Activation/Inhibition of mast cells by supra-optimal antigen concentrations

作者：Huber Michael^*

来源：Cell Communication and Signaling, 2013, 11(1): 7.

DOI：10.1186/1478-811X-11-7

• Mast cell
• Allergy
• SHIP1
• Lyn
• PKC-delta
• High-affinity receptor for IgE
• Dose-response behavior
• Inhibitory signalosome

Mast cells (MCs) are tissue resident cells of hemopoietic origin and are critically involved in allergic diseases. MCs bind IgE by means of their high-affinity receptor for IgE (Fc epsilon RI). The Fc epsilon RI belongs to a family of multi-chain immune recognition receptors and is activated by cross-linking in response to multivalent antigens (Ags)/allergens. Activation of the Fc epsilon RI results in immediate release of preformed granular substances (e.g. histamine, heparin, and proteases), generation of arachidonic acid metabolites, and production of pro-inflammatory cytokines. The Fc epsilon RI shows a remarkable, bell-shaped dose-response behavior with weak induction of effector responses at both low and high (so-called supra-optimal) Ag concentrations. This is significantly different from many other receptors, which reach a plateau phase in response to high ligand concentrations. To explain this unusual dose-response behavior of the Fc epsilon RI, scientists in the past have drawn parallels to so-called precipitin curves resulting from titration of Ag against a fixed concentration of antibody (Ab) in solution (a.k.a. Heidelberger curves). Thus, for high, supra-optimal Ag concentrations one could assume that every IgE-bound Fc epsilon RI formed a monovalent complex with %26quot;its own Ag%26quot;, thus resulting in marginal induction of effector functions due to absence of receptor cross-linking. However, this was never proven to be the case. More recently, careful studies of Fc epsilon RI activation and signaling events in MCs in response to supra-optimal Ag concentrations have suggested a molecular explanation for the descending part of this bell-shaped curve. It is obvious now that extensive Fc epsilon RI/IgE/Ag clusters are formed and inhibitory molecules and signalosomes are engaged in response to supra-optimal cross-linking (amongst them the Src family kinase Lyn and the inositol-5%26apos;-phosphatase SHIP1) and they actively down-regulate MC effector responses. Thus, the analysis of MC signaling triggered by supra-optimal crosslinking holds great potential for identifying novel targets for pharmacologic therapeutic intervention to benefit patients with acute and chronic allergic diseases.

• 出版日期2013-1-22