Mast cells and mastocytosis

Metcalfe, Dean D.

doi:10.1182/blood-2007-11-078097

Cited by 484 publications

(556 citation statements)

References 94 publications

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“…Mast cells are found in most healthy vascularized tissues, and their numbers expand markedly under inflammatory conditions (56). Multiple lines of evidence show that mediators from surrounding cells are critical to the regulation of MC phenotype and survival, although many mechanistic details are lacking (57).…”

Section: Discussionmentioning

confidence: 99%

IL-33/ST2 axis promotes mast cell survival via BCLXL

Wang

Kaieda

Ameri

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues. MC express the IL-33 receptor IL-1 receptor-related protein ST2 at high level, and this IL-1 family cytokine both activates MC directly and primes them to respond to other proinflammatory signals. Whether IL-33 and ST2 play a role in MC survival remains to be defined. In skin-derived human MC, we found that IL-33 attenuated MC apoptosis without altering proliferation, an effect mediated principally through the antiapoptotic molecule B-cell lymphoma-X large (BCLXL). Murine MC demonstrated a similar mechanism, dependent entirely on ST2. In line with these observations, St2−/− mice exhibited reduced numbers of tissue MC in inflamed arthritic joints, in helminthinfected intestine, and in normal peritoneum. Together, these data reveal a cell-intrinsic role for the IL-33/ST2 axis in the regulation of apoptosis in MC, identifying thereby a previously unappreciated pathway supporting expansion of the MC population with inflammation.arthritis | helminth infection M ast cells (MC) are tissue-resident effector cells that contribute both to innate and adaptive immunity (1). MC help defend against bacterial and helminthic infection (2, 3) and play a role in tissue remodeling (4, 5). MC can also contribute to a variety of allergic and nonallergic inflammatory diseases, such as anaphylaxis, atopic dermatitis, asthma, inflammatory arthritis, psoriasis, and multiple sclerosis (6, 7). Under many of these conditions, the number of MC in affected tissues increases by tenfold or more, amplifying the contribution of MC-derived mediators to ongoing inflammation (6-8). Regulation of the MC population is poorly understood, and therapeutic intervention to limit MC accumulation potentially could attenuate injury associated with inflammatory diseases (9, 10).The survival of mature MC in tissues depends on signals from neighboring cells (11,12). The single most important mediator in this process is stem cell factor (SCF), a master regulator of MC proliferation, differentiation, survival, and activation. Mice with genetic mutations affecting SCF or its receptor Kit have few or no MC in healthy or inflamed tissues, whereas activating mutations of Kit give rise to pathologic mastocytosis (13-15). IL-3 is another well-recognized MC growth factor (16). SCF/Kit and IL-3 interface with several antiapoptotic pathways, up-regulating the antiapoptotic protein B-cell lymphoma-2 (BCL-2) and downregulating the proapoptotic protein Bim (14,(17)(18)(19). Aside from SCF/Kit and IL-3, other cytokines have been reported to support MC survival, but their effects appear to be restricted to specific MC subtypes. IL-4 promotes survival of intestinal MC via both BCL-2 and B-cell lymphoma-X large (BCLXL) but may suppress survival in human cord blood MC as well as murine bone marrowderived MC (BMMC) (20-23). IL-10 can either promote or impair survival depending on the type of MC studied (21,22).Recently, substantial attention has focused on the role of IL-33 in MC biolog...

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Section: Discussionmentioning

confidence: 99%

IL-33/ST2 axis promotes mast cell survival via BCLXL

Wang

Kaieda

Ameri

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Systemic mastocytosis (SM) is a hematopoietic disease characterized by expansion of tissue mast cells (MCs) in various organ systems, including the bone marrow (BM), liver and spleen [1][2][3][4]. Despite recurrent mutations in codon 816 of the KIT protooncogene, SM is an extremely heterogeneous disease, ranging from a completely indolent course to lifethreatening disease-variants with short survival-times [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

