Pathological mechanisms and their relationships to features and endotypes
As mentioned above, in Western countries, CRSwNP is primarily characterized by type 2 eosinophilic inflammation and mixed inflammatory histopathology, while both eosinophilic and non-eosinophilic patterns are found in polyps from Asian patients 56,66. Interestingly, there has been a shift in the endotype distribution over time with an increase in the degree of eosinophilia observed in NPs from Asian patients 67,68. Furthermore, recent research suggests that neutrophilic inflammation may also play a role in the pathogenesis of Western NP 69. Thus, it is clear that inflammatory patterns in CRSwNP show geographic variability across Europe, Asia, and Oceania 56. While the neutrophilic inflammatory endotype has been demonstrated in parts of Asia and Europe, evidence is accumulating that, at least in the Western countries, CRSsNP, like CRSwNP, has a predominantly type 2 eosinophilic pattern57,70.
Both innate and adaptive immune responses are important in the pathogenesis and endotypes of CRS. The NP tissue is characterized by dysregulated epithelium, elevated Th2 cells, innate lymphoid type 2 (ILC2) cells, B cells, mast cells, eosinophils, and basophils48-51,54,71,72. The sinonasal epithelium is the principal source of TSLP which is essential for type 2 inflammation and activates ILC2 cells and effector Th2 cells 45. Investigators around the world have demonstrated elevated thymic stromal lymphopoietin (TSLP) in eosinophilic NP tissue 73-76. As already mentioned, Th2 and ILC2 are important sources of type 2 cytokines, including IL-4, 5, and 13 77. IL-5 promotes eosinophilic inflammation, and IL-4 and IL-13 activate isotype switching, mucus production, M2 macrophage differentiation, and remodeling in CRSwNP 45. Type 2 inflammation is believed to drive NP formation by promoting fibrin deposition and retention of plasma proteins and edema 33,78. In addition to expansion of Th2 and ILC2, B cells and plasmablasts are also increased and produce IgE and other immunoglobulins in NP tissue40,79. While CRSwNP is mainly type 2 (T2) in the West, some patients manifest type 1 (T1), type 3 (T3), or mixed inflammatory patterns with a combination of T1, T2, and T3 inflammation. T1 and T3 inflammation are associated with elevated IFN γ and IL-17A, respectively. A subset of patients with CRS lacks an elevation of any T1, T2, or T3 markers and are classified as untypeable. This subgroup may represent another endotype of CRS whose inflammatory pattern is yet to be identified (see Figure 2) .
The three major inflammatory endotypes are also present in CRSsNP55,57,58. It was initially proposed that type 1 inflammation associated with elevated IFN-γ was present in CRSsNP; however, this has not been confirmed in other studies40,57,80. Tan et al. investigated markers of inflammation in the ethmoid tissue from patients with CRS and controls and did not find a difference in IFN-γ among CRSsNP, CRSwNP, and controls. Type 2 markers of inflammation, including ECP, IL-5, and IL-13, were highest in NP and ethmoid tissue from patients with CRSwNP57. Interestingly, T2 markers of inflammation were also significantly elevated in the ethmoid tissue from patients with CRSsNP compared to the ethmoid tissue from controls. Furthermore, IL-17A, the primary marker of T3 inflammation, was elevated in the ethmoid tissue of a subset of patients with CRSsNP. More recently, Kato and colleagues have demonstrated that gene expression in CRSsNP is reminiscent of that in CRSwNP. As in CRSwNP, in CRSsNP, T1 is associated with T cells (Th1 and CD8+), NK cells, and antigen-presenting cells (APC), whereas T2 is associated with eosinophils, mast cells, Th2 cells, ILC2, and APCs and T3 CRSsNP is associated with Th17 cells, B cells, neutrophils, and APCs55. Wang et al. have also demonstrated that type 1 inflammation is predominant in Chinese patients from Beijing with CRSsNP, whereas patients from Chendgu, China, lack elevation of T1, T2, or T3 markers 56. Figure 2 shows a hypothetical overview of the inflammatory patterns of cells and responses as related to the three primary endotypes, independent of the phenotype (i.e. the presence or absence of polyps). We have adopted a shorthand that encompasses both endotype and the major phenotype. Type 2 CRSwNP is T2wNP in this scheme, while mixed type 1 and 3 CRSsNP would be T1,3sNP , etc. Figure 3 presents the pure and mixed endotypes and summarizes associated biomarkers. Occasionally, either CRSsNP or CRSwNP patients are identified that have all three endotypes elevated (T1,2,3sNP and T1,2,3wNP). The Tomassen paper identified 10 clusters/endotypes based on type 1 and 2 cytokines and inflammatory markers 43. Clusters associated with low or no IL-5 resembled predominantly the CRSsNP phenotype and had a low likelihood of comorbid asthma. The highest IL-5 clusters were mostly CRSwNP patients expressing IgE to Staphylococcus aureusenterotoxins. One of their clusters expressed IL-17 and had a mixed CRSsNP/wNP phenotype.