Risk factors and management of severe life‐threatening anaphylaxis in patients with clonal mast cell disorders

Several different risk factors and conditions may predispose to severe life‐threatening anaphylaxis. Systemic mastocytosis (SM) is one such condition. Although many SM patients are suffering from mild or even no mediator‐related symptoms, others have recurrent episodes of severe anaphylaxis, with clear signs of a mast cell activation syndrome (MCAS) despite prophylactic therapy with anti‐mediator‐type drugs. In several of these patients, an IgE‐dependent allergy is diagnosed. The severity and frequency of MCAS reactions neither correlate with the burden of neoplastic mast cells nor with the levels of specific IgE or the basal tryptase level. However, there is a relationship between severe anaphylaxis in SM and the type of allergen. Notably, many of these patients suffer from hymenoptera venom allergy. Currently recommended therapies include the prophylactic use of anti‐mediator‐type drugs, long‐term immunotherapy for hymenoptera venom allergic patients, and epinephrine‐self‐injector treatment for emergency situations. In patients who present with an excess burden of mast cells, such as smouldering SM, cytoreductive therapy with cladribine (2CdA) may reduce the frequency of severe events. For the future, additional treatment options, such as IgE‐depletion or the use of tyrosine kinase inhibitors blocking IgE‐dependent mediator secretion as well as KIT activation, may be useful alternatives.     

Variable presence of KITD816V in clonal haematological non‐mast cell lineage diseases associated with systemic mastocytosis (SM–AHNMD)

In a substantial number of patients with systemic mastocytosis (SM), an associated clonal haematological non‐mast cell lineage disease (AHNMD) is detectable. Although most of these patients display KIT mutations, especially KIT^D816V, little is known about their exact frequency and their distribution in AHNMD subtypes. We examined 48 patients with SM–AHNMD for the presence of mutant KIT in the SM and AHNMD components of the disease. Mast cells and AHNMD cells were obtained from immunostained bone marrow sections by laser microdissection and examined by melting point analysis of nested‐PCR products. KIT^D816V was found in AHNMD cells in the vast majority of patients with SM–chronic myelomonocytic leukaemia (CMML, 89%). Unexpectedly, KIT^D816V was far less frequently detectable in AHNMD cells in patients with SM–myeloproliferative neoplasm (MPN, 20%) and SM–acute myeloid leukaemia (AML, 30%). None of the patients with lymphoproliferative AHNMDs displayed KIT codon 816 mutations in AHNMD cells (0/8). In FIP1L1/PDGFRA‐positive chronic eosinophilic leukaemia (CEL), neither the SM nor the CEL component of the disease exhibited the KIT mutation. Our findings demonstrate that KIT codon 816 mutations are variably present in AHNMD cells in patients with SM–AHNMD, depending on the subtype of AHNMD. The high frequency of KIT^D816V in neoplastic mast cells and leukaemic myelomonocytic cells in SM–CMML may point to a common precursor in these patients, and may have implications for the biology of the disease and the development of KIT‐targeting therapies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Typical antimicrobials induce mast cell degranulation and anaphylactoid reactions via MRGPRX2 and its murine homologue MRGPRB2

Mast cells are unique immune cells that function as sentinels in host defence reactions, including immediate hypersensitivity responses and allergic responses. The mast cell‐specific receptor named MAS‐related G protein‐coupled receptor X2 (MRGPRX2) triggers mast‐cell degranulation, a key process in anaphylactoid reactions. It is widely observed that antimicrobials can induce pseudo‐allergic reactions (i.e. IgE‐independent mechanism) with symptoms ranging from skin inflammation to life‐threatening systemic anaphylaxis. However, their direct involvement and the mechanisms underlying anaphylactoid reactions caused by antimicrobials have not been demonstrated. Structurally different antimicrobials were screened by Ca²⁺ imaging using MRGPRX2 overexpressing HEK293 cells. MRGPRX2 related anaphylactoid reactions induced by these components were investigated by body temperature drop and mast cell degranulation assays. We showed that MRGPRX2 is involved in allergic‐like reactions to three types of antimicrobials in a dose‐dependent manner. However, mast cells lacking the receptor show reduced degranulation. Furthermore, mice without MAS‐related G protein‐coupled receptor B2 (the orthologous gene of MRGPRX2) exhibited reduced substance‐induced inflammation. Interestingly, β‐lactam and antiviral nucleoside analogues did not induce anaphylactic reactions, which were also observed in vitro. These results should alarm many clinicians that such drugs might induce anaphylactoid reactions and provide guidance on safe dosage of these drugs.     

