ABSTRACT
ABSTRACT: Systemic mastocytosis (SM) is defined by the expansion and accumulation of neoplastic mast cells (MCs) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor-independent KIT activation and accumulation of MC. Tumor necrosis factor α (TNF) is a proapoptotic and inflammatory cytokine that has been implicated in the clonal selection of neoplastic cells. We found that KIT D816V increases the expression and secretion of TNF. TNF expression in neoplastic MCs is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation in human BM cells, whereas KIT D816V+ cells are less susceptible to the cytokine, potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of samples from patients with SM. TNF serum levels are significantly elevated in patients with SM and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM.
Subject(s)
Mastocytosis, Systemic , Mastocytosis , Humans , Animals , Mice , Tumor Necrosis Factor-alpha , Survivin/genetics , Prognosis , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/genetics , CytokinesABSTRACT
Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient's blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.
Subject(s)
Hepatitis A Virus Cellular Receptor 2 , Inflammatory Bowel Diseases , Stem Cell Transplantation , Humans , Cytokines/metabolism , Hepatitis A Virus Cellular Receptor 2/genetics , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/etiology , Intestinal Mucosa , Stem Cell Transplantation/adverse effectsABSTRACT
BACKGROUND: Epidemiologic data on occupational anaphylaxis is scarce, and there is a need of more knowledge about work-related anaphylactic episodes. METHODS: Based on the data of the Anaphylaxis Registry, we identified cases related to occupational exposure and analyzed the elicitors, demographics, severity of clinical reaction and management. RESULTS: Since 2017, 5851 cases with an information about the occupational relation of the anaphylactic episode were registered whereby 225 (3.8%) were assigned to be caused by an occupational allergen. The vast majority of these occupational anaphylaxis cases were caused by insects (n = 186, 82.7%) followed by food (n = 27, 12.0%) and drugs (n = 8, 3.6%). Latex elicited occupational anaphylaxis in only two cases. Beekeepers, gardeners, farmers, and individuals working in professions associated with food handling, for example, employees in restaurants, bakery, pastry, and cooks were most frequently affected. The comparison of the occupational insect venom-induced anaphylaxis to a group of non-occupational insect anaphylaxis in adults (n = 1842) revealed a significant younger age in occupational anaphylaxis (46 vs. 53 years), a predominance of bee-induced cases (38% vs. 17%), and a higher rate of venom immunotherapy in a primary care setting (3.3% vs. 1.3%, p = .044). In the occupational- versus non-occupational adults with food-induced anaphylaxis atopic dermatitis as concomitant atopic disease was observed more frequently (n = 486; 20% vs. 10%), although this was not significant. CONCLUSION: Our data demonstrate the impact of venom allergy in work-related anaphylaxis. Foods and drugs are less frequently elicitors, and latex-induced occupational anaphylaxis was rare. More data are needed to determine risk factors associated with occupational anaphylaxis.
Subject(s)
Anaphylaxis , Arthropod Venoms , Adult , Humans , Bees , Animals , Anaphylaxis/etiology , Anaphylaxis/chemically induced , Latex , Risk Factors , Arthropod Venoms/adverse effects , Allergens , Insecta , RegistriesABSTRACT
BACKGROUND: Ambient pollen exposure causes nasal, ocular, and pulmonary symptoms in allergic individuals, but the shape of the exposure-response association is not well characterized. We evaluated this association and determined (1) whether symptom severity differs between subpopulations; (2) how the association changes over the course of the pollen season; and (3) which pollen exposure time lags affect symptoms. METHODS: Adult study participants (n = 396) repeatedly scored severity of nasal, ocular, and pulmonary allergic symptoms, resulting in three composite symptom scores. We calculated hourly individually relevant pollen exposure to seven allergenic plants (alder, ash, birch, hazel, grasses, mugwort, and ragweed) considering personal sensitization and exposure time lags of up to 96 h. We fitted generalized additive mixed models, with a random personal intercept, adjusting for weather and air pollution as potential time-varying confounders. RESULTS: We identified a clear nonlinear positive association between pollen exposure and ocular and nasal symptom severity in the pollen allergy group: Symptom severity increased steeply with increasing exposure initially, but attenuated beyond approximately 80 pollen/m3. We found no evidence of an exposure threshold, below which no symptoms occur. While recent pollen exposure in the last approximately 5 h affected symptoms most, associations lingered for up to 60 h. Grass pollen exposure (compared to tree pollen) and younger age (18-30 years, as opposed to 30-65 years) were both associated with higher nasal and ocular symptom severity. CONCLUSIONS: The lack of a threshold and attenuated dose-response curve may have implications for pollen warning systems, which may be revised to include multiday pollen concentrations in the future.
