Mast cells FceRI

Taube C, Wei X, Swasey CH, et al Mast cells, FceRI, and IL-13 are required for development of airway hyperresponsiveness after aerosolized allergen exposure in the absence of adjuvant. J Immunol 2004 172 6398-6406. 

Human basophils and mast cells are the only cells expressing the tetrameric high-affinity receptor of IgE (FceRI) and synthesizing histamine [26], Basophils and mast cells (FceRI + cells) play a prime role in the pathophysiology of allergic disorders through the elaboration and release of numerous proinflammatory and immunoregulatory molecules and the expression of a wide spectrum of receptors for cytokines and chemokines [27,28]. 

Yamaguchi M, Lantz CS, Oettgen HC, Katona IM, Fleming T, Miyajama L Kinet JP, GaUi SJ. IgE enhances mouse mast cell FceRI expression in vitro and in vivo evidence for a novel amplification mechanism in IgE-dependent reactions. J Exp Med 1997 185 663-672. 

Ryan JJ, DeSimone S, Klisch G, Shelburne C, McReynolds LJ, Han K, Kovacs R, Mirmonsef P, Huff TF. IL-4 inhibits mouse mast cell FceRI expression through a STAT6-dependent mechanism J Immunol 1998 161 6915-6923. 

Yamaguchi M, Sayama K, Yano K, Lantz CS, Noben-Trauth N, Ra C, Costa JJ, Galli SJ. IgE enhances FceRI expression and IgE-dependent release of histamine and lipid mediators from human umbilical cord blood- derived mast cells synergistic effect of IL-4 and IgE on human mast cell FceRI expression and mediator release. J Immunol 1999 162 5455-5465. 

It is generally accepted (based on clinical and in vitro studies) that mast cells (and basophils), IgE and FceRI are involved in most cases of allergen-induced anaphylaxis in humans. However, it is difficult to define the exact roles and relative importance of mast cells, basophils, and other potential effector cells (e.g monocytes/macrophages, dendritic cells) in either IgE-dependent or IgE-independent human anaphylaxis. Unlike in mice, we neither have access to mast cell- or basophil-deficient humans nor can we genetically manipulate human subjects to produce such phenotypes. 

Like all immunoreceptor family members, FceRI lacks intrinsic tyrosine kinase activity. IgE and antigen-induced crosshnking of FceRI initiates a complex series of phosphate transfer events via the activation of non-receptor Src, Syk and Tec family protein tyrosine kinases (fig. 1). The Src family kinase Lyn, which associates with the FceRI p subunit in mast cells, transphosphorylates neighboring FceRI ITAMs after receptor aggregation [7, 26]. Once phosphorylated, the p chain ITAM binds to the SH2 domain of additional Lyn molecules, while the phosphorylated y chain ITAM recruits Syk to the receptor complex, where it is activated by both autophosphorylation and phosphorylation by Lyn [2, 7,15, 26]. 

Downstream of early FceRI-induced signaling events (such as Ca + influx), the final stages of mast cell degranulation require membrane fusion events. The exocytosis of... 

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). 

Galli SJ, Kinet JP Absence of FceRI a chain results in upregulation of FcyRIII-dependent mast cell degranulation and anaphylaxis. Evidence of competition between FceRI and FcyRIII for limiting amounts of FcR (3 and y chains. J Clin Invest 1997 32 99 915-925. 

Kalesnikoff J. Rios EJ, Chen CC, Alejandro Barbieri M. Tsai M. Tam SY, Galli SJ Roles of RabGEFl/ Rabex-5 domains in regulating FccRI surface expression and FceRI-dependent responses in mast cells. Blood 2007 109 5308-5317. 

---