The FcεRIβ Subunit Functions as an Amplifier of FcεRIγ-Mediated Cell Activation Signals

particular individual to an allergen is more intense than that of another are poorly understood. However, the and Jean-Pierre Kinet importance of genetic background in the development Laboratory of Allergy and Immunology of atopic disease is underscored by the tendency of Department of Pathology severe atopic disease to run in families. Recently, sev-Beth Israel Hospital eral studies have reported associations of atopic dis-Harvard Medical School ease with molecules involved in the IgE/Fc⑀RI signaling 99 Brookline Avenue pathway, most notably correlation of serum IgE levels Boston, Massachusetts 02215 with the severity or occurrence of asthma (Martinez et al. linkage between serum IgE levels and a large cytokine Summary locus that includes IL-4 (Meyers et al., 1991, 1994), and association of polymorphisms of the Fc⑀RI␤ chain (an The high affinity IgE receptor (Fc⑀RI) plays a central Fc⑀RI subunit) gene with the development of an atopic role in the initiation of allergic responses. Fc⑀RI is multimeric and is expressed as either ␣␥2 trimers or Shirakawa et al., 1994). Taken together, these studies ␣␤␥ 2 tetramers. Recently, polymorphisms of the ␤ suggest that perturbations in IgE/Fc⑀RI-mediated cell chain gene have been associated with the develop-activation can contribute to the initiation or maintenance ment of various allergic phenotypes. Until now, the of atopic diseases and that, at least in some individuals, role of ␤ in Fc⑀RI-dependent signaling was largely the ␤ chain may be a component of such a perturbation. unknown. For that reason, we compared the signaling Understanding how atopy-associated Fc⑀RI␤ poly-characteristics of various wild-type and mutant ␣␥ 2 morphisms might affect the in vivo response of an indi-and ␣␤␥ 2 Fc⑀RI complexes. These studies demon-vidual to allergens is complicated by the existence of strate that the ␥ dimer functions as an autonomous two distinct types of Fc⑀RI complexes in humans. Based activation module, while ␤ functions as an amplifier on analyses demonstrating that surface expression of that provides a gain of 5-to 7-fold, as measured by rodent ␣ occurs only when ␤ and ␥ are both also present, Syk activation and calcium mobilization. Fc⑀RI was originally thought to exist as a tetramer of one ␣ subunit, one ␤ subunit, and one disulfide-linked Introduction ␥ subunit dimer (␣␤␥ 2) (Blank et al., 1989). However, the human ␣ subunit was later found to express as an ␣␥2 The prevailing view of the pathophysiology of atopic complex in transfectants (Miller et al., 1989), and ␣␥ 2 …