Allergic individuals exposed to minute quantities of allergen experience an immediate response. Immediate hypersensitivity reflects the permanent sensitization of mucosal mast cells by allergen-specific IgE antibodies bound to their high-affinity receptors (FcepsilonRI). A combination of factors contributes to such long-lasting sensitization of the mast cells. They include the homing of mast cells to mucosal tissues, the local synthesis of IgE, the induction of FcepsilonRI expression on mast cells by IgE, the consequent downregulation of FcgammaR (through an insufficiency of the common gamma-chains), and the exceptionally slow dissociation of IgE from FcepsilonRI. To understand the mechanism of the immediate hypersensitivity phenomenon, we need explanations of why IgE antibodies are synthesized in preference to IgG in mucosal tissues and why the IgE is so tenaciously retained on mast cell-surface receptors. There is now compelling evidence that the microenvironment of mucosal tissues of allergic disease favors class switching to IgE; and the exceptionally high affinity of IgE for FcepsilonRI can now be interpreted in terms of the recently determined crystal structures of IgE-FcepsilonRI and IgG-FcgammaR complexes. The rate of local IgE synthesis can easily compensate for the rate of the antibody dissociation from its receptors on mucosal mast cells. Effective mechanisms ensure that allergic reactions are confined to mucosal tissues, thereby minimizing the risk of systemic anaphylaxis.

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IgE-expressing B cells are over 1000 times more frequent in the nasal B cell than the peripheral blood B cell population. We have investigated the provenance of these B cells in the nasal mucosa in allergic rhinitis. It is generally accepted that expression of activation-induced cytidine deaminase and class switch recombination (CSR) occur in lymphoid tissue, implying that IgE-committed B cells must migrate through the circulation to the nasal mucosa. Our detection of mRNA for activation-induced cytidine, multiple germline gene transcripts, and ε circle transcripts in the nasal mucosa of allergic, in contrast to nonallergic control subjects, however, indicates that local CSR occurs in allergic rhinitis. The germline gene transcripts and ε circle transcripts in grass pollen-allergic subjects are up-regulated during the season and also when biopsies from allergic subjects are incubated with the allergen ex vivo. These results demonstrate that allergen stimulates local CSR to IgE, revealing a potential target for topical therapies in allergic rhinitis.

Our results provide the first evidence of local receptor revision and class switching to IgE, and B-cell differentiation into IgE-secreting plasma cells in NP.

Abs have a paramount place in the treatment of certain, mainly lymphoid, malignancies, although tumors of nonhemopoietic origin have proved more refractory ones. We have previously shown that the efficacy of immunotherapy of solid tumors, in particular ovarian carcinoma, may be improved by the use of IgE Abs in place of the conventional IgG. An IgE Ab (MOv18 IgE) against an ovarian-tumor-specific Ag (folate binding protein), in combination with human PBMC, introduced into ovarian cancer xenograft-bearing mice, greatly exceeded the analogous IgG1 in promoting survival. In this study, we analyzed the mechanisms by which MOv18 IgE may exert its antitumor activities. Monocytes were essential IgE receptor-expressing effector cells that mediated the enhanced survival of tumor-bearing mice by MOv18 IgE and human PBMC. Monocytes mediated MOv18 IgE-dependent ovarian tumor cell killing in vitro by two distinct pathways, cytotoxicity and phagocytosis, acting respectively through the IgE receptors FcεRI and CD23. We also show that human eosinophils were potent effector cells in MOv18 IgE Ab-dependent ovarian tumor cell cytotoxicity in vitro. These results demonstrate that IgE Abs can engage cell surface IgE receptors and activate effector cells against ovarian tumor cells. Our findings offer a framework for an improved immunotherapeutic strategy for combating solid tumors.