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Pathophysiology

Ongoing research continues to shed light on the complexity and heterogeneity of asthma, with Type 2 inflammation emerging as an important underlying driver of both eosinophilic and allergic phenotypes.

TYPE 2 INFLAMMATION

The term ‘Type 2 driven asthma’ is an emerging nomenclature for asthma which refers to the release of cytokines that stimulate a Type 2 immune response from both innate and adaptive immune cells.1

The two classes of asthma are broadly based on two types of T helper cells (Th1 and Th2) which are subpopulations of CD4+ T cells and are separated based on cytokine secretion profiles.1 However, the bridge between an innate and adaptive immune response in allergic lung inflammation is multifaceted in asthma, and the distinction between Type 2 and non-Type 2 asthma based on T helper cells does not take into consideration a host of other contributing factors.1,2

Th1 cells secrete cytokines such as IFN-γ, IL-2, and lymphotoxin-alpha and are effective against intracellular pathogens. In contrast, Th2 cells secrete cytokines IL-4, IL-5, IL-9 and IL-13, which coordinate an inflammatory response against helminths and extracellular pathogens, and orchestrate the main pathology associated with asthma.1,2

Epithelial and sputum gene expression analysis has led to the discovery of a Th2-high or Th2-low phenotype, based on the degree of inflammation.2 However, it is important to consider that Type 2 asthma is also mediated by the innate immune response, such emerging classes of immune cells and their role in airway inflammation is constantly evolving.3


TYPE 2 INNATE LYMPHOID CELLS

ILCs are non-T and non-B effector cells classed as innate immune cells divided into 3 types based on the cytokines produced. ILC2s produce and express Th2 cytokines and despite lacking antigen specific receptors they are activated after allergen exposure. ILC2s contribute to the modulation of immune responses in the airway as well as remodelling and airway hyper-responsiveness. ILC2s are highly regulated and ILC cytokine production leads to the asthma pathophysiology as well as exacerbations.3–5

FROM ALLERGEN
INHALATION
TO ASTHMA

Dendritic cells are key antigen presenting cells in the airways that can elicit an antigen-specific adaptive immune response involving T cells and B cells. Upon inhalation of an allergen, airway epithelial cells secrete chemokines, which recruit dendritic cells to the mucosal surface and promote maturation.

Alveolar dendritic cells actively uptake particles as they move through the lungs and drive traffic to the lymph nodes, resulting in T cell differentiation. Exposure of airway epithelial cells to triggers such as allergens, pollutants and infectious agents, leads to the recruitment of dendritic cells. The dendritic cells act as a bridge between the innate and the adaptive immune systems by presenting allergens to adaptive immune cells.6,7 Following differentiation from naïve T cells, T helper cell subsets drive inflammation and asthma pathology through the production of cytokines which have various knock-on effects.

CYTOKINES
AND THEIR
ROLE IN
PATHOGENESIS

The constellation of cytokines secreted in Type 2 asthma drives inflammation and pathology, and the understanding of signalling cascades and positive feedback loops is evolving.

Cytokines secreted by Th2 cells (IL-3, IL-4, IL-5, IL-9 and IL-13) drive the recruitment of mast cells, basophils and eosinophils leading to the characteristic symptoms of asthma including airway remodelling, hyper-responsiveness, mucus production, increased exacerbation and decreased lung function.4,8

ISOTYPE
SWITCHING
OF B CELLS
AND IgE

In Type 2 asthma, the population of B cells and plasma cells in the airway mucosa are widely of the IgE subset. IgE producing plasma B cells contribute to mucus production, epithelial cell fibrosis and airway remodelling.

IgE class switched B cells secrete IgE which binds to receptors on mast cells and triggers the release of chemokines leading to allergic responses. IgE binds to mast cells and basophils which sensitises the cells for degranulation and histamine release upon secondary stimulation. As IgE memory plasma cells can reside in the bone marrow for decades, the role of IgE cells in allergy can be instrumental in exacerbations.9

IL-4, IL-5, AND IL-13 ARE KEY DRIVERS OF TYPE 2 INFLAMMATION WITH DISTINCT AND OVERLAPPING ROLES1

Adapted from Robinson D, et al 2017.1

Type 2 inflammation is emerging as an important underlying driver of both eosinophilic and allergic phenotypes

BURDEN OF
ASTHMA

Learn about the prevalence and healthcare burden of asthma.

Explore facts & figures

DEFINING
ASTHMA CONTROL

Discover how asthma control goes beyond exacerbation reduction.

Get more information

TYPE 2
COMORBIDITIES

Type 2 inflammation has been associated with several chronic
conditions. Find out how they can present additional challenges.

Learn about comorbidities

CD4+, cluster of differentiation 4-positive T cell; IFN-γ, interferon gamma; IgE, immunoglobulin E; IL, interleukin; ILCs, innate lymphoid cells; ILC2, Type 2 innate lymphoid cells; Th, T helper cell.

References:
  1. Robinson D, et al. Revisiting Type 2-high and Type 2-low airway inflammation in asthma: current knowledge and therapeutic implications. Clin Exp Allergy. 2017;47(2):161–175.
  2. Woodruff P, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(5):388–395.
  3. Barlow J and McKenzie A. Type-2 innate lymphoid cells in human allergic disease. Curr Opin Allergy Clin Immunol. 2014;14(5):397–403.
  4. Holgate S, et al. Asthma. Nat Rev Dis Primers. 2015;1:15025.
  5. Ray A, et al. Current concepts of severe asthma. J Clin Invest. 2016;126(7):2394–2403.
  6. Thornton E, et al. Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung. J Exp Med. 2012;209(6):1183–1199. Moon H, et al. Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitization. Immunity. 2018;49(2):275–287.
  7. Moon H, et al. Airway Epithelial Cell-Derived Colony Stimulating Factor-1 Promotes Allergen Sensitisation. Immunity. 2018;49(2):275–287.
  8. Lambrecht B and Hammad H. The immunology of asthma. Nat Immunol. 2015;16(1):45–56.
  9. Gould H and Sutton B. IgE in allergy and asthma today. Nat Rev Immunol. 2008;8(3):205–17.