The Atopic State and the TH2 Paradigm

Extensive evidence has accumulated that may define the underlying immunologic basis for the atopic phenotype, that is, individuals with allergic asthma, allergic rhinitis, and atopic eczema (24). The atopic condition can be viewed as a TH2 lymphocyte-driven response to allergens of complex genetic and environmental origins (36). The reciprocal action of IL-4 and IFN-g on IgE production led to several studies on the T-cell origin of these cytokines. Mosmann and Coffman ( 37) described two distinct types of helper T cells in murine systems and defined them as TH1 or TH2 cells by the pattern of cytokine secretion. TH1 cells produced IL-2, IFN-g, and lymphotoxin. TH2 cells produced IL-4, IL-5, IL-6, and IL-10.

A significant body of evidence has further defined the role of T H2 cells in the human atopic state related to IL-4 production, IgE synthesis, and the maturation and recruitment of eosinophils by IL-5 and the maturation of IgE B cells by IL-5 and IL-6 (24,36). T cells having the TH2 cytokine profile have been cloned from individuals with a variety of atopic diseases, (24) have been identified in the airway of atopic asthmatic patients, and have been implicated as fundamental to persistent airway inflammation in asthma (38,39).

Once a TH2 response is established, there is downregulation of TH1 cells by the cytokines IL-4 and IL-10. TH1 cells are capable of downregulating TH2 cytokine secretion through the reciprocal action of IFN-g on T H2 cells, a physiologic control that is abrogated by the predominant T H2 cell response in the atopic individual (40) (Fig 3.4).

Allergic Rhinitis Th2

FIG. 3.4. The TH2 cell paradigm in allergic disease. The interaction of allergen, dendritic cell, and cytokine environment causes naive CD4 + T cells to differentiate to the Th2 phenotype with the capacity for enhanced secretion of cytokines that drive and maintain the allergic inflammatory response. The established T H2 response downregulates the influence of TH1 cells and the inhibitory effect of interferon-g (IFN-g), by the action of cytokines IL-10 and IL-4. These cytokine pathways are under complex genetic control that defines the atopic phenotype. (Adapted from Holgate ST. The epidemic of allergy and asthma. Nature 1999;402s:2-4, with permission.)

The expression of the atopic state is dependent on genes that control the T H2 response, total IgE production, and specific IgE responsiveness to environmental allergens. High serum IgE levels have been shown to be under the control of a recessive gene, and specific allergen responses are associated with human leukocyte antigens (41). The chromosomal location and identification of these genes are under intense investigation ( 42).

The recent observation that mast cells and basophils produce IL-4, leading to IgE synthesis ( 24), adds an amplification loop that maintains the atopic state with continued exposure to allergen, leading to mast cell and basophil activation and mediator and cytokine release with enhanced and sustained IgE production.

Studies of the interaction of histamine releasing factor (HRF) and human basophil histamine release revealed that there may be two kinds of IgE: IgE that reacts with HRF (IgE+) and IgE that does not (IgE-) (43). The amino acid sequence of this HRF has been determined (44). These observations may add to the role of IgE in several diseases in which no definable allergen is present.

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