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.

The distinguishing structural feature of immunoglobulin E (IgE), the antibody responsible for allergic hypersensitivity, is the C epsilon 2 domain pair that replaces the hinge region of IgG. The crystal structure of the IgE Fc (constant fragment) at a 2.6-A resolution has revealed these domains. They display a distinctive, disulfide-linked Ig domain interface and are folded back asymmetrically onto the C epsilon 3 and C epsilon 4 domains, which causes an acute bend in the IgE molecule. The structure implies that a substantial conformational change involving C epsilon 2 must accompany binding to the mast cell receptor Fc epsilon RI. This may be the basis of the exceptionally slow dissociation rate of the IgE-Fc epsilon RI complex and, thus, of the ability of IgE to cause persistent allergic sensitization of mast cells.

The low-affinity immunoglobulin E (IgE) receptor, CD23 (FcɛRII), binds both IgE and CD21 and, through these interactions, regulates the synthesis of IgE, the antibody isotype that mediates the allergic response. We have determined the three-dimensional structure of the C-type lectin domain of CD23 in solution by nuclear magnetic resonance spectroscopy. An analysis of concentration-dependent chemical shift perturbations have allowed us to identify the residues engaged in self-association to the trimeric state, whereas ligand-induced changes have defined the binding sites for IgE and CD21. The results further reveal that CD23 can bind both ligands simultaneously. Despite the C-type lectin domain structure, none of the interactions require calcium. We also find that IgE and CD23 can interact to form high molecular mass multimeric complexes. The interactions that we have described provide a solution to the paradox that CD23 is involved in both up- and down-regulation of IgE and provide a structural basis for the development of inhibitors of allergic disease.

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.

H‐NS is a major component of the bacterial nucleoid, involved in condensing and packaging DNA and modulating gene expression. The mechanism by which this is achieved remains unclear. Genetic data show that the biological properties of H‐NS are influenced by its oligomerization properties. We have applied a variety of biophysical techniques to study the structural basis of oligomerization of the H‐NS protein from Salmonella typhimurium. The N‐terminal 89 amino acids are responsible for oligomerization. The first 64 residues form a trimer dominated by an α‐helix, likely to be in coiled–coil conformation. Extending this polypeptide to 89 amino acids generated higher order, heterodisperse oligomers. Similarly, in the full‐length protein no single, defined oligomeric state is adopted. The C‐terminal 48 residues do not participate in oligomerization and form a monomeric, DNA‐binding domain. These N‐ and C‐terminal domains are joined via a flexible linker which enables them to function independently within the context of the full‐length protein. This novel mode of oligomerization may account for the unusual binding properties of H‐NS.