The central component of allergic asthma is the development of an immunoglobulin E (IgE) antibody-mediated response to allergens that requires the interaction of a number of leukocytes. Inhaled allergens are endocytosed by antigen presenting cells (APCs), which are usually dendritic cells in the airways that function in surveying the environment for pathogens. Dendritic cells travel to lymph nodes and present antigens on the cell surface via major histocompatibility complex proteins; they also interact with CD4+ naive T cells that contain receptors specific to the antigen.
Dendritic cells are crucial to the development of an immune response and serve as gatekeepers of the immune system. Through the production of an assortment of mediators and cell surface molecules, dendritic cells have the capability of inducing tolerance or eliciting an immune response.
15 Dendritic cells can further control the nature of the immune response by promoting differentiation of CD4+ T cells into various types of T-helper (Th) cells with specific functions.
15,16 The stimulation of 1 type of response vs another type of response is based on the nature of the mediators produced by dendritic cells, which, in turn, is influenced by products of the epithelium (ie, TSLP and other cytokines) and other signals from the environment.
15,16 Expression of IL-4, OX40L, and the cluster of differentiation (CD) marker CD86 promote differentiation of T cells into T-helper 2 (Th2)-specific helper cells, which are central to allergic diathesis.
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T-helper 2 lymphocytes drive the formation of allergic reaction and activation of inflammatory cells via the production of cytokines crucial to allergic disease.
8 The T-cell receptors and co-stimulatory molecules on the surfaces of Th2 cells engage allergen-specific B cells. Production of IL-4 and IL-13 promote antibody class switching in B cells to synthesize IgE antibodies.
8 The Th2 cells and allergen-specific B cells can differentiate into memory cells, facilitating and quickening future allergic responses.
Immunoglobulin E is secreted from B cells into circulation, where it binds to high-affinity FcϵR1 receptors on the surfaces of mast cells (in interstitial tissue) and basophils.
8 Immunoglobulin E continues to be synthesized even in the absence of allergen, and IgE is maintained on the surfaces of mast cells and basophils. Upon the next encounter with allergen, the antigen binds to membranebound IgE, stimulating release of such mediators as histamine, leukotrienes, and cytokines.
8 Because this process results from the binding of antigen to existing antibody-receptor complexes, an immediate response occurs (ie, within minutes), forming the basis for immediate hypersensitivity reactions.
Other cytokines produced by Th2 cells are capable of activating other leukocytes and playing key roles in allergic inflammation. Interleukin 5 is a potent survival factor for eosinophils, which are central effector cells in patients with asthma.
17 Systemic administration of IL-5 to patients with asthma increases circulating eosinophils and their precursors from the bone marrow.
18 Blockade of IL-5 with monoclonal antibodies in animal studies has reduced eosinophil numbers in the blood and lungs and inhibited allergen-induced asthma.
19 The role of IL-5 in disease in humans is complex and may be more important in patients with certain asthma phenotypes (eg, the severe late-onset hypereosinophilic endotype). T helper cells also release IL-9, which occurs in elevated concentrations in the airways of patients with asthma and in mice with experimentally induced asthma.
20 Interleukin 9 promotes mast cell growth, tissue eosinophilia, and production of other Th2 cytokines.
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A class of Th cells known as Th17 cells has recently been identified as a component in asthmatic inflammation.
22 In mouse models, allergen sensitization causes Th17 cells to home to the lungs, where they enhance neutrophilic infiltration and augment Th2-mediated eosinophilic inflammation.
22 T-helper 17 cells secrete IL-17, which has been shown to occur in elevated levels in the airway and blood of patients with asthma.
22 The IL-17 family consists of 6 members (A-F), which emerging evidence suggests are involved in numerous other inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and psoriasis.
22 Interleukin 17 upregulates a diverse set of cytokines, chemokines, adhesion molecules, and growth factors.
22 Its exact role in asthma and allergic disease and its interplay with Th2 pathways and other leukocyte pathways are areas of active research with implications for the understanding of disease pathogenesis and treatment.