilonRI) as well as by additional receptors such as the lipopolysaccharide (LPS) receptor and the receptor tyrosine kinase Kit (stem cell factor [SCF] receptor). Thus, pharmacological interventions which stabilize MCs in response to different receptors would be preferable in diseases with pathological systemic MC activation such as systemic mastocytosis. 1,4-Benzodiazepines (BDZs) have been reported to suppress MC effector functions. In the present study, our aim was to analyze molecularly the effects of BDZs on MC activation by comparison of the effects of the two BDZs Ro5-4864 and clonazepam, which markedly differ in their affinities for the archetypical BDZ recognition sites, i.e., the GABAA receptor and TSPO (previously termed peripheral-type BDZ receptor). Ro5-4864 is a selective agonist at TSPO, whereas clonazepam is a selective agonist at the GABAA receptor. Ro5-4864 suppressed pro-inflammatory MC effector functions in response to antigen (Ag) (degranulation/cytokine production) and LPS and SCF (cytokine production), whereas clonazepam was inactive. Signaling pathway analyses revealed inhibitory effects of Ro5-4864 on Ag-triggered production of reactive oxygen species, calcium mobilization and activation of different downstream kinases. The initial activation of Src family kinases was attenuated by Ro5-4864 offering a molecular explanation for the observed impacts on various downstream signaling elements. In conclusion, BDZs structurally related to Ro5-4864 might serve as multifunctional MC stabilizers without the sedative effect of GABAA receptor-interacting BDZs.

Concepts: Immune system, Protein, Signal transduction, Cell biology, Mast cell, Protein kinase, Tyrosine kinase, Mastocytosis

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Mast cell activation (MCA) occurs in a number of different clinical conditions, including IgE-dependent allergies, other inflammatory reactions, and mastocytosis. MCA-related symptoms may be mild, moderate, severe, or even life-threatening. The severity of MCA depends on a number of different factors, including genetic predisposition, the number and releasability of mast cells involved in the reaction, the type of allergen, presence of specific IgE, and presence of certain comorbidities. In severe reactions, MCA can be documented by a substantial increase in the serum tryptase level above baseline. When symptoms are recurrent, are accompanied by an increase in mast cell-derived mediators in biological fluids, and are responsive to treatment with mast cell-stabilizing or mediator-targeting drugs, the diagnosis of mast cell activation syndrome (MCAS) is appropriate. Based on the underlying condition, these patients can further be classified into i) primary MCAS where KIT-mutated, clonal mast cells are detected, ii) secondary MCAS where an underlying inflammatory disease, often in the form of an IgE-dependent allergy, but no KIT-mutated mast cells, is found, and iii) idiopathic MCAS, where neither an allergy or other underlying disease, nor KIT-mutated mast cells are detectable. It is important to note that in many patients with MCAS, several different factors act together to lead to severe or even life-threatening anaphylaxis. Detailed knowledge about the pathogenesis and complexity of MCAS, and thus establishing the exact final diagnosis, may greatly help in the management and therapy of these patients.

Concepts: Immune system, Asthma, Cell biology, Immunoglobulin E, Allergy, Mast cell, Anaphylaxis, Mastocytosis

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Anemia, inflammation, and oxidative stress are interconnected. Erythrocytes are continuously exposed to oxidative stress, normally and during inflammatory diseases. Systemic mastocytosis and genetic depletion of mast cells affect anemia. In the present study, a direct role for mast cells in clearance of erythrocytes was explored. We show, for the first time, direct phagocytosis of opsonized as well as oxidatively damaged erythrocytes in vitro by mast cell lines, bone marrow derived mast cells (BMMCs) and in vivo by murine peritoneal mast cells. Also, activated mast cells, as may be present in inflammatory conditions, showed a significantly higher uptake of oxidatively damaged erythrocytes than resting mast cells. This suggests the involvement of mast cells in erythrocyte clearance during oxidative stress or inflammatory disorders. Partial inhibition of phagocytosis by various inhibitors indicated that this process may be controlled by several pathways. Our study provides important evidence for a scavenging role for mast cells in anemia due to inflammation and oxidative stress.

Concepts: Immune system, Inflammation, Red blood cell, Bone marrow, Cell biology, Mast cell, Mastocytosis, Eicosanoid

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The signaling lymphocytic activation molecule family member 8 (SLAMF8)/CD353 is a member of the CD2 family of proteins. Its ligand has not been identified. SLAMF8 is expressed by macrophages and suppresses cellular functions. No study has yet explored SLAMF8 expression or function in human mastocytosis, which features oncogenic KIT-mediated proliferation of human mast cells. SLAMF8 protein was expressed in human mastocytosis cells, immunohistochemically. SLAMF8 expression was also evident in the human mast cell lines, HMC1.2 (expressing oncogenic KIT) and LAD2 (expressing wild-type KIT) cells. SLAMF8-knockdown significantly reduced the KIT-mediated growth of HMC1.2 cells but not that of LAD2 cells. SLAMF8-knockdown HMC1.2 cells exhibited significant attenuation of SHP-2 activation and oncogenic KIT-mediated RAS-RAF-ERK signaling. An interaction between SLAMF8 and SHP-2 was confirmed in HMC1.2 cells and all pathological mastocytosis specimens examined (19 of 19 cases, 100%). Thus, SLAMF8 is involved in oncogenic KIT-mediated RAS-RAF-ERK signaling and the subsequent growth of human neoplastic mast cells mediated by SHP-2. SLAMF8 is a possible therapeutic target in human mastocytosis patients. This article is protected by copyright. All rights reserved.

Concepts: Immune system, White blood cell, Protein, Gene, Cell, Cell biology, Mast cell, Mastocytosis

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Most cases of paediatric cutaneous mastocytosis (CM) occur before the age of 2 years, and regression occurs in only 67% of children. Given the absence of any specific therapy, CM is usually treated symptomatically. A few publications have reported the beneficial effect of calcineurin inhibitors for CM.

Concepts: The Age, Mastocytosis, Calcineurin, Pimecrolimus