During this reporting period, in collaborative efforts, we have examined the control of mast cell function and proliferation, characterized N-linked glycans in human mast cells, and examined the role of human mast cells in the detection of dengue virus. First, in a collaboration with Dr. Cliff Takemoto and his colleagues, we reported that the transcription factor, microphthalmia-associated transcription factor (MITF), is highly expressed in bone marrow of patients with mastocytosis and activating mutations in KIT, and KIT markedly up-regulates MITF. We also found that MITF is required for the proliferative phenotype. Further experiments suggested posttranscriptional regulation. Using an array screen, we identified candidate miRNAs regulated by KIT . Thus miR-539 and miR-381 are down-regulated by KIT signaling and repress MITF expression through conserved miRNA binding sites in the MITF 3'-untranslated region. In a second collaborative effort, we examined the interaction between mouse mast cells and mouse bone marrow-derived mast cells. Mast cell degranulation, cytokine production and chemotaxis were thus evaluated in vitro following co-culture with BMSCs either in cell contact or a transwell. We found that stromal cells will effectively suppress specific mast cell degranulation, pro-inflammatory cytokine production, chemokinesis and chemotaxis. Mast cell degranulation within mouse skin or the peritoneal cavity was similarly suppressed following in vivo administration of stromal cells. These inhibitory effects were dependent on up-regulation of COX2 in BMSCs and were facilitated through the activation of EP4 receptors on MCs. In a third collaborative effort, we examined the key effector cells in allergic inflammation (eosinophils, basophils, and mast cells) in order to compare their glycomes to help understand the contribution of carbohydrates to the induction and regulation of allergic inflammatory responses. Results revealed substantive quantities of terminal GlcNAc containing structures in both the eosinophil and basophil samples, while mast cells display greater relative quantities of sialylated terminal epitopes. These cell surface glycan structures through interaction with glycan-binding proteins (e.g. lectins) may help regulate cellular functions and might thus have important implications for the pathogenesis of inflammatory and allergic diseases. In a fourth collaborative effort, we examined the role of mast cells in dengue infection. We found that rodent, monkey, and human mast cells are able to detect dengue virus (DENV) which induces mast cell activation and degranulation. The response of mast cells to DENV involves the activation of antiviral intracellular host response pathways, melanoma differentiation-associated gene 5 and retinoic acid inducible gene 1, and the de novo transcription of cytokines, including TNF- and IFN-, and chemokines. Mast cells also played a role in response in vivo. Mast cell deficient mice show increased viral burden within draining lymph nodes. Containment of DENV was linked to the mast cell-driven recruitment of natural killer and natural killer T cells into the infected skin.
| Valent, Peter; Akin, Cem; Arock, Michel et al. (2012) Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 157:215-25 |
| North, Simon J; von Gunten, Stephan; Antonopoulos, Aristotelis et al. (2012) Glycomic analysis of human mast cells, eosinophils and basophils. Glycobiology 22:12-22 |
| Brown, J M; Nemeth, K; Kushnir-Sukhov, N M et al. (2011) Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism. Clin Exp Allergy 41:526-34 |
| Castells, Mariana; Metcalfe, Dean D; Escribano, Luis (2011) Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol 12:259-70 |
| Lee, Youl-Nam; Brandal, Stephanie; Noel, Pierre et al. (2011) KIT signaling regulates MITF expression through miRNAs in normal and malignant mast cell proliferation. Blood 117:3629-40 |
| Gilfillan, Alasdair M; Austin, Sarah J; Metcalfe, Dean D (2011) Mast cell biology: introduction and overview. Adv Exp Med Biol 716:2-12 |
| Kataoka, Tatsuki R; Kumanogoh, Atsushi; Bandara, Geethani et al. (2010) CD72 negatively regulates KIT-mediated responses in human mast cells. J Immunol 184:2468-75 |
| Stone, Kelly D; Prussin, Calman; Metcalfe, Dean D (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125:S73-80 |
| Gilfillan, Alasdair M; Peavy, Richard D; Metcalfe, Dean D (2009) Amplification mechanisms for the enhancement of antigen-mediated mast cell activation. Immunol Res 43:15-24 |
| Metcalfe, Dean D; Schwartz, Lawrence B (2009) Assessing anaphylactic risk? Consider mast cell clonality. J Allergy Clin Immunol 123:687-8 |
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