Evaluation of mast cell activation syndromes: impact of pathology and immunohistology

Mast cell activation syndromes (MCAS) are clinically defined disease states with a largely unknown morphological background. Since mastocytosis may be associated with MCAS, it is crucial in every patient to document or exclude mastocytosis by appropriate histological, molecular, and serological investigations of tissues/organs that are commonly involved in mastocytosis like skin, mucosa of the gastrointestinal tract and bone marrow. Accordingly, histopathological investigation including immunohistological stains is crucial to reach the final diagnosis in such patients and to classify MCAS into primary MCAS, which can present with or without evidence of overt mastocytosis, or secondary MCAS, where an underlying disease with or without tissue inflammation is detected. Cases without evidence of mastocytosis, monoclonal mast cells, or any underlying disease should be termed idiopathic MCAS. When the activating point mutant KIT D816V is detectable but criteria for diagnosis of mastocytosis are not completely met, a so-called (mono)clonal MCAS as a subvariant of primary MCAS should be diagnosed.     

Shared clonal cytogenetic abnormalities in aberrant mast cells and leukemic myeloid blasts detected by single nucleotide polymorphism microarray‐based whole‐genome scanning

Systemic mastocytosis (SM) is characterized by a clonal proliferation of aberrant mast cells within extracutaneous sites. In a subset of SM cases, a second associated hematologic non‐mast cell disease (AHNMD) is also present, usually of myeloid origin. Polymerase chain reaction and targeted fluorescence in situ hybridization studies have provided evidence that, in at least some cases, the aberrant mast cells are related clonally to the neoplastic cells of the AHNMD. In this work, a single nucleotide polymorphism microarray (SNP‐A) was used to characterize the cytogenetics of the aberrant mast cells from a patient with acute myeloid leukemia and concomitant mast cell leukemia associated with a KIT D816A mutation. The results demonstrate the presence of shared cytogenetic abnormalities between the mast cells and myeloid blasts, as well as additional abnormalities within mast cells (copy‐neutral loss of heterozygosity) not detectable by routine karyotypic analysis. To our knowledge, this work represents the first application of SNP‐A whole‐genome scanning to the detection of shared cytogenetic abnormalities between the two components of a case of SM‐AHNMD. The findings provide additional evidence of a frequent clonal link between aberrant mast cells and cells of myeloid AHNMDs, and also highlight the importance of direct sequencing for identifying uncommon activating KIT mutations. © 2016 Wiley Periodicals, Inc.     

Oral allergy syndrome and anaphylactic reactions in BALB/c mice caused by soybean glycinin and β-conglycinin

Background Soybean protein is used in a number of food products but is also a common cause of food allergy. Soybean glycinin and β‐conglycinin represent up to one‐third of protein in the soybean. Many reports have indicated that glycinin and β‐conglycinin have been characterized as major soybean allergens involved in food hypersensitivity. Objective To investigate oral allergy syndrome and anaphylactic reactions in BALB/c mice caused by soybean glycinin and β‐conglycinin with an intragastric feeding protocol without using an adjuvant. Methods BALB/c mice were sensitized by gavages with glycinin and β‐conglycinin, and allergen‐specific IgE and IgG1 responses were studied by a passive cutaneous anaphylaxis assay. Serum histamine release and blood pressure were measured according to other methods. Epithelium and mast cell dye used the method of light microscopy. Results Sensitization with soybean allergens induced high levels of antigen‐specific IgE and IgG1 and increased serum histamine in BALB/c mice. Percentiles of intact mast cell of small intestine in mice sensitized with glycinin and β‐conglyinin significantly decreased for 28 days. Degranulation of mast cells and damage of the epithelium in the small intestine of mice sensitized with globulins were observed. The level of blood pressure in sensitized mice reached a minimum at 3 h. Conclusion Soybean‐specific IgE and IgG1 antibodies increased, with high levels of histamine release, severe degranulation of mast cells and damage of the epithelium of small intestine in mice sensitized with glycinin and β‐conglyinin.     

