Immune defenses against multicellular parasites are found mainly at the sites of parasite entry, namely, under the skin and in the mucosal tissues of the airways and the gut. Cells of the innate and adaptive immune systems at these sites are specialized to secrete cytokines that promote a type 2 response to parasitic infection. In the presence of an invading parasite, dendritic cells taking up antigens in these tissues migrate to regional lymph nodes, where they tend to drive antigen-specific naive CD4 T cells to become effector TH2 cells. TH2 cells themselves secrete IL-4, IL-5, IL-9, and IL-13, thus maintaining an environment in which further differentiation of TH2 cells is favored. The cytokine IL-33, which can be produced by activated mast cells and by damaged or injured epithelial cells, also contributes to amplification of the TH2 response. IL-33 can act directly on TH2 cells via the IL-33 receptors that these cells express. Allergic responses against common environmental antigens are normally avoided because mucosal dendritic cells that encounter antigen in the absence of danger signals such as those provoked by microbial infection generally induce naive CD4 T cells to differentiate into antigen-specific regulatory T cells (T cells). The T cells suppress T-cell responses and contribute to a state of tolerance to the antigen (see Section 12-8) rather than allowing the production of effector or helper cells that might support the production of an allergic response.
The cytokines and chemokines produced by TH2 cells both amplify the TH2 response and stimulate the class switching of activated B cells to IgE production. As we saw in Chapter 10, IL-4 or IL-13 provides the first signal that switches B cells to IgE production. IL-4 and IL-13 acting on T and B lymphocytes activate the Janus-family tyrosine kinases Jak1 and Jak3 (see Section 7-20), ultimately leading to phosphorylation (and thereby activation) of the transcriptional regulator STAT6. Mice lacking functional IL-4, IL-13, or STAT6 have impaired TH2 responses and an impaired ability to switch to production of IgE, demonstrating the key importance of these cytokines and their signaling pathways in the IgE response. The second signal for IgE production is a co-stimulatory interaction between CD40 ligand on the T-cell surface and CD40 on the B-cell surface. This interaction is essential for all antibody class switching. Patients with a genetic deficiency of CD40 ligand produce no IgG, IgA, or IgE, and display a hyper-IgM syndrome phenotype (see Section 13-9).
Murine mast cells and basophils can also produce the signals that drive IgE production by B cells. Mast cells and basophils express FcεRI, and when they are activated by antigen cross-linking their FcεRI-bound IgE, they express cell-surface CD40 ligand and secrete IL-4. Similar data exist for human basophils that have also been primed by inflammatory stimuli (Fig. 14.3). Like TH2 cells, they can induce class switching and IgE production by B cells. Generally, class switching to IgE occurs in lymph nodes (secondary lymphoid organs) that drain the site of antigen entry or in inducible lymphoid follicles (also called tertiary lymphoid tissues) that form in mucosal and other tissues at sites of persistent inflammation. The potential for formation in mucosal tissues of tertiary lymphoid follicles with germinal centers containing B cells that have switched to production of IgE means that mast cells or basophils can amplify the B-cell response close to the site of the allergic reaction. One goal of therapy for allergies is to block this amplification process and thus prevent allergic reactions from becoming self-sustaining.