Immunological mechanisms
Despite clearly distinguishable, CRS phenotypes do not provide full knowledge into the underlying cellular and molecular pathophysiologic mechanisms of the disease, which are increasingly relevant because of the different association with comorbidities and their responsiveness to treatments as corticosteroids, surgery and/or biological agents [1,23]. Indeed, CRS etiology is very complex to define. At the basis of CRSwNP, in Western countries, there is the so-called Type 2 inflammation and related cytokines. Type 2 immune responses are defined by the cytokines interleukin-4 (IL-4), IL-5, IL-9 and IL-13, which can be host protective, yet, when dysregulated, have pathogenic activity [24]. Type 2 immunity induces a complex response involving granulocytes (eosinophils, basophils), mastocytes, type 2-innate lymphoid cells (ILC2), IL-4- and/or IL-13-conditioned macrophages and T helper 2 (Th2) cells [24]. These cells are crucial to the pathogenesis of CRS and related disorders (asthma [25]), therefore, driving mechanisms that control intensity, maintenance and resolution of type 2 immunity are reasonably important regulators of disease progression and have to be fully understood for therapeutical purposes.
In the context of damaged airways epithelium as in CRSwNP, triggers that initiate and perpetuate type 2 inflammation may be different: viruses, bacteria, allergens, cigarette smoke, pollutants, etc. Yet, there is increasing evidence that viruses may enhance type 2 immunological response by stimulating epithelial expression of cytokines Thymic Stromal Lymphopoietin (TSLP), IL-25 and IL-33 [26,27]. In turn, these cytokines promote an intense cellular response by activating mast cells, ILC2 and Th2 that release IL-5, IL-13 and IL-4. The product of this immune cascade is the activation of eosinophils (by means of IL-5 and IL-13) and B-cells (through IL-4) [27]. IL-4 and IL-13 and their common receptor complex (IL-4Rα) are significantly elevated in CRSwNP. Despite sharing the same signaling pathway, they play distinct roles: IL-4 is mainly involved in the survival and proliferation of Th2 cells and isotype class switching of B cells to produce IgE, while IL-13 induces airway hyperreactivity and mucus hyperproduction, as well as smooth muscle proliferation and fibrosis (i.e. tissue remodeling) [28,29]. IL-4 and IL-13 induce the abovementioned conditioned-state of macrophages, typical feature of CRSwNP [27].
Another molecule that in implicated in the pathogenesis of both CRSsNP and CRSwNP is transforming growth factor-β (TGF-β). TGF-β signals are fundamental in safe-guarding specific regulatory T cells (Treg) functions [30]. As Treg cells and TGF-β pathway are critical regulators of T cell tolerance, together they play important roles in the development of immune disorders, such as asthma and allergy [31]. In addition, TGF-β is a key factor in the remodeling process found in sinonasal mucosa with CRS. Specifically, TGF-β pathways were found to be upregulated in CRSsNP and downregulated in CRSwNP [32]. In the former scenario, TGF-β upregulation leads to induction of proliferation of fibroblasts, increased collagen deposition and extracellular matrix (ECM) production, as well as reduced metalloproteinases (MMP) activity, hence resulting in fibrosis and basement membrane thickening [33]. In CRSwNP, TGF-β downregulation contributes to greater MMP activity, degradation of ECM and deposition of albumin, which results in intense edematous stroma, subepithelial and perivascular inflammatory cells infiltration, formation of pseudocysts and polypoid degeneration [34].
Further mechanisms underlying CRS are complex and likely still unknown. As phenotyping is sometimes found insufficient to treatment efficacy, endotyping becomes necessary. In the scenario of Precision Medicine, identifying the specific pathophysiologic process of a patient’s endotype may permit more effective treatments, better patient’s outcomes and lower expenditures [35]. Also, defining the endotype is required to access the use of new targeted biotherapeutic molecules, such as anti-IgE and anti-cytokine monoclonal antibodies [36].