Subject(s)
Allergens , Environmental Exposure , Pollen , Rhinitis, Allergic, Seasonal , Severity of Illness Index , Humans , Pollen/immunology , Rhinitis, Allergic, Seasonal/immunology , Rhinitis, Allergic, Seasonal/diagnosis , Rhinitis, Allergic, Seasonal/etiology , Adult , Male , Female , Allergens/immunology , Middle Aged , Environmental Exposure/adverse effects , Young Adult , Aged , Seasons , Adolescent , Symptom AssessmentABSTRACT
BACKGROUND: Abrocitinib efficacy by comorbidity status in patients with moderate-to-severe atopic dermatitis (AD) has not been previously assessed. This post hoc analysis evaluated the efficacy and safety of abrocitinib in patients with AD and allergic comorbidities. METHODS: Data were pooled from patients who received abrocitinib 200 mg, 100 mg, or placebo in phase 2b (NCT02780167) and phase 3 (NCT03349060, NCT03575871) monotherapy trials. Patients with and without allergic comorbidities (allergic asthma, rhinitis, conjunctivitis, or food allergy) were evaluated for Investigator's Global Assessment (IGA) response (clear [0] or almost clear [1]), ≥75% improvement in the Eczema Area and Severity Index (EASI-75), ≥4-point improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4), and Dermatology Life Quality Index (DLQI) response (<2 with baseline score ≥2). Other outcomes were Patient-Oriented Eczema Measure (POEM), SCORing Atopic Dermatitis (SCORAD), Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD), and treatment-emergent adverse events (TEAEs). RESULTS: Of 942 patients, 498 (53%) reported at least one allergic comorbidity (asthma only, 33%; conjunctivitis only or rhinitis only or both, 17%; food allergies only, 15%; >1 allergic comorbidity, 34%). Regardless of comorbidity status, from Week 2 to Week 12, higher percentages of patients treated with either abrocitinib dose achieved IGA 0/1, EASI-75, PP-NRS4, or DLQI 0/1 versus placebo-treated patients. Changes from baseline in POEM, SCORAD, and PSAAD were greater with abrocitinib than with placebo in patients with and without allergic comorbidities. Most TEAEs were mild or moderate. CONCLUSIONS: Efficacy and safety data support abrocitinib use to manage AD in patients with or without allergic comorbidities.
Subject(s)
Asthma , Conjunctivitis , Dermatitis, Atopic , Eczema , Rhinitis , Humans , Comorbidity , Dermatitis, Atopic/complications , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/drug therapy , Double-Blind Method , Immunoglobulin A , Pruritus , Severity of Illness Index , Treatment OutcomeABSTRACT
Derived from the myeloid lineage, granulocytes, including basophils, eosinophils, and neutrophils, along with mast cells, play important, often disparate, roles across the allergic disease spectrum. While these cells and their mediators are commonly associated with allergic inflammation, they also exhibit several functions either promoting or restricting tumor growth. In this Position Paper we discuss common granulocyte and mast cell features relating to immunomodulatory functions in allergy and in cancer. We highlight key mechanisms which may inform cancer treatment and propose pertinent areas for future research. We suggest areas where understanding the communication between granulocytes, mast cells, and the tumor microenvironment, will be crucial for identifying immune mechanisms that may be harnessed to counteract tumor development. For example, a comprehensive understanding of allergic and immune factors driving distinct neutrophil states and those mechanisms that link mast cells with immunotherapy resistance, might enable targeted manipulation of specific subpopulations, leading to precision immunotherapy in cancer. We recommend specific areas of investigation in AllergoOncology and knowledge exchange across disease contexts to uncover pertinent reciprocal functions in allergy and cancer and allow therapeutic manipulation of these powerful cell populations. These will help address the unmet needs in stratifying and managing patients with allergic diseases and cancer.
