Allergy Asthma Immunol Res.  2013 Jul;5(4):189-196. 10.4168/aair.2013.5.4.189.

Immunopathogenesis of Allergic Asthma: More Than the Th2 Hypothesis

Affiliations
  • 1Department of Life Science, Pohang University of Science and Technology (POSTECH), Pohang, Korea. juinea@postech.ac.kr

Abstract

Asthma is a chronic obstructive airway disease that involves inflammation of the respiratory tract. Biological contaminants in indoor air can induce innate and adaptive immune responses and inflammation, resulting in asthma pathology. Epidemiologic surveys indicate that the prevalence of asthma is higher in developed countries than in developing countries. The prevalence of asthma in Korea has increased during the last several decades. This increase may be related to changes in housing styles, which result in increased levels of indoor biological contaminants, such as house dust mite-derived allergens and bacterial products such as endotoxin. Different types of inflammation are observed in those suffering from mild-to-moderate asthma compared to those experiencing severe asthma, involving markedly different patterns of inflammatory cells and mediators. As described in this review, these inflammatory profiles are largely determined by the involvement of different T helper cell subsets, which orchestrate the recruitment and activation of inflammatory cells. It is becoming clear that T helper cells other than Th2 cells are involved in the pathogenesis of asthma; specifically, both Th1 and Th17 cells are crucial for the development of neutrophilic inflammation in the airways, which is related to corticosteroid resistance. Development of therapeutics that suppress these immune and inflammatory cells may provide useful asthma treatments in the future.

Keyword

Allergic asthma; endotoxin; immunopathogenesis; T helper cell

MeSH Terms

Allergens
Asthma
Developed Countries
Developing Countries
Dust
Housing
Inflammation
Korea
Neutrophils
Prevalence
Pulmonary Disease, Chronic Obstructive
Respiratory System
Stress, Psychological
T-Lymphocytes, Helper-Inducer
Th17 Cells
Th2 Cells
Allergens
Dust

Figure

  • Fig. 1 General scheme of helper T cell priming and polarization. T cell priming requires both signals 1 and 2. Signal 1 is the antigen-specific signal that is mediated by T-cell receptor triggering by MHC class-II-associated peptides processed from antigens. Signal 2 is the costimulatory signal, mediated mainly by triggering of CD28 (by CD80 and CD86 expressed by dendritic cells after ligation of pattern-recognition receptors (PRR), which are specialized to sense pathogens through recognition of pathogen-associated molecular patterns (PAMP). Primed T cells are induced by signal 3 to differentiate into T cells that secrete distinct cytokines. Signal 3 is the polarizing cytokine signal (such as IL-12, IL-6 and IL-4) that promotes the development of Th1, Th17 or Th2 cells, respectively. The nature of signal 3 depends on the activation of a particular PRR by PAMP. Generally, Th1 cells are important for protection against intracellular pathogens, Th17 cells against extracellular pathogens, and Th2 cells against large worms (helminths). Furthermore, T cell responses to innocuous antigens (allergens) are important for the development of chronic inflammation in the airways. The Th2 cell response is related to eosinophilic inflammation, whereas both Th1 and Th17 cells induce non-eosinophilic (or neutrophilic) inflammation.

  • Fig. 2 Proposed mechanism of Th2 cell polarization by inhalation of allergen contaminated with endotoxin (lipopolysaccharide). At low levels, lipopolysaccharide (LPS) induces TNF-α production by airway structural cells, such as epithelial cells, mast cells, or NKT cells. Immature dendritic cells (DCs) uptake allergens, and then migrate to draining lymph nodes (DLN). During allergen uptake by DC, TNF-α, produced in response to low-level LPS, induces DC maturation, expression of costimulatory molecules, and upregulation of DC IL-4 expression. In DLN, mature DCs induce proliferation of naïve T cells (T cell priming), which subsequently differentiate into Th2 cells, via IL-4 and the STAT6 signaling pathway.

  • Fig. 3 Proposed mechanism of Th1 cell polarization by inhalation of allergen contaminated with endotoxin (lipopolysaccharide). At high levels, lipopolysaccharide (LPS) induces IFN-γ production by airway structural cells, such as epithelial cells, macrophages or NK cells. Immature dendritic cells (DCs) uptake allergens, and then migrate to draining lymph nodes (DLN). During allergen uptake by DC, IFN-γ, produced in response to high-level LPS, induces DC maturation, expression of costimulatory molecules, and upregulation of DC IL-12 expression. In DLN, mature DCs induce proliferation of naïve T cells (T cell priming), which subsequently differentiate into Th1 cells, via IL-12 and the STAT4 signaling pathway.

  • Fig. 4 Proposed mechanism of Th17 cell polarization by inhalation of allergen contaminated with endotoxin (lipopolysaccharide). At high levels, lipopolysaccharide (LPS) induces VEGF production by airway structural cells, such as epithelial cells, macrophages or NK cells. Immature dendritic cells (DCs) uptake allergens, and then migrate to draining lymph nodes (DLN). During allergen uptake by DCs, VEGF (produced by high-level LPS) induces DC maturation and expression of costimulatory molecules via the VEGFR1-dependent pathway. IL-6 expression in DCs is also upregulated by VEGF via the VEGFR2-dependent pathway. In DLN, mature DCs induce proliferation of naïve T cells (T cell priming), which subsequently differentiate into Th17 cells, via IL-6 and the STAT3 signaling pathway.


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