New Treatment Modalities for Allergic Disease
The Role of IgE Antibody in Allergic Diseases: New Paradigm
Judith A. Woodfolk, M.D. Ph.D.
Asthma and Allergic Diseases Center
University of Virginia, Charlottesville, VA
The association between IgE antibodies (ab) and allergic disease is well established. However, the mechanisms whereby IgE ab contributes to the pathogenesis of allergic disease and to allergic symptoms are still being elucidated. Binding of IgE ab to its high affinity receptor, FcεRI, on the surface of mast cells with subsequent release of inflammatory mediators plays a central role in the allergic inflammatory cascade. Under appropriate conditions, the dendritic cell drives the allergic response by activating Th2 effector cells. Uptake of allergens by FcεRI-bound IgE on the surface of dendritic cells targets allergen to intracellular compartments containing major histocompatibility class II molecules. This mechanism, termed antigen focusing, leads to enhanced efficiency of antigen presentation to T cells. Thus, IgE antibodies likely contribute to the allergic phenotype by diverse but complementary pathways. Though the association between IgE ab and allergic symptoms is clear, the relationship between the magnitude of IgE ab responses and disease severity is less well defined. Definition of the modified Th2 response to cat allergen (IgG4pos IgEneg ) has provided insight into the relevance of different antibody isotypes to allergic disease. Ongoing epidemiologic studies support the view that production of IgE but not IgG or IgG4 ab is a prerequisite for the development of allergic symptoms. The regulatory cytokine, IL-10, has been shown to suppress the production of IgE while enhancing IgG4 ab. However, cytokine induction in T cell cultures stimulated with allergen-derived peptides suggests a central role for IL-10 in the regulation of both IgE- and non-IgE-mediated responses. This view represents a shift in the Th1/Th2 paradigm. The development of high titer IgE ab, eg. in atopic dermatitis, could be attributed, at least in part, to IL-10 dysregulation. Multiple factors may influence regulation of the immune response to allergens including properties of the allergen itself, environment and genetics. Recent observations at the B- and T-cell level are important for advancing our understanding of the response to immunotherapy and anti-IgE therapy, and for defining immune mechanisms which drive allergic responses.
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