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].