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.