The importance of the epithelium and epithelial cytokines in uniting upper and lower airway diseases

Broadly, the airway epithelium consists of a continuous, impermeable sheet of cells, held together with tight junctions and adhesion proteins, which sits on the basement membrane.^{15,18,19,21,22} In both the upper and lower airways, ciliated and secretory cells facilitate clearance of mucus and airway debris.^15,18,20,22 In the upper airways, about 20% of the epithelium is composed of goblet cells,¹⁸ which produce mucus with antioxidant, antiprotease, and antimicrobial properties.²¹ Moving into the lower airways and bronchioles, there are fewer goblet cells^18,21; instead, club cells secrete products that have anti-inflammatory and immunosuppressive capacity,^18,22 which helps to maintain homeostasis.²² At the end of the bronchial tree, Type 1 alveolar cells, which facilitate gas exchange, and Type 2 alveolar cells, which secrete surfactants, form the alveoli.¹⁸ A key factor which differentiates the lower airway epithelium from the upper is the presence of smooth muscle, which drives bronchoconstriction.^1,23

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Similarities in the cellular composition and structure of the upper and lower airway epithelium.^1,15,20

CRSwNP 

Nasal polyps are gray masses within the nose or sinuses that originate from the ethmoid sinus and project into the nasal cavity.^16,26 CRSwNP is characterized by nasal congestion, a decreased sense of smell and taste, and sleep disruption.^9,13,27 These symptoms place a substantial burden on patients, severely impacting their quality of life.^9,27,28 Patients report negative impacts on their psychological and social wellbeing due to decreased enjoyment of food, embarrassment about their symptoms (ie, nasal discharge), and poor sleep quality.^9,28

Key unmet needs remain for patients with CRSwNP, including feeling that the burden of disease they experience is underestimated by healthcare providers, and the ineffectiveness of current available treatments.²⁸

CRSwNP is most commonly associated with a Type 2 (T2) endotype, although many patients show evidence of a mixed endotype.^25,29 Endotypes vary geographically²⁴; while T2 inflammation is the predominant endotype in Western countries,^25,29 Asian countries may have higher proportions of Type 1 (T1) and Type 3 (T3) disease.^24,29 In recent decades, there has been an increase in the proportion of T2 endotypes in Asian countries, which may be caused by increasingly Western lifestyles in this region.²⁴

In patients with a T2 endotype, epithelial disruption leads to a cycle of T2 inflammation.³⁰ The defective epithelial barrier is more easily permeable, and epithelial cytokines (TSLP, IL-33, and IL-25) are released in response to external triggers acting on the epithelium.^16,30 All three epithelial cytokines have been shown to be overexpressed in patients with CRSwNP.^31–33 The release of TSLP and IL-33 in turn leads to the production of downstream mediators (ie, IL-4, IL-5, and IL-13) through the activation of innate Type 2 lymphoid cells (ILC2s) and mast cells^24,30,33; ILC2s, mast cells, and the T2 cytokines IL-5 and IL-13 have all shown to be elevated in patients with CRSwNP.¹⁶ These cytokines amplify the T2 inflammatory response,^30,33 while IL-4 and IL-13 may perpetuate barrier dysfunction through induction of additional TSLP expression.³⁰

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In patients with a T2 endotype, the release of TSLP and IL-33 leads to the production of IL-4, IL-5, and IL-13 through the activation of ILC2s and mast cells.^24,30,33

CRSsNP 

Of the two phenotypes, CRSsNP is considered to be the less severe disease.^16,24 Patients experience the nasal congestion and altered smell and taste that is characteristic of CRSwNP; additionally, nasal discharge and facial pain/pressure are key symptoms for patients with CRSsNP.^13,25  

For patients with CRSsNP, a key unmet need is the limited efficacy evidence for some existing treatments, in addition to the lack of research into novel treatments, as compared with CRSwNP.^12,24,34 

CRSsNP is a heterogeneous disease, characterized by multiple inflammatory endotypes.^25,34 Previously, CRSsNP was associated with T1 inflammation²⁴; however, it is now clear that the picture is more complex.²⁵ As with CRSwNP (albeit to a lesser extent), T2 inflammation is the dominant endotype for CRSsNP in Western patients,^24,25 whereas in some Asian populations, T1 inflammation predominates.²⁴ The presence of overlapping endotypes was found to be common (26%) in a study of US patients, as was the presence of no identifiable endotype (30%).²⁵

In patients with a T1 endotype, external stimuli acting on the epithelium activate dendritic cells (DCs) to produce IL-12 and IL-18.¹³ These act on innate Type 1 lymphoid cells (ILC1s) to release interferon (IFN)-γ and tumor necrosis factor (TNF)-α.¹³ It has been suggested that bacteria may play a role in CRSsNP³⁵; however, reports are conflicting and further research is needed to understand causality.^35,36 

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In patients with a T1 endotype, DCs produce IL-12 and IL-18 which act on ILC1s to release IFN-γ and TNF-α.¹³

Allergic rhinitis

Allergic rhinitis occurs following an immunoglobulin E (IgE)-mediated reaction to inhaled allergens, resulting in T2 inflammation in the respiratory tract.⁵ There remains an unmet need in the diagnosis of allergic rhinitis, owing to poor public awareness, limited access to specialists (eg, allergologists), and confounding diagnoses.^6,44

The early allergic response in allergic rhinitis involves allergen binding to IgE, triggering mast cell degranulation, resulting in acute allergic symptoms.^5,41 The late allergic response involves epithelial cytokines TSLP, IL-33, and IL-25 being released from the epithelium during allergen exposure.^5,6,43 These cytokines play a role in the initiation and maintenance of T2 inflammation through production of cytokines IL-4, IL-5, and IL-13,^5,6,41,43 all of which can lead to chronic allergic symptoms and inflammation in allergic rhinitis, as well as remodeling and nasal hyperresponsiveness.^5,41 Allergic rhinitis is also associated with an increased onset of airway hyperresponsiveness.^45,46 

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In patients with allergic rhinitis, TSLP, IL-33, and IL-25 are released following allergen exposure, leading to T2 inflammation through the cytokines IL-4, IL-5, and IL-13.^5,41,43

Non-allergic rhinitis  

Non-allergic rhinitis includes a group of heterogeneous rhinitis conditions, independent of an IgE-mediated mechanism and characterized by the presence of at least two nasal symptoms.^15,41,47 Patients with non-allergic rhinitis often have similar symptoms to patients with allergic rhinitis, but experience less sneezing and itching and more nasal congestion, nasal discharge, and sinus headaches.⁴⁸ 

Non-allergic rhinitis is also associated with significant disease burden^8,40; improvements in understanding of this disease and development of novel assessment and diagnostic tools are needed.⁴⁰

The exact mechanism of non-allergic rhinitis is still poorly understood, owing to the multiple heterogeneous presentations of the disease and a lack of both a uniform definition and international consensus on diagnostic criteria.^14,40,41 However, ILC2s are hypothesized to be potentially involved in a non-allergic rhinitis subtype (non-allergic rhinitis with eosinophilia syndrome [NARES]).⁵ In this process, TSLP, IL-33, and IL-25 can activate ILC2s, leading to eosinophil activation via production of IL-5.⁵ Infiltration of mast cells into nasal tissue has been implicated in other subtypes, non-allergic rhinitis eosinophilic mast cell syndrome (NARESMA), and non-allergic rhinitis with mast cells (NARMA).⁴⁹

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In patients with NARES, it is hypothesized that TSLP, IL-33, and IL-25 activate ILC2s, which leads to eosinophil activation via IL-5.⁵