Subject(s)
Granulocytes , Hypersensitivity , Mast Cells , Neoplasms , Humans , Mast Cells/immunology , Mast Cells/metabolism , Neoplasms/immunology , Neoplasms/therapy , Hypersensitivity/immunology , Hypersensitivity/therapy , Hypersensitivity/etiology , Granulocytes/immunology , Granulocytes/metabolism , Tumor Microenvironment/immunology , Animals , Disease SusceptibilityABSTRACT
BACKGROUND: Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS: Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS: Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS: HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 years.
Subject(s)
Mastocytosis , Registries , Humans , Adult , Middle Aged , Male , Female , Aged , Mastocytosis/epidemiology , Mastocytosis/diagnosis , Mastocytosis/complications , Prevalence , Young Adult , Adolescent , Aged, 80 and over , Pilot Projects , Risk Factors , Hypersensitivity/epidemiology , Hypersensitivity/diagnosisABSTRACT
BACKGROUND: Recent studies have related high pollen concentrations to increased cardiovascular morbidity and mortality, yet very little research concerns pre-clinical cardiovascular health, including effects on blood pressure (BP). The EPOCHAL panel study investigated the exposure-response relationship between ambient pollen exposure and systolic and diastolic BP in adults. METHODS: BP was measured in 302 adults with and in 94 without pollen allergy during the pollen season, on approximately 16 days per person (6253 observations). Average individually-relevant pollen exposure in the 96 h prior to each BP measurement was calculated by summing up the averages of all ambient pollen concentrations to which the individual was found to be sensitized in a skin prick test, and which originated from seven highly allergenic pollen types (hazel, alder, birch, ash, grasses, mugwort and ragweed). Generalized additive mixed models were used to study the association between mean individually-relevant pollen exposure in the last 96 h and BP, adjusting for individual and environmental time-varying covariates. Effect modification by pollen allergy status, sex and BMI was evaluated. RESULTS: Positive non-linear associations between individually-relevant pollen exposure and both systolic and diastolic BP were found in the allergic but not in the non-allergic group. BP increased sharply for exposures from zero to 60/80 pollen/m3 (diastolic/systolic BP), followed by a tempered further increase at higher concentrations. Increases of 2.00 mmHg [95% confidence interval (CI): 0.80-3.19] in systolic and 1.51 mmHg [95% CI: 0.58-2.45] in diastolic BP were associated with 96-h average pollen exposure of 400 pollen/m3, compared to no exposure. Obesity and female sex were associated with larger BP increases. CONCLUSIONS: The finding that short-term pollen concentration is associated with increased systolic and diastolic BP in persons with pollen allergy strengthens the evidence that pollen may cause systemic health effects and trigger cardiovascular events.
