Regulation of IgE Synthesis

FceRII (CD23) receptor plays an important role in regulation of IgE synthesis. In comparison to FceRI, it shows low affinity to IgE. It is found on dendritic cells, macrophages, monocytes, platelets, T and B lymphocytes, and eosinophils. In its soluble form, it sometimes activates B lymphocytes to produce IgE. 

The function of Fc receptors for IgE on lymphocytes is possibly related to regulation of IgE synthesis and those on granulocytes, monocytes and macrophages to IgE-mediated phagocytic reactions. Mononuclear cells also secrete molecules capable of binding IgE (IgE binding factors), which appear to be related to the Fc receptor and may have a role in immunomodulation [106,107]. 

Vercelli D, Geha R. Regulation of IgE synthesis from the membrane to the genes. Springer Semin Immunopathol 1993 15 5-16. 

Yu P, Kosco-VHbois M, Richards M, Kohler G, Earners MC. Negative feedback regulation of IgE synthesis by murine CD23. Nature 1994 369 753-756. 

The corticosteroids have an array of actions in several systems that may be relevant to their effectiveness in asthma. These include inhibition of cytokine and mediator release, attenuation of mucus secretion, up-regulation of (3-adrenoceptor numbers, inhibition of IgE synthesis, attenuation of eicosanoid generation, decreased microvascular permeability, and suppression of inflammatory cell influx and inflammatory processes. The effects of the steroids take several hours to days to develop, so they cannot be used for quick relief of acute episodes of bronchospasm. 

In the context of cytokine regulation of IgE responses it is worth noting that other molecules may play direct or indirect roles that are possibly of lesser importance. It has been shown, for instance, that interleukin 8 inhibits selectively the synthesis of IgE by IL-4 primed human B lymphocytes through a mechanism that is independent of the action of IFN-7(Kimata et al 1992). In addition, recent evidence suggests that interleukin 7 (IL-7), a cytokine produced by stromal cells in the thymus and bone marrow, may indirectly influence IgE responses secondary to differential effects on the production of IL-4 and IFN-y It was observed that IL-7 caused a preferential upregulation of ILN-y expression by activated human T-lymphocytes (Borger et al., 1996). 

CD23 45 B cells, follicular dendritic cells, monocytes IgE synthesis regulation, induction of inflammatory cytokines... 

IFN7 T cells NK cells Activates tumoricidal and microbicidai activities of monocytes and macrophages Enhances MHC ciass 1 and ii moiecuie expression on monocytes, macrophages, epithelium, endothelium and connective tissue cells Inhibits induction and proliferation of TH2-type T cells Regulates antibody synthesis by direct effects on B cells inhibits IgE synthesis Activates NK cells and cytotoxic T cells... 

CDS T cells might regulate IgE pioduction by suppressing IgE synthesis througji the inhibitory eflfect of IFN7 on B cells and/or by altering the diflFerentiation and function of TH2-like T cells. There is in vivo... 

The studies of mast cell cytokine production described above have shown that maximal induction of cytokine synthesis and release usually occurs in response to IgE-dependent activation. In common with many cell types, there is evidence that FccRI on mast cells is coupled to the phospholipase C effector system that controls two distinct signal transduction pathways, one regulated by Ca " ions and the other by protein kinase C (PKC). Exocytotic degranulation is associated with an increased cytoplasmic level of Ca ions, and activation of mast cells can be therefore achieved by the use of calcium iono-phores which raise intracellular calcium concentrations through a receptor-independent mechanism. Alternative mast cell stimuli include phorbol-12-myristate-13-acetate (PMA) which activates PKC and induces mediator secretion from basophils and rodent mast cells but not from human mast cells, and concanavalin A (Con A), a lectin which can stimulate mast cells by cross-linking of cell-bound IgE and/or cell surface glycoproteins. 

Romagnani, S. (1990). Regulation and dysregulation of human IgE synthesis. Immunol Today 11, 316-321. 

Cytotoxic activity of both NK cells and Tc lymphocytes is enhanced by IL-12 (it acts synergistically with IL-2 to induce IFNy synthesis by these cells and is considered as the most potent NK-ceH stimulator known). This cytotoxic enhancement occurs in parallel with depression of IgE production and reduction of IL-4 secretion (IL-12 and IL-4 cross regulate one another s activities). IL-12 effects are only seen early, whereas IL-4 effects are maintained. Studies have suggested a molecular basis for these temporal differences... 

CHRETIEN, I., PENE, J BRIERE, R, DE WAAL MALEFYT, R ROUSSET, F. DE VRIES, J. (1990) Regulation of human IgE synthesis. 1. Human IgE synthesis in vitro is determined by the reciprocal antagonistic effects of interleukin 4 and interferon-y. European Journal of Immunology, 20, 243-251. 

Studies support the view that CD4+ (Th2) and cytotoxic CD8+ (Tc) T cells are a major source of Th2-type cytokines in the airways in asthma (29-32). Co-localization studies of BAL and bronchial biopsy samples from both atopic and nonatopic asthmatics confirm that T cells are the predominant cells encoding mRNA for IL-3, IL-4, IL-5, IL-10, and GM-CSF. T cells are considered to play an important role in regulating IgE synthesis in asthma. This is mediated by the increased T-cell production of IL and IL-13 and the accentuated expression of the accessory molecule CD40L on activated T cells in asthma, which binds to its ligand on B cell after B cell-T cell physical contact, delivering essen-... 

Bronchial biopsies in stable atopic asthmatics have observed these components (19,64). Several Th2-type cytokines, (IL-4, IL-5, IL-13, but not JFNy) and C-C chemokines are produced by multiple cells types, which regulate IgE synthesis and lead to the generation of eosinophilic airway inflammation (Fig. 9) (321). Allergic tissue damage results from the release of basic proteins, leukotrienes, and PAF secreted by activated eosinophils. It is clear that the mast cell plays an important role in the immediate response and that T cells play a key role in orchestrating the nature and severity of the inflammation by the secretion of cytokines. As stated earlier, the eosinophil is regarded as the primary effector cell due to the capacity to secrete major basic protein and eosinophil cationic protein, which have profound cytotoxic effects on the airway epithelium (316). 

Although IL-4 and IL-13 regulation provide compelling targets for therapy, once the IgE isotype switch has occurred, IgE synthesis is no longer dependent on IL-4 and therefore the elimination of IgE-secreting cells is required in parallel to IL-4/IL-13 modulation. 

Alevy YG, Compas MB, Shaffer A, Rup B, Kahn LE. Regulation of human IgE synthesis by soluble factors. Papain treatment of a FcE receptor-positive B-cell line (RPMI-1788) releases regulatory factors for IgE synthesis. Int Arch Allergy Appl Immunol 1988 86 125-130. 

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