“…Despite recurrent mutations in codon 816 of the KIT protooncogene, SM is an extremely heterogeneous disease, ranging from a completely indolent course to lifethreatening disease-variants with short survival-times [1][2][3][4]. According to the proposed classification of the World Health Organization (WHO) and the EU-US consensus group, patients with advanced SM can be divided into aggressive SM (ASM), SM with an associated clonal hematologic non-MC-lineage disease (SM-AHNMD) and MC leukemia (MCL) [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

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Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage

Valent

Berger²,

Cerny-Reiterer

et al. 2014

Ann Hematol

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Mast cell leukemia (MCL) is a rare, life-threatening malignancy defined by a substantial increase in neoplastic mast cells (MCs) in bone marrow (BM) smears, drug-resistance and a poor prognosis. In most patients, the survival-time is less than 1 year. However, exceptional cases may present with a less malignant course. We report on a 49-year-old female patient with MCL Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts diagnosed in 2013. In February 2013, first symptoms, including flushing, headache and diarrhoea, were recorded. In addition, mild anemia was detected. The disease was characterized by a massive increase in well-granulated, mature and often spindle-shaped MCs (80%) in BM smears. The serum tryptase level amounted to 332 ng/mL. Like in most other MCL patients, no skin lesions were detected. However, unlike in other patients, tryptase levels remained stable and no other signs or symptoms of MCL-induced organ damage were found. Sequencing studies revealed an isolated S476I point-mutation in KIT but no mutation in codon 816. The patient received histamine receptor blockers, but refused cytoreductive therapy. After 9 months, still no progression or organ damage was detected. However, progression with transformation to acute MCL occurred after 12 months. We propose that the chronic type of MCL with stable conditions, absence of organ damage and a mature MC morphology, is recognized as a distinct entity that should be distinguished from the acute variant of MCL.

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“…and34). Degranulation occurs when FcεRI are cross‐linked by antigen‐bound IgE, resulting in the recruitment of tyrosine kinases, tyrosine‐protein kinase (LYN) and spleen tyrosine kinase (SYK) to the transmembrane immunoreceptor tyrosine‐based activation motif (ITAMs) of the receptor.…”

Section: Introductionmentioning

confidence: 99%

Polymer‐Coated Metal‐Oxide Nanoparticles Inhibit IgE Receptor Binding, Cellular Signaling, and Degranulation in a Mast Cell‐like Cell Line

et al. 2015

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Previous reports have shown that nanoparticles (NPs) can both enhance and suppress immune effector functions; however the mechanisms that dictate these responses are still unclear. Here, the effects of polyacrylic acid (PAA) functionalized metal‐oxide NP are investigated on RBL‐2H3 (representative mammalian granulocyte‐like cell line) cell viability, cellular degranulation, immunoglobulin E (IgE) receptor binding, and cell signaling pathways related to immune function. The increasing development of PAA‐NPs as pesticide dispersants and as drug carriers in therapeutics necessitates their investigation for safe production. Using two in vitro experimental approaches, this study demonstrates that pre‐exposing RBL‐2H3 cells, or IgE antibodies, to PAA‐NPs (TiO2, CeO2, ZnO, Fe2O3, and PAA‐Capsules (NP coating control) over 24 h, significantly decrease the binding capacity of IgE for Fcε receptors, inhibit the phosphorylation of intracellular signaling proteins (e.g., MAPK ERK) that mediate degranulation, and inhibited RBL‐2H3 cell degranulation. In addition, and unlike the other NPs tested, PAA‐TiO2 significantly reduced RBL‐2H3 viability, in a time (4–24 h) and dose‐dependent manner (>50 μg mL−1). Together, these data demonstrate that PAA‐NPs at sub‐lethal doses can interact with cell surface structures, such as receptors, to suppress various stages of the RBL‐2H3 degranulatory response to external stimuli, and modify immune cell functions that can impact host‐immunity.

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Mast cells and mastocytosis

Cited by 484 publications

References 94 publications

IL-33/ST2 axis promotes mast cell survival via BCLXL

IL-33/ST2 axis promotes mast cell survival via BCLXL

Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage

Polymer‐Coated Metal‐Oxide Nanoparticles Inhibit IgE Receptor Binding, Cellular Signaling, and Degranulation in a Mast Cell‐like Cell Line

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