Subject(s)
Blood Pressure , Pollen , Humans , Male , Female , Adult , Middle Aged , Environmental Exposure/adverse effects , Young Adult , Rhinitis, Allergic, Seasonal/etiology , Rhinitis, Allergic, Seasonal/epidemiology , Allergens , Air Pollutants/analysisABSTRACT
BACKGROUND: Systemic mastocytosis is characterized by expansion of clonal mast cells in various tissues. Several biomarkers with diagnostic and therapeutic potential have recently been characterized in mastocytosis, such as the serum marker tryptase and the immune checkpoint molecule PD-L1. OBJECTIVE: We aimed to investigate whether serum levels of other checkpoint molecules are altered in systemic mastocytosis and whether these proteins are expressed in mastocytosis infiltrates in the bone marrow. METHODS: Levels of different checkpoint molecules were analyzed in serum of patients with different categories of systemic mastocytosis and healthy controls and correlated to disease severity. Bone marrow biopsies from patients with systemic mastocytosis were stained to confirm expression. RESULTS: Serum levels of TIM-3 and galectin-9 were increased in systemic mastocytosis, particularly in advanced subtypes, compared with healthy controls. TIM-3 and galectin-9 levels were also found to correlate with other biomarkers of systemic mastocytosis, such as serum tryptase and KIT D816V variant allele frequency in the peripheral blood. Moreover, we observed expression of TIM-3 and galectin-9 in mastocytosis infiltrates in bone marrow. CONCLUSIONS: Together, our results demonstrate for the first time that serum levels of TIM-3 and galectin-9 are increased in advanced systemic mastocytosis. Moreover, TIM-3 and galectin-9 are expressed in bone marrow infiltrates in mastocytosis. These findings provide a rationale for exploring TIM-3 and galectin-9 as diagnostic markers and eventually therapeutic targets in systemic mastocytosis, particularly in advanced forms.
ABSTRACT
In the ovaries, cyclic adenosine 3',5'-monophosphate (cAMP) is a second messenger supporting the generation of steroids. Phosphodiesterases (PDEs) are regulators of intracellular cAMP, and therefore, potential regulators of ovarian function. Interestingly, the family of PDE genes are differentially expressed in human oocytes and granulosa cells from primordial and primary follicles, suggesting diverse roles. In this study, we addressed the functions of PDE3B and PDE8B in primordial follicle regulation using inhibitors of PDE3B and PDE8B in murine ovary primary in vitro cultures. Inhibition of PDE8B in ovarian cultures prevented primordial follicle activation, while inhibition of PDE3B had no effect on follicle distribution in the ovary, under the tested conditions. As cAMP levels may increase steroid levels, we assessed the protein levels of the steroidogenic acute regulatory protein (StAR) and aromatase enzymes, and found that inhibition of PDE3B reduced StAR protein levels, whereas inhibition of PDE8 did not alter StAR expression in our murine ovary culture system conditions. Our results showed that ketotifen-induced inhibition of PDE8B can decrease primordial follicle activation, whereas we observed no effect of follicle distribution, when PDE3B was inhibited. Expression of the StaR enzyme was not altered when PDE8B was inhibited, which might reflect not sufficient inhibition by ketotifen to induce StAR alterations, or redundant mechanisms.
Subject(s)
Ovary , Phosphoric Diester Hydrolases , Animals , Female , Humans , Mice , 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Ketotifen/metabolism , Ketotifen/pharmacology , Oocytes , Ovarian Follicle/metabolism , Ovary/metabolism , Phosphoric Diester Hydrolases/genetics , Phosphoric Diester Hydrolases/metabolism , Steroids/metabolismABSTRACT
BACKGROUND: Thymic stromal lymphopoietin (TSLP) promotes TH2 inflammation and is deeply intertwined with inflammatory dermatoses like atopic dermatitis. The mechanisms regulating TSLP are poorly defined. OBJECTIVE: We investigated whether and by what mechanisms mast cells (MCs) foster TSLP responses in the cutaneous environment. METHODS: Ex vivo and in vivo skin MC degranulation was induced by compound 48/80 in wild-type protease-activated receptor 2 (PAR-2)- and MC-deficient mice in the presence or absence of neutralizing antibodies, antagonists, or exogenous mouse MC protease 6 (mMCP6). Primary human keratinocytes and murine skin explants were stimulated with lysates/supernatants of human skin MCs, purified tryptase, or MC lysate diminished of tryptase. Chymase and histamine were also used. TSLP was quantified by ELISA, real-time quantitative PCR, and immunofluorescence staining. RESULTS: Mas-related G protein-coupled receptor X2 (Mrgprb2) activation elicited TSLP in intact skin, mainly in the epidermis. Responses were strictly MC dependent and relied on PAR-2. Complementarily, TSLP was elicited by tryptase in murine skin explants. Exogenous mMCP6 could fully restore responsiveness in MC-deficient murine skin explants. Conversely, PAR-2 knockout mice were unresponsive to mMCP6 while displaying increased responsiveness to other inflammatory pathways, such as IL-1α. Indeed, IL-1α acted in concert with tryptase. In primary human keratinocytes, MC-elicited TSLP generation was likewise abolished by tryptase inhibition or elimination. Chymase and histamine did not affect TSLP production, but histamine triggered IL-6, IL-8, and stem cell factor. CONCLUSION: MCs communicate with kerationocytes more broadly than hitherto suspected. The tryptase/PAR-2 axis is a crucial component of this cross talk, underlying MC-dependent stimulation of TSLP in neighboring kerationocytes. Interference specifically with MC tryptase may offer a treatment option for disorders initiated or perpetuated by aberrant TSLP, such as atopic dermatitis.
