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Sensitization to allergens in the airway

Allergen can be sampled by dendritic cells in the airway lumen, and can enter tissues through disrupted epithelium (not shown) or, for some allergens with protease activity, can gain access to submucosal dendritic cells by cleaving epithelial-cell tight junctions. Activated dendritic cells mature and migrate to regional lymph nodes or to sites in the local mucosa, where they present peptides derived from the processed allergen in the context of major histocompatibility complex (MHC) class II molecules to naive T cells. In the presence of ‘early interleukin 4’ (IL-4) (potentially derived from a range of cells, including basophils, mast cells, eosinophils, natural killer T cells and T cells), naive T cells acquire the characteristics of T helper 2 (TH2) cells, a process that may be enhanced by engagement of Notch at the surface of T cells with Jagged on dendritic cells). TH2 cells produce IL-4 and IL-13. In the presence of these cytokines and the ligation of suitable co-stimulatory molecules (CD40 with CD40 ligand, and CD80 or CD86 with CD28), B cells undergo immunoglobulin class-switch recombination, in which the gene segments that encode the immunoglobulin heavy chain are rearranged such that antibody of the IgE class is produced. Basophils and mast cells also can produce IL-4 and/or IL-13, and can stimulate B cells through CD40 (not shown). IgE diffuses locally and enters the lymphatic vessels. It subsequently enters the blood and is then distributed systemically. After gaining access to the interstitial fluid, allergen-specific or non-specific IgE binds to the high-affinity receptor for IgE (FcεRI) on tissue-resident mast cells, thereby sensitizing them to respond when the host is later re-exposed to the allergen. Sensitization does not produce symptoms (for example, if sensitization occurs by way of the airways, bronchoconstriction does not occur). This TH2-cell response to allergen can be downregulated or modified by various mechanisms (not shown).