Mast cells activation

Mast Cell Regulation. Recent experiments have elucidated the deleterious role of mast cell activation in atherosclerotic mice. Atheromata from mast cell... 

This chapter highlights the mechanisms responsible for mast cell activation during anaphylactic responses to environmental substances. In addition to discussing in detail the activation of mast cells and basophils by IgE and antigen, we also will describe how mouse models have been used to analyze the importance of various proteins, cells, mediators and activation mechanisms in the expression of anaphylaxis in that species. 

The route of antigen administration can alter the speed of antigen access to the circulation and, thus, the systemic symptoms in anaphylaxis models. For example, allergen ingestion typically induces anaphylaxis that includes gastrointestinal symptoms, such as diarrhea [4]. These intestinal anaphylaxis models in mice are dependent on IgE-induced mast cell activation, and the release of PAF and serotonin (rather than histamine) [1,4]. 

Negative Regulation of FceRI-Dependent Mast Cell Activation... 

Adding another layer of complexity to the regulation of mast cell activation levels in vivo is the observation that activated mast cells can respond to, and in some cases produce, a myriad of mediators that may serve to amplify FceRI-induced responses. For example, stem cell factor (SCF), the ligand for KIT, both can enhance FceRI-dependent activation of mouse or human mast cells and, under certain circumstances, can directly induce mast cell degranulation [6, 25, 62]. Thus, elevated SCF levels and/or activating KIT mutations (such as those that occur in mastocytosis) may exacerbate mast cell-driven reactions. Indeed, patients (both adult and children) with extensive skin disease associated with mastocytosis are at increased risk to develop severe anaphylaxis [63]. Moreover, it was recently reported that cases of idiopathic anaphylaxis are... 

Other GPCRs that positively influence FceRI-induced mast cell activation events include the receptors for prostaglandin E2 (the EP3 receptor), SIP (the SIP2 receptor). 

Gilfillan AM. Peavy RD. Metcalfe DD Amphfication mechanisms for the enhancement of antigen-mediated mast cell activation. Immunol Res 2008. 38... 

Hong H, Kitaura J, Xiao W, Horejsi V, Ra C, Lowell CA, Kawakami Y Kawakami X Xhe Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn. Blood 2007 110 2511-2519. 

Baba Y Nishida K, Fujii Y Hirano X Hikida M, Kurosaki X Essential function for the calcium sensor SXIMl in mast cell activation and anaphylactic responses. Nat Immunol 2008 9 81-88. 

Vennekens R, Olausson J, Meissner M, Bloch W, Mathar I, Philipp SE, Schmitz F, Weissgerber R Nilius B, Flockerzi V, Freichel M Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel XRPM4. Nat Immunol 2007 8 312-320. Guo Z, Xurner C, Castle D Relocation of the t-SNARE SNAP-23 from lamellipodia-like cell surface projections regulates compound exocytosis in mast cells. Cell 1998 94 537-548. 

BH, Tilley SL Enhanced mast cell activation in mice deficient in the A2b adenosine receptor. J Exp Med 2007 204 117-128. 

Mast cells are present in the normal human heart and even more abundant in diseased hearts [ 16-18,25,47]. Within heart tissue, mast cells he between myocytes and are in close contact with blood vessels. They are also found in the coronary adventitia and in the shoulder regions of coronary atheroma [20, 21], The density of cardiac mast cells is higher in patients with dilated and ischemic cardiomyopathy than in accident victims without cardiovascular diseases [25], Importantly, in some of these conditions there is in situ evidence of mast cell activation [16,34],... 

Mast cells express high-affinity IgE Fc receptors (FceRI) on their surface, contain cytoplasmic granules which are major sources of histamine and other inflammatory mediators, and are activated to release and generate these mediators by IgE-dependent and non-IgE-dependent mechanisms [1]. Disturbances either in the release of mast cell mediators or in mast cell proliferation are associated with clonal mast cell disorders including monoclonal mast cell activation syndrome (MMAS) and mastocytosis respectively, which are in turn associated with some cases of anaphylaxis [2], Molecular mechanisms have been identified which may link increased releasability of mast cell mediators and conditions leading to increased mast cell numbers [3]. Patients with mastocytosis have an increased risk to develop anaphylaxis [4, 5] and those with anaphylaxis may suffer from unrecognized mastocytosis or may display incomplete features of the disease [6-8]. 

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