Subject(s)
Dermatitis, Atopic , Receptor, PAR-2 , Animals , Chymases/metabolism , Cytokines/metabolism , Histamine/metabolism , Humans , Keratinocytes/metabolism , Mast Cells/metabolism , Mice , Receptor, PAR-2/genetics , Receptor, PAR-2/metabolism , Tryptases/metabolism , Thymic Stromal LymphopoietinABSTRACT
Mast cell (MC) activation is a key event in allergic reactions, other inflammatory states, and MC activation syndromes. MC-stabilizing agents, mediator-targeting drugs, and drugs interfering with mediator effects are often prescribed for these patients. However, the clinical efficacy of these drugs varies depending on the numbers of involved MCs and the underlying pathology. One straightforward approach would be to eradicate the primary target cell. To date however, no MC-eradicating treatment approach has been developed for patients with MC activation disorders. Nevertheless, recent data suggest that long-term treatment with agents effectively inhibiting KIT function results in the virtual eradication of tissue MCs and a sustained decrease in serum tryptase levels. In many of these patients, MC depletion is associated with a substantial improvement in mediator-induced symptoms. In patients with an underlying KIT D816V-positive mastocytosis, such MC eradication requires an effective inhibitor of KIT D816V, such as avapritinib. However, the use of KIT inhibitors must be balanced against their potential side effects. Here we discuss MC-eradicating strategies in various disease models, the feasibility of this approach, available clinical data, and future prospects for the use of KIT-targeting drugs in MC activation disorders.
Subject(s)
Mast Cell Activation Disorders , Mastocytosis, Systemic , Mastocytosis , Humans , Mast Cells/pathology , Mastocytosis/drug therapy , Mastocytosis/pathology , Mastocytosis, Systemic/drug therapy , Proto-Oncogene Proteins c-kit/genetics , Staurosporine/therapeutic useABSTRACT
Mast cell neoplasms are an emerging challenge in the fields of internal medicine, allergy, immunology, dermatology, laboratory medicine, and pathology. In this review, we discuss the current standards for the diagnosis and prognostication of mast cell neoplasms with special reference to clinically relevant germline and somatic gene variants. In patients with cutaneous mastocytosis or with indolent systemic mastocytosis (SM), various KIT-activating mutations act as key molecular drivers of the disease. In adults, KIT p.D816V is by far the most prevalent driver, whereas other KIT mutants are detected in nearly 40% of children. In advanced SM, including aggressive SM, SM with an associated hematological neoplasm, and mast cell leukemia, additional somatic mutations in other genes, such as SRSF2, JAK2, RUNX1, ASXL1, or RAS, may be detected. These drivers are more frequently detected in SM with an associated hematological neoplasm, particularly in male patients. Recently, hereditary alpha-tryptasemia has been identified as a genetic trait more prevalent in SM compared with healthy controls. Moreover, hereditary alpha-tryptasemia is more frequent in patients with SM with Hymenoptera venom allergy and severe mediator-related symptoms than in patients with SM without symptoms. On the basis of this knowledge, we propose a diagnostic algorithm in which genetic markers are applied together with clinical and histopathologic criteria to establish the diagnosis and prognosis in SM.
