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Concept: Mastocytosis


Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.

Concepts: Immune system, DNA, Protein, Cancer, Mast cell, Symptom, Medical sign, Mastocytosis


IgE antibodies (Ab) specific to galactose-α-1,3-galactose (alpha-gal) are responsible for a delayed form of anaphylaxis that occurs 3 to 6 hours after red meat ingestion. In a unique prospective study of seventy participants referred with a diagnosis of idiopathic anaphylaxis (IA), six (9%) were found to have IgE to alpha-gal. Upon institution of a diet free of red meat, all patients had no further episodes of anaphylaxis. Two of these individuals had indolent systemic mastocytosis (ISM). Those with ISM had more severe clinical reactions but lower specific IgE to alpha-gal and higher serum tryptase levels, reflective of the mast cell burden. The identification of alpha-gal syndrome in patients with IA supports the need for routine screening for this sensitivity as a cause of anaphylaxis, where reactions to alpha-gal are delayed and thus may be overlooked. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Immunoglobulin E, Allergy, Mast cell, Anaphylaxis, Mastocytosis, Copyright, Tryptase


Disease overview:Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in one or more extra-cutaneous organs.

Concepts: Immune system, Cell biology, Mast cell, Mastocytosis, Immune system disorders


Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by accumulation of dysfunctional mast cells. Demonstration of familial clustering would be an important step towards defining the genetic contribution to the risk of systemic MCAD. The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT) among affected family members in three selected pedigrees. Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population. The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p<0.0001). In three families with a high familial loading of MCAD, the subtype of MCAD and the severity of mediator-related symptoms varied between family members. In addition, genetic alterations detected in KIT were variable, and included mutations at position 816 of the amino acid sequence. In conclusion, our data provide evidence for common familial occurrence of MCAD. Our findings observed in the three pedigrees together with recent reports in the literature suggest that, in familial cases (i.e., in the majority of MCAD), mutated disease-related operator and/or regulator genes could be responsible for the development of somatic mutations in KIT and other proteins important for the regulation of mast cell activity. Accordingly, the immunohistochemically different subtypes of MCAD (i.e. mast cell activation syndrome and systemic mastocytosis) should be more accurately regarded as varying presentations of a common generic root process of mast cell dysfunction, than as distinct diseases.

Concepts: Family, Immune system, DNA, Protein, Genetics, Disease, Mast cell, Mastocytosis


Experimental IgE-mediated food allergy depends on intestinal anaphylaxis driven by interleukin-9 (IL-9). However, the primary cellular source of IL-9 and the mechanisms underlying the susceptibility to food-induced intestinal anaphylaxis remain unclear. Herein, we have reported the identification of multifunctional IL-9-producing mucosal mast cells (MMC9s) that can secrete prodigious amounts of IL-9 and IL-13 in response to IL-33, and mast cell protease-1 (MCPt-1) in response to antigen and IgE complex crosslinking, respectively. Repeated intragastric antigen challenge induced MMC9 development that required T cells, IL-4, and STAT6 transcription factor, but not IL-9 signals. Mice ablated of MMC9 induction failed to develop intestinal mastocytosis, which resulted in decreased food allergy symptoms that could be restored by adoptively transferred MMC9s. Finally, atopic patients that developed food allergy displayed increased intestinal expression of Il9- and MC-specific transcripts. Thus, the induction of MMC9s is a pivotal step to acquire the susceptibility to IgE-mediated food allergy.

Concepts: Immune system, Gene expression, Asthma, Immunoglobulin E, Allergy, Mast cell, Anaphylaxis, Mastocytosis


Human hematopoietic progenitors are generally assumed to require stem cell factor (SCF) and KIT signaling during differentiation for the formation of mast cells. Imatinib treatment, which inhibits KIT signaling, depletes mast cells in vivo. Furthermore, the absence of SCF or imatinib treatment prevents progenitors from developing into mast cells in vitro. However, these observations do not mean that mast cell progenitors require SCF and KIT signaling throughout differentiation. Here, we demonstrate that circulating mast cell progenitors are present in patients undergoing imatinib treatment. In addition, we show that mast cell progenitors from peripheral blood survive, mature, and proliferate without SCF and KIT signaling in vitro. Contrary to the prevailing consensus, our results show that SCF and KIT signaling are dispensable for early mast cell development.

Concepts: Immune system, Stem cell, Cell biology, In vivo, Mast cell, In vitro, Complement system, Mastocytosis


Over the past few years substantial advances have been made in understanding the pathogenesis, evolution, and complexity of mast cell neoplasms. New diagnostic and prognostic parameters and novel therapeutic targets with demonstrable clinical impact have been identified. A number of these new markers, molecular targets, and therapeutic approaches have been validated and translated into clinical practice. At the same time, the classification of mastocytosis and related diagnostic criteria have been refined and updated by the consensus group and the World Health Organization (WHO). As a result, more specific therapies tailored towards prognostic sub-groups of patients have been developed. Emerging treatment concepts employ drugs directed against KIT and other relevant targets in neoplastic mast cells, and will hopefully receive recognition by health authorities in the near future. The current article provides an overview of recent developments in the field, with emphasis on the updated WHO classification, refined criteria, additional prognostic parameters, and novel therapeutic approaches. Based on these emerging concepts, the prognosis, quality of life, and survival of patients with advanced mastocytosis are expected to improve in the coming years.

