The many paths to asthma: phenotype shaped by innate and adaptive immunity

Abstract

Asthma is a very complex and heterogeneous disease that is characterized by airway inflammation and airway hyper-reactivity (AHR). The pathogenesis of asthma is associated with environmental factors, many cell types, and several molecular and cellular pathways. These include allergic, non-allergic and intrinsic pathways, which involve many cell types and cytokines. Animal models of asthma have helped to clarify some of the underlying mechanisms of asthma, demonstrating the importance of T helper type 2 (T(H)2)-driven allergic responses, as well as of the non-allergic and intrinsic pathways, and contributing to understanding of the heterogeneity of asthma. Further study of these many pathways to asthma will greatly increase understanding of the distinct asthma phenotypes, and such studies may lead to new therapies for this important public health problem.

Figure 1

The heterogeneity of asthma. Asthma is a complex disease caused by multiple factors. There are several different forms of asthma (allergic, non-allergic and intrinsic), and in some patients these forms can coexist. Allergic asthma can be induced by allergens and is mediated by T_H2 immune responses. Non-allergic asthma can also be caused by several factors, such as air pollution and infection. Non-T_H2 cells and various cells of the immune system other than T_H2 cells contribute to non-allergic asthma. Some of the many genes involved in development of spontaneous asthma are presented here.

Figure 2

APCs in the lung. (a) DCs are key APCs in the lung. After antigen challenge, lung DCs process antigen and induce antigen-specific T_H2 cell responses. TCr, T cell antigen receptor. (b) Other cells can also function as APCs to initiate T_H2 responses. Basophils, eosinophils, mast cells and natural helper cells express MHC class II and costimulatory molecules. Therefore, these cells of the innate immune system can be the initial sources of T_H2 cytokines as well as potential APCs in the lung. SCF, stem cell factor; LTC₄, leukotriene C₄; Lin, lineage.

Figure 3

Newly identified cells of the innate immune system and pathways in asthma. Although adaptive immunity is critical for asthma pathogenesis, asthma also involves innate, antigen-independent immune responses. IL-25 induces T_H2 cytokines such as IL-5 and IL-13 from natural helper cells in the absence of T_H2 cells and stimulates NKT cells to produce IL-13, thereby promoting AHr and airway remodeling. IL-33 acts on multiple targets; it stimulates mast cells, eosinophils, basophils, natural helper cells and NKT cells to elicit T_H2 cytokines. TSLP activates mast cells and NKT cells to secrete T_H2 cytokines. The finding of these cytokines, IL-25, IL-33 and TSLP, and cells of the innate immune system greatly extends understanding of the pathogenesis of asthma.