Subject(s)
Hematologic Neoplasms , Mastocytosis, Systemic , Adult , Child , Cytogenetic Analysis , Genetic Markers , Humans , Male , Mast Cells/pathology , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/genetics , Mastocytosis, Systemic/pathology , Mutation , Proto-Oncogene Proteins c-kit/geneticsABSTRACT
The immune system interacts with many nominal 'danger' signals, endogenous danger-associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)-associated molecular patterns. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regard to clinical responses to anti-cancer immune and targeted therapies. Cross-disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes.
Subject(s)
Hypersensitivity , Neoplasms , Humans , Hypersensitivity/diagnosis , Hypersensitivity/etiology , Hypersensitivity/therapy , Immunity , Inflammation , Neoplasms/etiology , Neoplasms/therapy , Signal TransductionABSTRACT
Mast cell activation syndromes (MCASs) are defined by systemic severe and recurrent mast cell activation, usually in form of anaphylaxis, a substantial, event-related increase of the serum tryptase level beyond the individual's baseline and a response of the symptomatology to drugs directed against mast cells, mast cell-derived mediators, or mediator effects. A number of predisposing genetic conditions, underlying allergic and other hypersensitivity states, and related comorbidities can contribute to the clinical manifestation of MCASs. These conditions include hereditary alpha tryptasemia, mastocytosis with an expansion of clonal KIT-mutated mast cells, atopic diathesis, and overt IgE-dependent and IgE-independent allergies. Several of these conditions have overlapping definitions and diagnostic criteria and may also develop concomitantly in the same patient. However, although criteria and clinical features overlap, each of these conditions is characterized by a unique constellation of variables and diagnostic criteria. Since two, three, or more conditions can coexist in the same patient, with obvious clinical implications, it is of crucial importance to diagnose the variant of MCAS precisely and to take all accompanying, underlying and potentially complicating conditions, and comorbidities into account when establishing the management plan. Indeed, most of these patients require multidisciplinary investigations and only a personalized treatment approach can lead to an optimal management plan providing an optimal quality of life and low risk of anaphylaxis.
Subject(s)
Anaphylaxis , Mast Cell Activation Syndrome , Mastocytosis , Anaphylaxis/diagnosis , Anaphylaxis/therapy , Humans , Immunoglobulin E , Mast Cells , Mastocytosis/diagnosis , Quality of Life , TryptasesABSTRACT
Mast cells are tissue-resident immune cells that play a central role in allergic disease. These contributions are largely dependent on the acquisition of antigen-specific immunoglobulin E (IgE). Despite this requirement, studies of mast cell and IgE interactions have overlooked the mechanism by which mast cells acquire IgE from the blood. To address this gap, we developed reporter IgE molecules and employed imaging techniques to study mast cell function in situ. Our data demonstrate that skin mast cells exhibit selective uptake of IgE based on perivascular positioning. Furthermore, perivascular mast cells acquire IgE by extending cell processes across the vessel wall to capture luminal IgE. These data demonstrate how tissue mast cells acquire IgE and reveal a strategy by which extravascular cells monitor blood contents to capture molecules central to cellular function.
Subject(s)
Immunoglobulin E/immunology , Mast Cells/immunology , Skin/immunology , Animals , Cell Tracking , Immunoglobulin E/metabolism , Immunophenotyping , Mast Cells/metabolism , Mice , Peritoneal Cavity/cytology , Peritoneum/immunology , Protein Binding/immunology , Receptors, IgE/immunology , Receptors, IgE/metabolism , Skin/metabolismABSTRACT
BACKGROUND: Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level. OBJECTIVE: We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator-related symptoms in patients with advSM. METHODS: In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study [ClinicalTrials.gov identifier NCT00782067]), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator-related symptoms were evaluated by using a specific physician-reported questionnaire. RESULTS: Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator-related symptoms. CONCLUSION: QOL and MC mediator-related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).
