Immunopathogenesis of Chronic Rhinosinusitis and Nasal Polyposis

Abstract

Chronic rhinosinusitis (CRS) is a troublesome, chronic inflammatory disease that affects over 10% of the adult population, causing decreased quality of life, lost productivity, and lost time at work and leading to more than a million surgical interventions annually worldwide. The nose, paranasal sinuses, and associated lymphoid tissues play important roles in homeostasis and immunity, and CRS significantly impairs these normal functions. Pathogenic mechanisms of CRS have recently become the focus of intense investigations worldwide, and significant progress has been made. The two main forms of CRS that have been long recognized, with and without nasal polyps, are each now known to be heterogeneous, based on underlying mechanism, geographical location, and race. Loss of the immune barrier, including increased permeability of mucosal epithelium and reduced production of important antimicrobial substances and responses, is a common feature of many forms of CRS. One form of CRS with polyps found worldwide is driven by the cytokines IL-5 and IL-13 coming from Th2 cells, type 2 innate lymphoid cells, and probably mast cells. Type 2 cytokines activate inflammatory cells that are implicated in the pathogenic mechanism, including mast cells, basophils, and eosinophils. New classes of biological drugs that block the production or action of these cytokines are making important inroads toward new treatment paradigms in polypoid CRS.

Keywords: acantholysis; acanthosis; allergy; chronic rhinosinusitis; eosinophilic inflammation; epithelial barrier; epithelial-to-mesenchymal transition (EMT); glandular hyperplasia; nasal polyp; sinus disease.

Figure 1

Panel a, overview of gross anatomical and inflammatory changes associated with chronic rhinosinusitis and illustration of the mucociliary flow pattern within the sinuses. Panel b, computed tomography images of a healthy person and one with severe chronic rhinosinusitis with nasal polyps (CRSwNP). Panel c, endoscopic images from a healthy person and from one with severe CRSwNP.

Figure 2

Tabulation of some of the important biomarkers of differentiated healthy epithelium (left) and epithelium undergoing repair-associated epithelial-to-mesenchymal transition (EMT) (right). Markers shown in blue on the left are reduced in chronic rhinosinusitis (CRS), and markers shown in red on the right are increased in CRS. The literature strongly supports the existence of an ongoing, chronic EMT response in CRS. Shown on the far right of the figure are some known EMT inducers that have been implicated in CRS. Abbreviations: H1F1α, hypoxia inducible factor-1-alpha; IGF-1, insulin-like growth factor-1; IL, interleukin; JAM, junctional adhesion molecule; MMP, matrix metalloproteinases; MUC1, mucin 1; TGF-α, transforming growth factor α; ZO-1; zonula occludens.

Figure 3

Epithelial dysfunction in chronic rhinosinusitis (CRS). A normal injury–repair cycle is shown on the left, illustrating loss of differentiation and polarity of epithelial cells associated with migration, proliferation, and reformation of junctional structures with neighboring epithelial cells. Epithelial permeability is indicated by the color on the basolateral side of the mucosae, with red indicating significant leak and green indicating a tight barrier. Changes in the injury–repair cycle hypothetically associated with CRS are shown on the right.

Figure 4

Hypothetical timeline and interactions of events in the formation of nasal polyps. (Left) The damaged epithelium responds to injury from pathogens, proteases, and irritants. Abbreviations: BAFF, B cell–activating factor; CCL23, chemokine (C-C motif) ligand 23; DC, dendritic cell; IL, interleukin; ILC2s, type 2 innate lymphoid cells; MCP-4, chemokine (C-C motif) ligand 13, also known as CCL13; PAMP, pathogen-associated molecular patterns; Th2, T helper cell type 2; tPA, tissue plasminogen activator; TSLP, thymic stromal lymphopoietin; VCAM1, vascular cell adhesion molecule 1.