Pathogenesis of nasal polyposis

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition that affects a large proportion of the population world-wide and is associated with high cost of management and significant morbidity. Yet, there is a lack of population-based epidemiologic studies using current definitions of CRSwNP, and the mechanisms that drive pathogenesis in this disease remain unclear. In this review, we summarize the current evidence for the plethora of factors that likely contribute to CRSwNP pathogenesis. Defects in the innate function of the airway epithelial barrier, including diminished expression of antimicrobial products and loss of barrier integrity, combined with colonization by fungi and bacteria likely play a critical role in the development of chronic inflammation in CRSwNP. This chronic inflammation is characterized by elevated expression of many key inflammatory cytokines and chemokines, including IL-5, thymic stromal lymphopoietin and CCL11, that help to initiate and perpetuate this chronic inflammatory response. Together, these factors likely combine to drive the influx of a variety of immune cells, including eosinophils, mast cells, group 2 innate lymphoid cells and lymphocytes, which participate in the chronic inflammatory response within the nasal polyps. Importantly, however, future studies are needed to demonstrate the necessity and sufficiency of these potential drivers of disease in CRSwNP. In addition to the development of new tools and models to aid mechanistic studies, the field of CRSwNP research also needs the type of robust epidemiologic data that has served the asthma community so well. Given the high prevalence, costs and morbidity, there is a great need for continued research into CRS that could facilitate the development of novel therapeutic strategies to improve treatment for patients who suffer from this disease.

Fig. 1

Summary of the events and cell types involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. Immune cells shown on the top of the figure are elevated in polyp tissue from most European and American patients and a subset of Asian patients. Recent studies discussed in the text provide the basis for a model in which local expansion of T cells, B cells and plasma cells occurs with the help of local dendritic cells, resulting in the production of cytokines and immunoglobulins at high levels in the tissue (top left). Recruitment and/or activation of effector cells, shown on the top right, is likely a consequence of the activation of adaptive immune cells, tissue cells (e.g. epithelium and endothelium) and innate lymphoid cells. Activation of structural cells can contribute to cellular recruitment, leak and activation of plasma proteins, deposition of fibrin and modification of the extracellular matrix. The actions of both the immune and the structural cells lead to tissue remodelling, as summarized in part on the lower right.

Fig. 2

Theoretical role of local activation of fibrin deposition by type 2 inflammatory responses in type 2 diseases. Recent studies by Takabayashi et al. have shown that type 2 cytokines can promote deposition of fibrin by two important mechanisms. The first is the enhancement of fibrin cross-linking by the induction of factor XIII-A (FXIII-A in the figure) in M2 macrophages. This factor cross-links fibrin that has been liberated from fibrinogen by the action of thrombin or other fibrinogen activators. The second mechanism is by diminishing levels of tissue plasminogen activator (tPA), which is a major enzyme in the dissolution of fibrin clots or cross-linked fibrin. Within airways, tPA is expressed by epithelial cells, and IL-13 and IL-4 diminish expression of this important fibrinolytic enzyme. We hypothesize that these mechanisms may have originally evolved as part of the normal antiparasite response, but are inappropriately activated in CRSwNP and may contribute to polyp formation.

Fig. 3

Predominant role of type 2 inflammation in the mediation of CRSwNP. Type 2 cytokines are traditionally viewed as being derived from Th2 cells within an adaptive immune response. Th2 cells are activated by antigen-presenting cells (APC), including DC, B cells and others, along with a Th2-skewing cytokine milieu (lower left – APC shown are DC and B cell). The namesake cytokines of Th2 cells include IL-4, IL-5 and IL-13; these cytokines drive the recruitment and/or activation of mast cells, eosinophils, basophils, goblet cells, M2 macrophages, B cells, etc., as well as many of the tissue responses resulting from the factors that these inflammatory cells produce. Mast cells are further activated by specific antigen after local or systemic synthesis of antigen-specific IgE. Recent findings have shown that type 2 cytokines can also be produced by group 2 innate lymphoid cells, known as ILC2, that do not require direct activation by APC and antigen. ILC2 nonetheless produces a similar spectrum of cytokines and elicits similar effector responses as Th2 cells. ILC2 can be activated by proteases, pathogens and other stimuli. Multiple pathways by which ILC2 are activated by such stimuli have been described, especially in murine systems, and the precise mechanisms by which ILC2 are activated in CRS are under intensive scrutiny (see top of the figure).