Post-translational suppression of the high affinity IgE receptor expression on mast cells by an intestinal bacterium

Mast cells, which express the high-affinity IgE receptor (FcεRI) on their surface, play a crucial role in inducing allergic inflammation. Since mast cells are activated by crosslinking of FcεRI with IgE and allergens, the cell surface expression level of FcεRI is an important factor in determining the sensitivity to allergens. Recently, the involvement of gut microbiota in the prevalence and regulation of allergy has attracted attention but the precise underlying mechanisms are not fully understood. In this study, the effect of intestinal bacteria on cell surface expression of FcεRI was examined. Bacteroides acidifaciens type A 43 specifically suppressed cell surface expression of FcεRI on mouse bone marrow-derived mast cells (BMMCs) without reduction in FcεRI α and β-chain mRNA and total protein expression. The suppressive effect required sustained exposure to this bacterium, with a corresponding reduction in Erk activation. Inhibition of Erk decreased cell surface distribution of FcεRI in BMMCs, at least in part, through facilitated endocytosis of FcεRI. These results indicate that B. acidifaciens type A 43 suppresses cell surface expression of FcεRI on mast cells in a post-translational manner via inhibition of Erk. The suppression of FcεRI expression on mast cells by specific bacteria might be the underlying mechanism involved in the regulation of allergy by gut microbiota.     

Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of 'MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D(2), or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets.     

The role of basophils in the pathogenesis of allergic disease

There has been much controversy surrounding the importance of basophils in allergy. These cells are, after all, comparatively rare and yet they display remarkable potential to contribute to the symptoms of allergic inflammation. Furthermore, by virtue of their ability to rapidly elaborate T helper type 2 (Th2)‐type cytokines, they are well endowed to support ongoing allergic immunity. Despite this, basophils have often been regarded as redundant in this function as in murine models of allergy, their more numerous tissue‐fixed mast cell counterparts also display Th2‐type cytokine‐releasing potential, which is rather different in most human mast cells. Surprisingly, it is from murine models that the basophil has re‐surfaced as a key orchestrator of Th2‐type immunity and chronic allergic inflammation, a property that has long been hypothesized by researchers into human basophil function but never demonstrated. Moreover, murine experimental models also highlighted the ability of basophils to take up and present antigens in an MHC‐dependent manner. Controversy regarding basophils, however, has remained as recent methods for depleting these cells in murine models of allergy and parasitic infection have yielded conflicting results, where the role for this cell oscillates from essential antigen‐presenting cells to mere supporting functions in controlling Th2 responses. This review highlights the recent advances in understanding the role of this rather enigmatic cell in allergy. Cite this as: F. H. Falcone, E. F. Knol and B. F. Gibbs, Clinical & Experimental Allergy, 2011 (41) 939–947.     

The impact of bacterial infection on mast cell degranulation

In developed countries, the prevalence of allergy is on the rise. Although the causes are unknown, it seems that (1) the disappearance of microbiota may play a role in the increase of allergies and (2) exposure to bacterial infections during childhood decreases the incidence of allergies. Although several cell types are involved in the development of allergy, mast cells play a major role in orchestrating inflammation. Upon activation, mast cell secretory granules fuse with the plasma membrane, resulting in the release of a number of inflammatory mediators. In addition to allergy, mast cells contribute to the innate immune response against a variety of bacteria. This is accomplished through the secretion of cytokines and other soluble mediators. Interestingly, there is growing evidence that mast cells exposed to bacteria down-regulate degranulation in response to IgE/Allergen stimulation. This inhibitory effect seems to require direct contact between bacteria and mast cells, but the intracellular mechanism by which bacterial contact suppresses allergic responses is unknown. Here, we review different aspects of mast cell physiology and discuss hypotheses as to how bacteria may influence mast cell degranulation.     

