Exploring the immunopathology of type 2 inflammatory airway diseases

Abstract

Significant advancements have been achieved in understanding the roles of different immune cells, as well as cytokines and chemokines, in the pathogenesis of eosinophilic airway conditions. This review examines the pathogenesis of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), marked by complex immune dysregulation, with major contributions from type 2 inflammation and dysfunctional airway epithelium. The presence of eosinophils and the role of T-cell subsets, particularly an imbalance between Treg and Th17 cells, are crucial to the disease's pathogenesis. The review also investigates the pathogenesis of eosinophilic asthma, a unique asthma subtype. It is characterized by inflammation and high eosinophil levels, with eosinophils playing a pivotal role in triggering type 2 inflammation. The immune response involves Th2 cells, eosinophils, and IgE, among others, all activated by genetic and environmental factors. The intricate interplay among these elements, chemokines, and innate lymphoid cells results in airway inflammation and hyper-responsiveness, contributing to the pathogenesis of eosinophilic asthma. Another scope of this review is the pathogenesis of Eosinophilic Granulomatosis with Polyangiitis (EGPA); a complex inflammatory disease that commonly affects the respiratory tract and small to medium-sized blood vessels. It is characterized by elevated eosinophil levels in blood and tissues. The pathogenesis involves the activation of adaptive immune responses by antigens leading to T and B cell activation and eosinophil stimulation, which causes tissue and vessel damage. On the other hand, Allergic Bronchopulmonary Aspergillosis (ABPA) is a hypersensitive response that occurs when the airways become colonized by aspergillus fungus, with the pathogenesis involving activation of Th2 immune responses, production of IgE antibodies, and eosinophilic action leading to bronchial inflammation and subsequent lung damage. This analysis scrutinizes how an imbalanced immune system contributes to these eosinophilic diseases. The understanding derived from this assessment can steer researchers toward designing new potential therapeutic targets for efficient control of these disorders.

Keywords: ABPA; AERD; AFRS; CRS; CRSwNP; EGPA; eosinophilic asthma; type 2 inflammation.

Figure 1

This figure demonstrates the common pathways in type two inflammation seen in patients with CRSwNP and eBA. Upon encountering environmental triggers, epithelial cells release interleukin-33 (IL-33), thymic stromal lymphopoietin (TSLP), and IL-25. These substances activate group 2 innate lymphoid cells (ILC-2), which in turn begin and sustain eosinophilic inflammation by secreting type 2 cytokines. ILC-2 also prompt dendritic cells (DCs) to secrete CCL17 through IL-13, thereby attracting Th2 cells to the local mucosa. Dendritic cells play a crucial role in steering naïve T cells toward a T helper 2 (Th2) response, facilitating their expansion. Concurrently, ILC-2s induce T cell responses and enhance B cell antibody production. Th2 cells generate IL-4, which triggers a class switch and the production of IgE in B cells. The cross-linking of IgE results in the degranulation of mast cells. Additionally, Th2 cells contribute to the mobilization and activation of eosinophils by producing the cytokine IL-5, which contributes to tissue inflammation.

Figure 2

The immunopathology of EGPA is thought to be initiated by unidentified allergens that provoke an adaptive immune reaction in susceptible individuals. T cells secrete cytokines associated with Th1 (IFN-γ), Th17 (IL-17), and Th2 (IL-4, IL-13, IL-5) responses, which activate eosinophils. A strong Th2 response stimulates B cells to produce IgG4, IgE, and ANCA. Eotaxin-3, which is increased and released, draws eosinophils to the endothelium and deeper into tissues. These eosinophils sustain T-cell activation by emitting IL-25. Eosinophils also release damaging agents such as eosinophil-derived neurotoxin, major basic protein, and eosinophil cationic protein when they degranulate, leading to tissue and vessel damage, necrosis, and fibrosis.

Figure 3

Spores of Aspergillus fumigatus, once inhaled, adhere to bronchial cells and develop into fungal networks. These fungi then secrete proteases and allergenic compounds that incite inflammation, excessive mucus, and harm the airway surfaces, compromising mucociliary function and aiding in additional fungal proliferation. Inflammatory signals from epithelial cells mobilize eosinophils and neutrophils to the airways, causing obstruction. Antigen Presenting Cells polarizes naïve Th0 to Th1, Th17 and Th2. The Th1 immune response is pivotal in eradicating the infection, but the Th2 response perpetuates fungal residency, associated with allergic aspergillosis. Th2 cells elicit the release of IL-4 and IL-13, leading to IgE antibody production by B cells and IL-5, which prompts eosinophils to inflict airway damage. Additionally, the Th17 response recruits granulocytes but can also contribute to damage due to immune responses. IL, interleukin; and Th, T lymphocyte helper.