The observation that treatment of peripheral blood mononuclear cells (consisting primarily of lymphocytes and monocytes) from atopic individuals with anti-CD3 and anti-CD28 stimulates production of substantial quantities of TH2 cytokines, whereas similar treatment of cells from non-atopic individuals does not, suggests that circulating leukocytes in atopic individuals have been previously stimulated in a fashion that programs them to generate type 2 responses. An increasing number of studies suggest that regulatory mechanisms that normally serve to suppress overly aggressive type 2 responses are also abnormal in subjects with atopy. When peripheral blood CD4+CD25+ Treg cells from atopic individuals are co-cultured with polyclonally activated CD4+ T cells, they are less effective at suppressing TH2 cytokine production compared with similar Treg cells from non-atopic individuals, and this defect is even more pronounced during the pollen season. More evidence for a role for Treg cells in atopy comes from mice deficient in the transcription factor FoxP3, the master switch for producing both natural (thymus-derived) and some types of induced Treg cells. These mice develop several manifestations of atopy, including increased numbers of blood eosinophils and increased levels of circulating IgE, as well as spontaneous allergic airway inflammation. Manipulation of the Treg pathway can ameliorate experimental asthmatic inflammation in mice. Increasing expression of the anti-inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) by treatment with IFN-γ or by unmethylated CpG DNA can induce the generation or activation of Treg cells. Induction of IDO activity in resident dendritic cells in the lung by stimulation with CpG DNA enhances Treg activity and ameliorates experimental asthma in mice. These findings suggest that therapies aiming to enhance Treg function could be beneficial in asthma and other atopic disorders. Other immunoregulatory molecules that might serve as immunotherapeutic agents for treatment of asthma include the cytokines IL-35 and IL-27, which, like IL-10, can inhibit TH2 responses. Alternatively, blockade of the cytokine IL-31 is anticipated to be therapeutically beneficial since IL-31 promotes TH2-driven inflammation.
Summary.
Allergens are generally innocuous antigens that commonly provoke an IgE antibody response in susceptible individuals. Such antigens normally enter the body at very low doses by diffusion across mucosal surfaces and trigger a type 2 immune response. The differentiation of naive allergen-specific T cells into TH2 cells is favored by cytokines such as IL-4 and IL-13. Allergen-specific TH2 cells producing IL-4 and IL-13 drive allergen-specific B cells to produce IgE. The specific IgE produced in response to the allergen binds to the high-affinity receptor for IgE on mast cells and basophils. IgE production can be amplified by these cells because, upon activation, they produce IL-4 and express CD40 ligand. The tendency to IgE overproduction is influenced by both genetic and environmental factors. Once IgE has been produced in response to an allergen, reexposure to the allergen triggers an allergic response. We describe the mechanism and pathology of the allergic responses themselves in the next part of the chapter.
Effector mechanisms in IgE-mediated allergic reactions.