Airway smooth muscle proliferation and survival is not modulated by mast cells

Background Airway smooth muscle (ASM) hyperplasia and mast cell localization within the ASM bundle are important features of asthma. The cause of this increased ASM mass is uncertain and whether it is a consequence of ASM–mast cell interactions is unknown. Objective We sought to investigate ASM proliferation and survival in asthma and the effects of co‐culture with mast cells. Methods Primary ASM cultures were derived from 11 subjects with asthma and 12 non‐asthmatic controls. ASM cells were cultured for up to 10 days in the presence or absence of serum either alone or in co‐culture with the human mast cell line‐1, unstimulated human lung mast cells (HLMC) or IgE/anti‐IgE‐activated HLMC. Proliferation was assessed by cell counts, CFSE assay and thymidine incorporation. Apoptosis and necrosis were analysed by Annexin V/propidium iodide staining using flow cytometry and by assessment of nuclear morphology using immunofluorescence. Mast cell activation was confirmed by the measurement of histamine release. Results Using a number of techniques, we found that ASM proliferation and survival was not significantly different between cells derived from subjects with or without asthma. Co‐culture with mast cells did not affect the rate of proliferation or survival of ASM cells. Conclusion Our findings do not support a role for increased airway smooth proliferation and survival as the major mechanism driving ASM hyperplasia in asthma. Cite this as: D. Kaur, F. Hollins, R. Saunders, L. Woodman, A. Sutcliffe, G. Cruse, P. Bradding and C. Brightling, Clinical & Experimental Allergy, 2010 (40) 279– 288.     

Role of Treg in immune regulation of allergic diseases

Allergy is a Th2‐mediated disease that involves the formation of specific IgE antibodies against innocuous environmental substances. The prevalence of allergic diseases has dramatically increased over the past decades, affecting up to 30% of the population in industrialized countries. The understanding of mechanisms underlying allergic diseases as well as those operating in non‐allergic healthy responses and allergen‐specific immunotherapy has experienced exciting advances over the past 15 years. Studies in healthy non‐atopic individuals and several clinical trials of allergen‐specific immunotherapy have demonstrated that the induction of a tolerant state in peripheral T cells represent a key step in healthy immune responses to allergens. Both naturally occurring thymus‐derived CD4⁺CD25⁺FOXP3⁺ Treg and inducible type 1 Treg inhibit the development of allergy via several mechanisms, including suppression of other effector Th1, Th2, Th17 cells; suppression of eosinophils, mast cells and basophils; Ab isotype change from IgE to IgG4; suppression of inflammatory DC; and suppression of inflammatory cell migration to tissues. The identification of the molecules involved in these processes will contribute to the development of more efficient and safer treatment modalities.     

Bortezomib treatment diminishes hazelnut‐induced intestinal anaphylaxis in mice

Food allergy is a common health problem and can cause anaphylaxis. Avoidance of the offending food allergen is still the mainstay therapeutic approach. In this study, we investigated the role of plasma cell reduction by proteasome inhibition in a murine model of food allergy and examined the impact of this treatment on the systemic and local immune response. For this purpose, intestinal anaphylaxis was induced in BALB/c mice with the food allergen hazelnut, in conjunction with different adjuvants (alum and Staphylococcal enterotoxin B SEB) and different administration routes (oral and intraperitoneal). In both models, allergy symptoms were observed, but the clinical severity was more pronounced in the hazelnut‐alum model than in the hazelnut‐SEB model. Accordingly, allergen‐specific immunoglobulin E (IgE) against hazelnut was detectable, and mast cell protease‐1 in serum was increased after allergen provocation. Treatment with the proteasome inhibitor bortezomib reduced plasma cells and resulted in an abolishment of hazelnut allergen‐specific IgE, which was associated with amelioration of clinical symptoms as well as a significant decrease in both CD19⁺ and follicular B lymphocytes. Our data demonstrate the importance of allergen‐specific IgE in food allergy and point to B cells as potential therapeutic targets for its treatment.     

