Fcepsilon- and Fcgamma-receptor signaling in diseases

It has become increasingly clear that receptors for the immunoglobulin Fc region play pivotal roles in immune homeostasis and disease. This review describes the fine regulation of the high-affinity IgE-receptor (FcepsilonRI) signaling, especially focusing on the early events that are coordinately regulated by Src family protein tyrosine kinases (PTKs), FcepsilonRI beta-subunit, and membrane lipid rafts. Because allergen-mediated FcepsilonRI cross-linking leads to the synthesis and release of a variety of proinflammatory mediators and cytokines, the duration and amplitude of the signal need to be strictly controlled, and the counterbalancing signaling is provided by specialized inhibitory receptors and molecules. However, recent work have revealed that Src family PTKs and FcepsilonRI beta-subunit transduce both positive and negative signaling with unexpectedly complex mechanisms. FcgammaRIIB exerts a unique inhibitory function on cell activation processes after the engagement of Fcgamma, FcepsilonRI and B cell receptors. Recent work has shown that FcgammaRIIB polymorphisms are associated with systemic lupus erythematosus, and that a transmembrane polymorphism in FcgammaRIIB results in an impaired distribution to lipid rafts and a reduced inhibitory function. Studies addressing the functions of disease-associated polymorphisms in the FcepsilonRI beta-subunit and low-affinity FcgammaRs are also considered.