Mast cell Fcγ receptors (FcγR) for IgG

Cross-linking of activating FcγR by IgG immune complexes (IgG-IC) launches transmembrane signalling by triggering ITAM tyrosine phosphorylation followed by dynamic protein phosphorylation cascades including SRC family of tyrosine kinase (Lyn), Syk, raft-associated transmembrane adapters (LAT and NTAL) and phosphatidylinositol 3-kinase etc (10). Mouse peritoneal MC degranulate upon treatment with IgG1-IC (11). Crosslinking of FcγRIIIA on connective tissue MC results in degranulation and generation of various lipid mediators (12). In contrast, BMMC cultured in IL-3 resemble mucosal MC, which do not express FcγRIIIA, and they internalize aggregated IgG without degranulation (13). Upregulation of FcγRI by interferon-g on human MC followed by treatment with IgG-IC results in the release of histamine and cytokines (14).

Mice lacking the ITIM-bearing inhibitory FcγRIIB demonstrate increased passive cutaneous anaphylaxis reflecting up-regulated MC activity (1). When coaggregated with receptors bearing ITAM, FcγRIIB negatively regulates ITAM-mediated cell activation. Inhibition of IgE- or IgG-mediated MC activation by FcγRIIB has been firmly established (15-17). It was also demonstrated that aggregation of either FcγRIIB or FcγRIIIA induces apoptosis of mouse BMMC (18). Interestingly, MC with a balanced expression of these two receptors are able to resist apoptosis induced by IgG-IC (18).

Although in vitro experiments undoubtedly support that MC respond to IgG receptor stimulation, information about in vivo contributions of IgG-IC in MC activation is less clear. Recent experiments using new models of genetically modified mice with deficiency in MC and basophils, antibody-mediated cell depletion experiments or experiments with mice specifically depleted of MC FcγR challenge a number of effects previously attributed to MC (9) such as autoimmune arthritis models or experimental allergic encephalomyelitis (EAE) (19-20). Furthermore, while IgG-mediated cutaneous anaphylaxis reactions as initially described in the 1950s undoubtedly show an important MC component, IgG-mediated passive systemic anaphylaxis mediated by FcγRIIIA and PAF release was ascribed to basophils after antibody depletion experiments (9). However, other data show that the strong expression of the inhibitory receptor FcγRIIB versus activating FcγRIIIA in mouse and human basophils rather prevents IgG-mediated activation of these cells (21). Intriguingly, FcγRIV-expressing neutrophils have been found to induce both passive and active systemic anaphylaxis (22).

It should be mentioned that doses of specific antibodies and antigens used to achieve these effects in experimental models are generally high and the relationship to human pathophysiology, where one finds a different distribution of receptors and where usually minute amounts of antigen suffice to induce an anaphylactic shock, remains to be established. IgG-mediated anaphylactic shocks rather seem to be the exception although adverse reactions like serum sickness upon repeated treatment with a heterologous serum or the Arthus reactions after vaccination have been reported very early on (23-24). However, in contrast to the IgE-mediated shock observed by Portier and Richet (25) these reactions develop slowly requiring relatively high doses of antigen.