The role of immunoglobulins in allergic disease: IgE and IgG4 immunofluorescent study of adenoid tissue

Upper airway allergy is a common problem in children. The most frequent tissue removed from children is adenoid tissue. Although conventional stains offer little help in characterization of the allergic response in this tissue, immunohistologic assessment does offer the opportunity to reveal immunoreactants present. Adenoid tissue from 91 allergic and nonallergic children was examined by a dual immunofluorescent method to detect mast cell membrane bound IgE and IgG4. Positive mast cell membrane staining was seen with IgE (FIEMC) but not with IgG4 in adenoid tissue from allergic children. Numerous IgG4 plasma cells were often seen in close relationship to FIEMC in adenoid stroma where blocking function of IgG4 may take place. False-positive FIEMC patients may represent transient or infrequent encounters with allergens. Disparate clinical allergy and tissue FIEMC status may also reflect different genetic control of IgE regulation and antigen (allergen) recognition.     

Atopic and non‐atopic eosinophilic oesophagitis are distinguished by immunoglobulin E‐bearing intraepithelial mast cells

Mulder D J, Mak N, Hurlbut D J & Justinich C J
(2012) Histopathology  61, 810–822 Atopic and non‐atopic eosinophilic oesophagitis are distinguished by immunoglobulin E‐bearing intraepithelial mast cells Aims: Eosinophilic oesophagitis (EoE) occurs in atopic individuals and features eosinophils and mast cells, but differences in the inflammatory cell density between the epithelium and lamina propria (LP) are not fully understood. The aim of this study was to determine if numbers of eosinophils, B lymphocytes and immunoglobulin E (IgE)‐bearing mast cells are increased in the mucosa of EoE patients with and without concurrent atopy. Methods and results: Oesophageal biopsies containing ≥4 high‐power fields (HPF) of epithelium and LP were identified for normal (n = 9), gastroesophageal reflux disease (GERD) (n = 5) and EoE (n = 25) patients. Patients were classified as atopic or not by clinical history. Immunohistochemistry identified mast cells, B lymphocytes and eosinophils. Eosinophil density was increased in the LP in EoE. Intraepithelial eosinophil density correlated with eosinophils/HPF, CD20⁺ B lymphocyte density and tryptase⁺ IgE⁺ mast cell density. Increased intraepithelial IgE⁺ cell density in EoE was associated with mast cells and not B lymphocytes. Intraepithelial IgE⁺ mast cell densities were significantly higher in biopsies from the subgroup of EoE patients with atopy. Conclusions: EoE diagnosis using maximal eosinophil count/HPF correlates with average counts/mm², and intraepithelial eosinophil densities are higher in children than adults with EoE. In EoE, numbers of eosinophils and mast cells are increased in the LP. IgE‐bearing mast cells are increased in atopic EoE patients but not in non‐atopic EoE patients.     

The function of CCR3 on mouse bone marrow‐derived mast cells in vitro

The mechanisms governing the population of tissues by mast cells are not fully understood, but several studies using human mast cells have suggested that expression of the chemokine receptor CCR3 and migration to its ligands may be important. In CCR3‐deficient mice, a change in mast cell tissue distribution in the airways following allergen challenge was reported compared with wild‐type mice. In addition, there is evidence that CCR3 is important in mast cell maturation in mouse. In this study, bone marrow‐derived mast cells (BMMCs) were cultured and CCR3 expression and the migratory response to CCR3 ligands were characterized. In addition, BMMCs were cultured from wild‐type and CCR3‐deficient mice and their phenotype and migratory responses were compared. CCR3 messenger RNA was detectable in BMMCs, but this was not significantly increased after activation by immunoglobulin E (IgE). CCR3 protein was not detected on BMMCs during maturation and expression could not be enhanced after IgE activation. Resting and IgE‐activated immature and mature BMMCs did not migrate in response to the CCR3 ligands eotaxin‐1 and eotaxin‐2. Comparing wild‐type and CCR3‐deficient BMMCs, there were no differences in mast cell phenotype or ability to migrate to the mast cell chemoattractants leukotriene B₄ and stem cell factor. The results of this study show that CCR3 may not mediate mast cell migration in mouse BMMCs in vitro. These observations need to be considered in relation to the findings of CCR3 deficiency on mast cells in vivo.     

