Key mediators in the immunopathogenesis of allergic asthma

Abstract

Asthma is described as a chronic inflammatory disorder of the conducting airways. It is characterized by reversible airway obstruction, eosinophil and Th2 infiltration, airway hyper-responsiveness and airway remodeling. Our findings to date have largely been dependent on work done using animal models, which have been instrumental in broadening our understanding of the mechanism of the disease. However, using animals to model a uniquely human disease is not without its drawbacks. This review aims to examine some of the key mediators and cells of allergic asthma learned from animal models and shed some light on emerging mediators in the pathogenesis allergic airway inflammation in acute and chronic asthma.

Keywords: Airway epithelium; Airway hyper-responsiveness; Allergic airway inflammation; Asthma; Innate lymphoid cells; Th17 cells.

Figure 1

Acute/Early Phase Allergic Response: Crosslinking of the FcεR on previously sensitized mast cells by allergen in the lungs leads to their activation and degranulation. Mast Cells release potent mediators including histamine, cysteine leukotrienes and prostaglandins which are responsible for acute inflammation in allergic asthma as well as laying the foundation for chronic inflammation. Basophils are also activated and release similar mediators to enhance this effect. The airway epithelium also participates in the acute response by releasing TSLP (which acts on mast cells), BAFF (which promotes B-cells to undergo class switch recombination, differentiate into plasma cells and produce IgE); Activin-A (which inhibits further TNF-α/IL-13 production from ASM cells), SP-A/SP-D (scavenges allergen preventing crosslinking of Fc receptors and subsequent degranulation of mast cells), and IL-33/IL-25 (which promotes type 2 ILCs to produce IL-13). ILC2- Innate Lymphoid Cells-Type 2, TSLP - Thymic Stromal Lymphopoietin, PGD2 - Prostaglandin D2, LTB4 - Leukotriene B4, BAFF - B-cell Activating Factor, Baso – basophil, SP - Surfactant Protein, ASM - Airway Smooth Muscle, TNF - Tumor Necrosis Factor.

Figure 2

Late phase mediators interact to promote chronic inflammation in allergic asthma. Dendritic cells constantly survey the airways, process and present antigens to naïve T-cells (Th0). This primes Th0 cells to develop into Th2 cells under the influence of IL-4. Th2 cells produce cytokines which targets other immune cells (IL-4/IL-13 targets B-cells to isotype switch; IL-5 recruits and activates eosinophils). Other T helper subsets (Th9 and Th17) are also involved in the late phase response and secrete various cytokines and chemokines which are involved in the recruitment of inflammatory cells. This drives chronic inflammation in the lungs and result in airway remodeling and disease pathogenesis. Mediators released from NKT-cells and γ/δT-cells may or may not play anti or pro-inflammatory roles in asthma pathogenesis IL – Interleukin, Th - T helper, DC - Dendritic cells, Neutro – Neutrophil, MBP - Major Basic Protein, ECP - Eosinophil Cationic Protein, IFN – Interferon, NKT - NK T-cells, γ/δT - gamma/delta T-cells, AHR - Airway Hyper-responsiveness, LT – Leukotriene, TSLP - Thymic Stromal Lymphopoietin

Figure 3

Subsets of T-lymphocytes in allergic airway inflammation and asthma: Naïve T-cells differentiate into different subsets of T-cells based on their transcription factors and cytokines in the environment. Natural regulatory T-cells (T-regs) and IL-10 producing regulatory T-cells (TR1) have the capability to suppress T helper cell as well as mast cell, basophils and eosinophil functions, thus decreasing the chronic inflammatory response in allergic asthma. Th - T-helper, TGF - Transforming Growth Factor, IL – Interleukin, T-bet - T- box expressed in T-cells, ROR - retinoic acid-related organ receptor, Foxp3 - forkhead box p3, TNF - Tumor Necrosis Factor, DC - Dendritic cell.