As noted earlier, the antigen dose, mode of antigen presentation, and genetic constitution of an animal influence the level of the IgE response induced by an antigen (i.e., its allergenic-ity). Breeding experiments with mice have shown that this genetic variation is not linked to the MHC. A genetic component also has been shown to influence susceptibility to type I hypersensitive reactions in humans. If both parents are allergic, there is a 50% chance that a child will also be allergic; when only one parent is allergic, there is a 30% chance that a child will manifest some kind of type I reaction.
The effect of antigen dosage on the IgE response is illustrated by immunization of BDF1 mice. Repeated low doses of an appropriate antigen induce a persistent IgE response in these mice, but higher antigen doses result in transient IgE production and a shift toward IgG. The mode of antigen presentation also influences the development of the IgE response. For example, immunization of Lewis-strain rats with keyhole limpet hemocyanin (KLH) plus aluminum hydrox ide gel or Bordetella pertussis as an adjuvant induces a strong IgE response, whereas injection of KLH with complete Fre-und's adjuvant produces a largely IgG response. Infection of mice with the nematode Nippostrongylus brasiliensis (Nb), like certain adjuvants, preferentially induces an IgE response. For example, Nb-infected mice develop higher levels of IgE specific for an unrelated antigen than do uninfected control mice.
The relative levels of the TH1 and TH2 subsets also are key to the regulation of type I hypersensitive responses. TH1 cells reduce the response, whereas TH2 cells enhance it. Cytokines secreted by TH2 cells—namely, IL-3, IL-4, IL-5, and IL-10— stimulate the type I response in several ways. IL-4 enhances class switching to IgE and regulates the clonal expansion of IgE-committed B cells; IL-3, IL-4, and IL-10 enhance mast-cell production; and IL-3 and IL-5 enhance eosinophil maturation, activation, and accumulation. In contrast, TH1 cells produce IFN-7 which inhibits the type I response.
The pivotal role of IL-4 in regulation of the type I response was demonstrated in experiments by W. E. Paul and coworkers. When these researchers activated normal, unprimed B cells in vitro with the bacterial endotoxin lipopolysaccharide (LPS), only 2% of the cells expressed membrane IgG1 and only 0.05% expressed membrane IgE. However, when un-primed B cells were incubated with LPS plus IL-4, the percentage of cells expressing IgG1 increased to 40%-50% and the percentage expressing IgE increased to 15%-25%. In an attempt to determine whether IL-4 plays a role in regulating IgE production in vivo, Paul primed Nb-infected mice with the harmless antigen TNP-KLH in the presence and absence of monoclonal antibody to IL-4. The antibody to IL-4 reduced the production of IgE specific for TNP-KLH in these Nb-infected mice to 1% of the level in control animals.
Further support for the role of IL-4 in the IgE response comes from the experiments of K. Rajewsky and coworkers with IL-4 knockout mice. These IL-4-deficient mice were unable to mount an IgE response to helminthic antigens. Furthermore, increased levels of CD4+ TH2 cells and increased levels of IL-4 have been detected in atopic individuals. When allergen-specific CD4+ T cells from atopic individuals are cloned and added to an autologous B-cell culture, the B cells synthesize IgE, whereas allergen-specific CD4+ T cells from nonatopic individuals do not support IgE production.
In contrast to IL-4, IFN-7 decreases IgE production, suggesting that the balance of IL-4 and IFN-7 may determine the amount of IgE produced (Figure 16-9). Since IFN-7 is secreted by the TH1 subset and IL-4 by the TH2 subset, the relative activity of these subsets may influence an individual's response to allergens. According to this proposal, atopic and nonatopic individuals would exhibit qualitatively different type I responses to an allergen: the response in atopic individuals would involve the TH2 subset and result in production of IgE; the response in nonatopic individuals would involve the Th1 subset and result in production of IgM or IgG. To test this hypothesis, allergen-specific T cells were cloned from atopic and nonatopic individuals. The cloned T cells from the
Effect of IL-4 and IFN-y on in vitro production of IgE. These plots show the amount of IgE produced by plasma cells cul g n n
0 10 20 30 40 50 100 200 IFN-y, |i/ml tured in the presence of various concentrations of IL-4 (a) or IFN-y (b). [Adapted from G. Del Prete, 1988, J. Immunol. 140:4193.]
atopic individuals were predominantly of the TH2 phenotype (secreting IL-4), whereas the cloned T cells from nonatopic individuals were predominantly of the TH1 phenotype (secreting IFN-y). Needless to say, there is keen interest in down-regulating IL-4 as a possible treatment for allergic individuals.
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