Concepts: Immune system, Medicine, Medical terms, Mast cell, World Health Organization, Anaphylaxis, Mastocytosis, Degranulation


Since the critical care physician will most likely be involved in a life-threatening expression of systemic mastocytosis, recognition of this disease is of utmost importance in the critical care management of these patients. Mastocytosis is a severely under-recognized disease because it typically occurs secondary to another condition and thus may occur more frequently than assumed. In this article, we will review the current knowledge on the treatment of mastocytosis crises with an emphasis on critical care management. Mastocytosis is characterized by the clonal proliferation and accumulation of mast cells in different tissues. Mast cell mediators contain a wide range of biologically active substances that may lead to itching and hives but may ultimately lead to anaphylactic shock caused by the release of histamine and other mediators from mast cells. The mainstay of therapy is the avoidance of potential triggers of mast cell degranulation and, if unsuccessful, blocking the cascade of mast cell mediators. The critical care physician should be well aware of the special precautions which should be kept in mind throughout the management of a mastocytosis crisis to avoid massive mast cell degranulation. Histamine-releasing drugs and certain physical triggers like temperature change should be avoided.

Concepts: Immune system, Cell biology, Shock, Mast cell, Histamine, Anaphylaxis, Mastocytosis, Degranulation


Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. Similar to other myeloproliferative neoplasms, increased production of pro-fibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, only little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the pro-angiogenic cytokine CCL-2 in neoplastic mast cells. Correspondingly, the KIT-targeting drug midostaurin and RNAi-mediated knockdown of KIT reduced expression of CCL-2. We also found that NFκB contributes to KIT-dependent upregulation of CCL-2 in mast cells. In addition, CCL-2 secreted by KIT D816V+ mast cells was found to promote the migration of human endothelial cells in vitro Furthermore, knockdown of CCL-2 in neoplastic mast cells resulted in reduced microvessel density and reduced tumor growth in NSG mice in vivo, compared to CCL-2-expressing cells. Finally, we measured CCL-2 serum concentrations in patients with SM and found that CCL-2 levels were significantly elevated in mastocytosis patients compared to controls. Furthermore, CCL-2 serum levels were higher in patients with advanced SM and were found to correlate with poor survival. In summary, we have identified CCL-2 as a novel, KIT D816V-dependent, key regulator of vascular cell migration and angiogenesis in SM. CCL-2 expression correlates with disease severity and prognosis. Whether CCL-2 may serve as a therapeutic target in advanced SM remains to be determined in forthcoming studies.

Concepts: Immune system, Cancer, Angiogenesis, Heart, Mast cell, Organ, Endothelium, Mastocytosis


Mast cell (MC) disease has long been thought to be just the rare disease of mastocytosis (in various forms, principally cutaneous and systemic), with aberrant MC mediator release at symptomatic levels due to neoplastic MC proliferation. Recent discoveries now show a new view is in order, with mastocytosis capping a metaphorical iceberg now called “MC activation disease” (MCAD, i.e. disease principally manifesting inappropriate MC activation), with the bulk of the iceberg being the recently recognized “MC activation syndrome” (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation. Given increasing appreciation of a great menagerie of mutations in MC regulatory elements in mastocytosis and MCAS, the great heterogeneity of MCAD’s clinical presentation is unsurprising. Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme. Preliminary epidemiologic investigation suggests MCAD, while often misrecognized, may be substantially prevalent, making it increasingly important that practitioners of all stripes learn how to recognize its more common forms such as MCAS. We review the diagnostically challenging presentation of MCAD (with an emphasis on MCAS) and current thoughts regarding its biology, epidemiology, natural history, diagnostic evaluation, and treatment. Key messages Recent discoveries show a new view of the realm of mast cell disease is in order, with mastocytosis capping a metaphorical iceberg now termed “MC activation disease” (MCAD, i.e. disease principally manifesting inappropriate MC activation) and with the bulk of the iceberg being comprised of the recently recognized “MC activation syndrome” (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation. Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme, but diagnostic recognition is challenged by great heterogeneity of clinical presentation which may be due to great underlying mutational heterogeneity in assorted mast cell regulatory elements. Although few biomarkers predictive of helpful therapy are yet available, most MCAD patients are able to eventually identify significantly helpful therapy by persistently and methodically stepping through trials of the many treatments shown helpful across this patient population.

Concepts: Immune system, Epidemiology, Cancer, Asthma, Allergy, Mast cell, Prevalence, Mastocytosis