study of the mast cells of the human duodenal mucosa

The ultrastructure of the process of degranulation of mast cells of human duodenal mucosa was examined. In normal controls little degranulation was seen, but in persons with false food allergy (pseudo-allergy) considerable degranulation of mast cells was delected. This is consistent with the hypothesis that some persons have an abnormal fragility of duodenal mast cells in the presence of histamine-releasing substances. Incubation of duodenal biopsy material with various histamine-releasing agents (compound 48/80, Concanavalin A, the calcium ionophore A 23187, and anti-IgE) confirmed the susceptibility of duodenal mast cells for antigen non-specific release of histamine, or that mediated by IgE. In a group of patients with immediaie-type, anaphylactic, food allergy, mast cells in the absence of antigen are in a normal state, but degranulation occurs on exposure in vitro or in vivo to specific antigen. The susceptibility to degranulation continues in persons cured of their food allergy. This suggests that a clinical cure is not due to a change of susceptibility of duodenal mast cells to release histamine, but is possibly associated with formation of blocking antibodies, and/or a modification in reactivity of basophils and mast cells of other organs.     

Expansion of circulating Foxp3+CD25bright CD4+ T cells during specific venom immunotherapy

Background Venom immunotherapy (VIT) induces long‐lasting immune tolerance to hymenoptera venom antigens, but the underlying mechanisms are not yet clarified. Regulatory T cells are thought to play an important role in allergic diseases and tolerance induction during specific immunotherapy. Aim Characterize longitudinally the impact of VIT on the pool of circulating regulatory T cells. Methods Fourteen hymenoptera venom‐allergic patients with severe reactions (grades III–IV) were studied before, 6 and 12 months after starting ultra‐rush VIT. Freshly isolated peripheral blood mononuclear cells were surface stained with a panel of markers of T cell differentiation and intracellularly for CTLA‐4 and Foxp3 and analysed by flow cytometry. foxp3 mRNA was quantified by real‐time PCR. VIT responses were assessed by measuring specific IgG4 and IgE levels. Eleven individuals with no history of insect venom allergy were studied as controls. Results VIT induces a significant progressive increase in both the proportion and the absolute numbers of regulatory T cells defined as CD25^bright and/or Foxp3⁺ CD4⁺ T cells. These changes are not related to alterations in the expression of activation markers or imbalances in the naïve/memory T cell compartments. foxp3 mRNA levels also increased significantly during VIT. Of note, the increase in circulating regulatory T cell counts significantly correlates with the venom‐specific IgG4/IgE ratio shift. Conclusion VIT is associated with a progressive expansion of circulating regulatory T cells, supporting a role for these cells in tolerance induction.     

Sclerosing mediastinitis and mast cell activation syndrome

BACKGROUND: Sclerosing mediastinitis (ScM) is a rare, potentially life-threatening disorder, idiopathic in roughly half the cases. Systemic symptoms not attributable to sclerosis often appear in idiopathic ScM. Mast cell activation disease (MCAD) is a potential cause of these symptoms and also can cause sclerosis. ScM has not previously been associated with MCAD. Presented here are the first two cases of ScM associated with MCAD, specifically mast cell activation syndrome (MCAS). CASE 1: A 58-year-old chronically polymorbid woman developed ScM following matched sibling allogeneic stem cell transplantation. Eight years later MCAS, likely underlying most of her chronic issues, was identified. CASE 2: A 30-year-old chronically polymorbid woman presented with superior vena cava syndrome and was diagnosed with ScM. On further evaluation, MCAS was identified. Treatment promptly effected symptomatic improvement; sclerosis has been stable. Non-compliance yielded symptomatic relapse; restored compliance re-achieved symptomatic remission. CONCLUSIONS: Different MCAS presentations reflect elaboration of different mediators, some of which can induce inflammation and fibrosis. Thus, MCAS may have directly and/or indirectly driven ScM in these patients. MCAS should be considered in ScM presenting with comorbidities better explained by mast cell mediator release.