Immunopathology of chronic rhinosinusitis

Abstract

Chronic rhinosinusitis (CRS) is a heterogeneous disease characterized by local inflammation of the upper airways and sinuses which persists for at least 12 weeks. CRS can be divided into two phenotypes dependent on the presence of nasal polyps (NPs); CRS with NPs (CRSwNP) and CRS without NPs (CRSsNP). Immunological patterns in the two diseases are known to be different. Inflammation in CRSsNP is rarely investigated and limited studies show that CRSsNP is characterized by type 1 inflammation. Inflammation in CRSwNP is well investigated and CRSwNP in Western countries shows type 2 inflammation and eosinophilia in NPs. In contrast, mixed inflammatory patterns are found in CRSwNP in Asia and the ratio of eosinophilic NPs and non-eosinophilic NPs is almost 50:50 in these countries. Inflammation in eosinophilic NPs is mainly controlled by type 2 cytokines, IL-5 and IL-13, which can be produced from several immune cells including Th2 cells, mast cells and group 2 innate lymphoid cells (ILC2s) that are all elevated in eosinophilic NPs. IL-5 strongly induces eosinophilia. IL-13 activates macrophages, B cells and epithelial cells to induce recruitment of eosinophils and Th2 cells, IgE mediated reactions and remodeling. Epithelial derived cytokines, TSLP, IL-33 and IL-1 can directly and indirectly control type 2 cytokine production from these cells in eosinophilic NPs. Recent clinical trials showed the beneficial effect on eosinophilic NPs and/or asthma by monoclonal antibodies against IL-5, IL-4Rα, IgE and TSLP suggesting that they can be therapeutic targets for eosinophilic CRSwNP.

Keywords: Chronic rhinosinusitis; Eosinophilia; Nasal polyps; TSLP; Type 2 inflammation.

Fig. 1

Potential mechanism for amplification of type 2 inflammation in eosinophilic CRSwNP. Several factors including fungi, proteases, S. aureus, bacteria, viruses and allergens can activate nasal epithelial cells to induce the production of epithelial derived cytokines TSLP, IL-33 and IL-1. Epithelial derived cytokines activate three types of immune cells in NPs. TSLP stimulates mDCs to induce naive CD4⁺ T cell differentiation into Th2 cells which then induce adaptive type 2 inflammation. TSLP and IL-33 stimulate ILC2s to induce the production of type 2 cytokines (innate type 2 inflammation). Mast cells are accumulated in the epithelium and are also present in the mucosal area in NPs. TSLP, IL-33 and IL-1 stimulate epithelial and mucosal mast cells to produce IL-5 and IL-13 (innate type 2 inflammation). Ag/IgE/IgER complexes on mast cells induce degranulation and thereafter mast cells produce IL-5 and IL-13 (adaptive type 2 inflammation). Production of PGD2 and LTC4 from mast cells also stimulates ILC2s. IL-5 promotes eosinophilia and eosinophils produce CCL23 to recruit macrophages and mDC. IL-4/13 activates macrophages, B cells and epithelial cells to induce eosinophil and Th2 cell recruitment, remodeling and IgE mediated reactions. M2 macrophages produce eotaxins and CCL18 to recruit eosinophils, mDCs and Th2 cells.

Fig. 2

Increased presence of immune cells in NPs. Representative H&E staining in NPs is shown in A. Representative immunostainings were performed with anti-ECP mAb (EG2) for eosinophils (B), anti-neutrophil elastase (NE) mAb for neutrophils (C), anti-tryptase mAb for mast cells (D), anti-CD163 mAb for M2 macrophages (E), anti-CD1c mAb for mDC1s (F), anti-CD3 mAb for T cells (G) and anti-CD20 mAb for B cells (H). Immunofluorescence assay was performed with anti-CD3 mAb (red fluorescence), anti-CD20 mAb (green fluorescence) and anti-CD138 mAb (orange fluorescence) for plasma cells (I), Nuclei were counterstained with 4^′6-diamidino-2- phenylindole (DAPI; blue fluorescence). Magnification; ×200.