Pathophysiologic mechanisms of chronic rhinosinusitis and their roles in emerging disease endotypes

Abstract

Objective: Chronic rhinosinusitis (CRS) is a heterogeneous disorder with distinct pathophysiologic mechanisms. Based on transcription factor expression and cytokine production patterns in different innate lymphoid cell (ILC) types, in parallel with those of adaptive CD4⁺ T-helper (T_H) cells and CD8⁺ cytotoxic T (Tc) cells, new perspectives on endotypes of patients are emerging for the immune response deviation into type 1 (orchestrated by ILC1s and Tc1, and T_H1 cells), type 2 (characterized by ILC2s and Tc2 and T_H2 cells), and type 3 (mediated by ILC3s and Tc17 and T_H17 cells). In addition, cluster analysis has been applied to endotyping of CRS in recent years, which has provided additional novel insights into CRS pathogenesis. This review assessed pathologic mechanisms of CRS based on type 1, 2, and 3 immune responses and how they inform us to begin to understand CRS endotypes. This review also assessed recent cluster analysis studies of CRS endotypes. The impact of endotype on therapeutic management of CRS also is summarized.

Data sources: Review of published literature.

Study selections: Relevant literature concerning CRS endotypes and possible underlying mechanisms was obtained from a PubMed search and summarized.

Results and conclusion: CRS with and without nasal polyps are composed of distinct endotypes with distinct deviated immune responses, pathogenic mechanisms, and different responses to medical and surgical treatment. An endotype of CRS with prominent type 2 immune responses is the best-studied endotype and generally can benefit from treatment with steroids and specific type 2 disrupting biologics.

Figure 1.. Type 2 immune responses and chronic rhinosinusitis

An overview of the type 2 immune responses in human chronic rhinosinusitis based on available evidence. After stimulation with innate immune activating stimuli, cytokines or injurious environmental agents such as proteases, epithelial cells produce thymic stromal lymphopoietin (TSLP), and perhaps in some cases interleukin (IL)-33 or IL-25, which activate group 2 innate lymphoid cells (ILC2s). Epithelial cell-derived TSLP up-regulates OX40L expression on dendritic cells (DCs), then DCs initiate the differentiation of naïve T cells into type 2 T helper (Th2) cells. Th2 cells, ILC2 and type 2 cytotoxic T (Tc2) cells orchestrate eosinophilic inflammation through production of type 2 cytokines. IL-4⁺IL-21⁺ T follicular helper (Tfh) cells initiate the differentiation of B cells into plasma cells, then mast cells are activated by IgE which is produced locally by plasma cells; the kynurenine (KYN)/aryl hydrocarbon (AhR) axis may be involved in this process. In addition, mast cells can also produce type 2 cytokines. Th2 inflammation can induce monocytes/macrophage differentiation into M2 macrophages. M2 macrophages produce coagulation factor XIII-A (FXIII-A) that induces excessive fibrin deposition by cross-linking of fibrin and via the antifibrinolytic pathways through binding α₂-Plasmin inhibitor (α₂-PI, also known as a2 antiplasmin) to fibrin. Meanwhile, tissue plasminogen activator (t-PA) levels are reduced in Th2 inflammation, causing impaired plasmin generation, which, in turn, decreases fibrinolysis. These events collectively result in retention of water and formation of edema in polyps. Th2 cytokine-mediated pendrin expression may increase mucus production. The cytokines IL-4 and IL-13 can diminish the expression of epithelial cell tight junction proteins. Neutrophil-derived oncostatin M (OSM) and eosinophil-derived DNA traps may also contribute to epithelium disruption.

Figure 2.. Type 1 and 3 immune responses and CRS

An overview of the type 1 and 3 immune responses in human chronic rhinosinusitis based on available evidence. In response to environmental stimuli, epithelial cells secrete osteopontin (OPN); OPN-stimulated dendritic cells (DCs) induce type 1 T helper (Th1) and type 17 T helper (Th17) cell differentiation. Th1 and Th17 cells as well as type 1 cytotoxic T (Tc1) and type 17 cytotoxic T (Tc17) cells orchestrate noneosinophilic inflammation through production of interferon γ (IFN-γ), interleukin (IL)-17A and IL-22. IL-17A upregulates the expression of IL-36γ in epithelial cells, and IL-36γ can act on neutrophils and further exaggerates neutrophilic inflammation by inducing IL-8/CXCL8 production from neutrophils. IL-22 induces epithelial cells to produce IL-8/CXCL8, then IL-8/CXCL8 act on neutrophils. Neutrophils can also produce oncostatin M (OSM), OPN and transform growth facto β2 (TGF-β2). TGF-β2 may be involved in fibrosis. IFN-γ and OSM may disturb epithelial barrier function by diminishing the expression of epithelial cell tight junction proteins. IFN-γ can induce activated but insufficient autophagy, leading to apoptosis of nasal epithelial cells. IL-17A⁺IL-21⁺ Tfh cells initiate B cell differentiation into plasma cells that produce IgG and IgA.