Subject(s)
Mastocytosis, Systemic/drug therapy , Protein Kinase Inhibitors/therapeutic use , Staurosporine/analogs & derivatives , Adult , Aged , Aged, 80 and over , Disease Progression , Female , Humans , Male , Mast Cells/pathology , Middle Aged , Quality of Life , Staurosporine/therapeutic use , Treatment OutcomeABSTRACT
The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/epidemiology , Disease Management , Mastocytosis, Cutaneous/drug therapy , Mastocytosis, Systemic/drug therapy , Pandemics , Pneumonia, Viral/epidemiology , Betacoronavirus/immunology , COVID-19 , Comorbidity , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Diphosphonates/therapeutic use , Expert Testimony , Glucocorticoids/adverse effects , Histamine Antagonists/therapeutic use , Humans , Immunosuppressive Agents/adverse effects , Mast Cells/drug effects , Mast Cells/immunology , Mast Cells/pathology , Mastocytosis, Cutaneous/diagnosis , Mastocytosis, Cutaneous/epidemiology , Mastocytosis, Cutaneous/pathology , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/epidemiology , Mastocytosis, Systemic/pathology , Myeloablative Agonists/adverse effects , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Precision Medicine/methods , Risk Factors , SARS-CoV-2 , Vitamin D/therapeutic useABSTRACT
Pediatric mastocytosis is a heterogeneous disease characterized by accumulation of mast cells in the skin and less frequently in other organs. Somatic or germline mutations in the KIT proto-oncogene are detected in most patients. Cutaneous mastocytosis is the most common form of the disease in children. In the majority of cases, skin lesions regress spontaneously around puberty. However, in few patients, mastocytosis is not a self-limiting disease, but persists into adulthood and can show signs of systemic involvement, especially when skin lesions are small-sized and monomorphic. Children with mastocytosis often suffer from mast cell mediator-related symptoms. Severe hypersensitivity reactions can also occur, mostly in patients with extensive skin lesions and blistering. In a substantial number of these cases, the triggering factor of anaphylaxis remains unidentified. Management of pediatric mastocytosis is mainly based on strict avoidance of triggers, treatment with H1 and H2 histamine receptor blockers, and equipment of patients and their families with epinephrine auto-injectors for use in severe anaphylactic reactions. Advanced systemic mastocytosis occurs occasionally. All children with mastocytosis require follow-up examinations. A bone marrow investigation is performed when advanced systemic mastocytosis is suspected and has an impact on therapy or when cutaneous disease persists into adulthood.
Subject(s)
Mastocytosis, Cutaneous/diagnosis , Mastocytosis, Cutaneous/drug therapy , Mastocytosis, Systemic/diagnosis , Mastocytosis, Systemic/drug therapy , Child , Epinephrine/pharmacology , Histamine H1 Antagonists/pharmacology , Histamine H2 Antagonists/pharmacology , Humans , Mast Cells/drug effects , Proto-Oncogene Mas , Skin/drug effectsABSTRACT
Hair cosmetics such as shampoos, hair dyes, bleaching agents or hair straightening creams contain frequent contact allergens. These can lead to allergic contact dermatitis especially in hairdressers, but also in their customers and in others who use hair products at home. While hairdressers suffer mainly from hand dermatitis, in customers and home-users, dermatitis primarily affects the head, neck and face. In this mini-review, we propose a diagnostic algorithm in two steps, based on patch testing, that can be used for the assessment of suspected hair product-induced contact dermatitis. In a first step, we recommend testing the German Contact Allergy Group (DKG) standard series, DKG ointment series, DKG preservative series, DKG hairdresser series, DKG fragrance series as well as (especially in hairdressers) the DKG rubber series. In a second step, if the culprit allergen cannot be identified with the help of the standardized test series and there is a well-founded suspicion, testing the patient's own products, such as shampoos, hair sprays and hair dyes, is recommended.