Encountering any particular antigen (Ag) for the first time sensitizes, or primes, a developed immune system. This elicits a primary T cell response characterized by a relatively slow clonal expansion of antigen-specific T cells secreting a variety of cytokines of no particular biological focus. Sensitization of T cells also allows the immune system to react with a memory, or anamnestic, response upon a second exposure—and all subsequent exposures—to the same antigen. A memory T cell response is very different from a primary response. Thus, maturation of the immune response requires this initial exposure or sensitization.
Memory T cells proliferate faster, require fewer activation signals than their naïve counterparts, and are able to migrate specifically, or home, to tissues in the body where an antigen-specific response is required (Caret et al. 1998; Carter and Swain 1998; Dutton et al. 1999; Early and Reen 1999a; Hayward and Groothuis 1991). Besides these differences, memory T cells are characterized by differentiation to two major types of effector cells (Figure 14.1). CD4+ T effector cells secrete cytokine profiles that distinguish them as T Helper 1 (TH1) cells, TH2 cells, or TGF-p-producing T regulatory (Treg) cells, a category that includes Tr1 (Groux et al. 1997) and TH3 (Chen et al. 1994) type cells. CD8+ T effectors cells are characterized by their cytolytic function. Moreover, memory T cells express different cell surface molecules than naïve T cells, and the functionality of these distinguishing markers even differs between neonates and adults (Early and Reen 1999b). It is the memory response that is elicited when an immune system is said to be "triggered," as opposed to the primary response that is evoked when the immune system is "sensitized."
Asthma is a triggered response most often associated with differentiation to the TH2 T cell subtype, although the involvement of other subsets has also been reported (Punnonen et al. 1997). TH2 cytokines include interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, and IL-13. The roles played by these and other cytokines in fetal sensitization and the pathogenesis of asthma will be discussed under the "Mechanisms of Asthma" section of this chapter.
A primary B cell response requires help from T cells and is characterized by the production of high titers of inherently low-affinity and cross-reactive antibodies of the IgM isotype (reviewed in: Lane 1996). Like a primary T cell response, this response is also relatively slow to start and is short-lived. However, primed B cells then undergo isotype switching and secrete low levels of other antibody isotypes (Lane 1996), including IgE. Tissue mast cells bearing high-affinity FceRI become armed with antigen-specific IgE antibodies. Triggering a memory B cell response upon subsequent antigen exposure results in high titers of high affinity antibodies of isotypes other than IgM, and these antibodies remain in the blood and tissues for longer periods than in a primary response. Among the Ag that induce switching to the IgE isotype are allergens, nonpathogenic Ags that evoke a nonproductive immune response. In cases where B cells have undergone isotype switching to IgE, secondary exposure to any particular allergen triggers an allergic, and sometimes an asthmatic, response. In these cases, the allergen-specific, FceRI-bound IgE antibodies on mast cells become cross-linked. Allergen-induced cross-linking causes mast cell degranulation leading to the release of a variety of allergy- and asthma-associated chemical mediators (reviewed in: Black 2002; Brightling et al. 2002; Carroll et al. 2002) (Figure 14.2). These mediators, their receptors, and other soluble factors playing roles in the pathogenesis of childhood asthma are also discussed later.
An asthmatic response is a memory response. Salek-Ardakani and coworkers recently provided strong evidence that asthma is caused by memory TH2 cells (Salek-Ardakani et al. 2003). Using sensitized animals, they demonstrated that the costim-ulatory molecule OX40 (CD134) is expressed on memory CD4 cells. Blocking OX40-OX40L interactions at the time of inhalation of aerosolized antigen was shown to inhibit the accumulation of memory effector cells in lung-draining lymph nodes and lung. Moreover, inhibition of the ligation of OX40 by OX40L was shown to prevent eosinophilia, airway hyperreactivity, mucus secretion, and TH2 cytokine production; this emphasizes that memory TH2 cells drive lung inflammation and that this aspect of the asthmatic response is, at least in part, under regulation by OX40.
Depending on the amount of the allergen, the asthmatic response can occur in two phases: an acute phase and a late phase. The acute-phase response is the result of immediate hypersensitivity and can include anaphylaxis, the cause of death when some asthmatic patients encounter an allergen (Fallon et al. 2001; Holt et al. 1999). Late-phase responses peak 6 to 9 hours after an acute response and can also be life-threatening. Although acute- and late-phase responses are brought on by different sets of mediators, both are linked to a single triggering exposure to allergen. In the lung, late-phase reactions are characterized by further wheezing (Kay 2001), eosi-nophil and neutrophil accumulation, and then CD4+ T cell infiltration of the lower airways (MacFarlane et al. 2000; Robinson et al. 1993; Ying et al. 1999). In addition, late-phase allergic responses are responsible for the remodeling of airways in asthma patients. These changes in tissue architecture are characterized by epithelial hypertrophy, fibrosis, goblet cell hyperplasia, and airway occlusion associated with mucus, cellular infiltrate, and extracellular needle-like crystal structures known as Charcot-Leyden crystals that are deposited by activated eosinophils (Fallon et al. 2001; Holt et al. 1999). Interestingly, in a recent study of the cross-section of the apical bronchus of the right upper lobes of 45 stable asthmatic patients with (n = 22) and without (n = 23) inhaled steroid treatment, Niimi and colleagues demonstrated that, although the thickened airway walls of asthmatic patients correlated with airway reactivity, they did not correlate with airway sensitivity, suggesting that airway wall thickening may serve a protective effect against airway narrowing by attenuating airway hyper-responsiveness in asthmatic patients (Niimi et al. 2003). The remodeling of airway structure and function, as well as how allergic sensitization and triggering lead to the complex cellular interactions associated with asthmatic inflammation, will be discussed next.
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