Asthma and allergic inflammation

Abstract

Studies of the initiation and maintenance of asthma and allergic inflammation implicate dysregulated interactions between mucosal epithelia and innate immune cells as the underlying cause of these disorders. The similarities of these responses with mucosal responses to parasitic intestinal worms may reveal pathways relevant to the perplexing rise of these chronic inflammatory disorders.

Figure 1

Initiation of allergic immunity is mediated through interactions of allergens with epithelia that result in release of the cytokines TSLP, IL-33, and IL-25. TSLP mediates DC migration and maturation that primes IL-4 competency (green) in helper T cells. Competent cells moving into follicular areas mature into IL-4-secreting TFH cells, and mediate B cell isotype-switching to IgE (and, in the mouse, to IgG1, in the germinal center reaction), which, in turn, binds to mast cells and basophils, thus extending their survival and facilitating allergen-specific activation of these cells. IL-33 promotes IL-4 release from basophils, and IL-33 and IL-25 promote IL-13 and IL-5 release from tissue IL25R+ cells (these cells also release IL-6 which supports B cell maturation and impairs T regulatory cell function). IL-4, IL-5 and IL-13 from these innate cells promote terminal differentiation and/or recruitment of Th2 cells to tissues, as well as alternative macrophage activation (AAMφ) and eosinophil recruitment. These effects are greatly augmented by activation of tissue Th2 cells, which contribute a diverse set of cytokines that feedback to facilitate the survival and activation of innate cells and the effects of Th2-associate cytokines on epithelia, smooth muscle and the stromal matrix. Memory T and B cells are generated that can facilitate more rapid responses to repeated stimulation, particularly if the regulatory T cell response is impaired (not shown).

Figure 2

The loss of universal helminth infection as occurred in earlier human evolution may alter the numbers or types of bacterial and fungal commensals and thus affect normal mucosal tissue homeostasis. In susceptible or highly exposed individuals, such alterations might alter the balance between immunotolerance, immunosurveillance and nutrient extraction. This imbalance may contribute to the appearance of inflammatory systemic dysregulation at mucosal surfaces, resulting in increases in asthma and allergic diseases, particularly in the setting of environmental changes that have increased exposure to indoor allergens and pollutants, and even to increases in obesity, which can be a risk factor for severe asthma.