Mechanisms controlling the human immunoglobulin E response: new directions in the therapy of allergic diseases.
The IgE response plays a critical role in the pathogenesis of human allergic diseases. A detailed understanding of the mechanisms underlying the regulation of IgE synthesis is thus important in the development of new treatments for allergic diseases. It is now well established that the induction of IgE synthesis in human B cells requires two signals. The first signal is delivered by IL-4, which induces Ig gene switching to the epsilon locus. The second signal can be delivered by a number of B-cell activators which, in combination with IL-4, cause the expression of productive epsilon mRNA transcripts and the synthesis of IgE protein. These second signals include contact-mediated signals delivered by T cells via cognate or noncognate interactions. Epstein-Barr virus infection, hydrocortisone, and MAb to the B-cell antigen CD40. Cytokines such as IL-5 and IL-6 significantly amplify IgE synthesis, whereas interferon gamma (IFN-gamma) inhibits IL-4-induced IgE synthesis. The production of cytokines is frequently compartmentalized to specific T-cell subsets: TH1, but not TH2, cells produce IL-2, IFN-gamma and lymphotoxin, whereas TH2 but not TH1 cells produce IL-4, IL-5, IL-6, and IL-10. These two T-cell subsets therefore produce cytokines that functionally antagonize each other, e.g. IFN-gamma inhibits proliferation of TH2 cells. Recent studies indicate that severe allergic diseases such as atopic dermatitis are associated with expansion of TH2 cells. These observations provide a rationale for the use of agents that interfere with IL-4 production or action, or alternatively, the use of IFN-gamma in the treatment of severe allergic diseases.
Leung
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Division of Pediatric Allergy Immunology, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002451:Cell Compartmentation; D016207:Cytokines / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000628:therapy*; D007073:Immunoglobulin E / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000276:immunology
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007073:Immunoglobulin E