Type 2 inflammation in asthma--present in most, absent in many

Abstract

Asthma is one of the most common chronic immunological diseases in humans, affecting people from childhood to old age. Progress in treating asthma has been relatively slow and treatment guidelines have mostly recommended empirical approaches on the basis of clinical measures of disease severity rather than on the basis of the underlying mechanisms of pathogenesis. An important molecular mechanism of asthma is type 2 inflammation, which occurs in many but not all patients. In this Opinion article, I explore the role of type 2 inflammation in asthma, including lessons learnt from clinical trials of inhibitors of type 2 inflammation. I consider how dichotomizing asthma according to levels of type 2 inflammation--into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes)--has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation.

Figure 1. Type 2 immune responses in asthma

Release of epithelial cell cytokines, particularly interleukin-33 (IL-33) and thymic stromal lymphopoeitin (TSLP), induces the expression of OX40 ligand (OX40L; also known as TNFSF4) on dendritic cells (DCs) to promote their mobilization to local draining lymph nodes where they activate naive CD4⁺ T cells to an IL-4-competent state. These IL-4-competent T cells in the lymph nodes migrate to B cell zones where they differentiate into T follicular helper (T_FH) cells and move into the circulation to complete maturation as T helper 2 (T_H2) cells. IL-4-secreting T_FH cells in parafollicular B cell areas mediate IgE class-switching in B cells, whereas T_H2 cells that migrate to the airway epithelium and to the subepithelial mucosa secrete IL-5 and IL-13 to mediate inflammatory and remodelling changes in the airway mucosa that predispose an individual to asthma and to asthma exacerbations. ILC2, group 2 innate lymphoid cell; TSLPR, TSLP receptor.

Figure 2. Airway pathology in asthma

Airway structures in medium-sized healthy airways (part a; a schematic representation is depicted in part c) and in a patient with asthma (part b; a schematic representation is depicted in part d). The airways in asthma show considerable structural remodelling, including goblet cell hyperplasia, subepithelial fibrosis and increases in smooth muscle volume. Figure parts a and b republished with permission of Dove Medical Press, from the Journal of Asthma and Allergy, Clinical update on the use of biomarkers of airway inflammation in the management of asthma, Wadsworth, S., Sin, D. and Dorscheid, D., 4, 2011; permission conveyed through Copyright Clearance Center, Inc.

Figure 3. Asthma can be divided into T_H2-low and T_H2-high subgroups

Levels of gene expression for T helper 2 (T_H2) cell cytokines or for the activation of epithelial cells by T_H2 cell cytokines show a continuum in the airways of patients with asthma (rather than a bimodal distribution). Individuals with asthma who have expression levels higher than the range found in healthy controls have specific clinical, pathological and treatment-response characteristics. This suggests a threshold effect of T_H2 cell cytokines in the airways above which type 2 inflammation influences the clinical features of asthma and the responsiveness to specific treatments. Biomarkers of type 2 inflammation in blood and exhaled air can identify individuals with asthma who are above and below this threshold, and are showing promise as predictors of responsiveness to a growing list of type 2 cytokine inhibitors that are in late-phase clinical trials for asthma.

Figure 4. Asthma as a core disease of smooth muscle that is modified by inflammation

Lessons learnt from clinical trials of inhibitors of type 2 inflammation suggest a conceptualization of asthma as a disease with a core abnormality in airway smooth muscle function that can be modified by inflammation to worsen disease severity and to promote susceptibility to asthma exacerbations. Although type 2 inflammation has been shown to be an important disease modifier by the effects of its inhibition in clinical trials, these same clinical trials also highlight that additional types of inflammation must contribute to certain forms of asthma. These non-type 2 inflammatory pathways are not well understood but may include those associated with obesity, infection or neutrophilia. T_H, T helper.