NP is a chronic inflammatory disease of the mucous membranes in the nose and paranasal sinuses. The role of the immune system in the pathogenesis of this disease is still unknown. To date, many studies have reported significant changes in presence of numerous inflammatory cells, mediators, cytokines, chemokines, and other inflammatory and immune modulating components in NPs, indicating that chronic inflammation is an important factor in development of NPs irrespective of the etiology.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a T(H)2-skewed eosinophilic inflammation, whereas chronic rhinosinusitis without nasal polyps (CRSsNP) represents a predominant T(H)1 milieu (18). In this report, the authors were able to show a significantly lower forkhead box P3 (FOXP3) mRNA and transforming growth factor beta-1 (TGF-beta1) protein expression, but a significantly higher T-bet, GATA-3, IL-5, and IL-13 mRNA expression compared with the healthy controls (Table 1). This T(H)2-skewed eosinophilic inflammation was shown by a decreased expression of multiple antimicrobial innate immune markers, including toll-like receptor 9, human beta-defensin 2 and surfactant protein A, in human sinonasal epithelial cells from CRSwNP. The authors suggested that the impaired mucosal innate immunity may contribute to microbial colonization (e.g., bacteria, fungi and etc.) and abnormal immune responses associated with CRSwNP (20). In another study, an increased expression level of complement component C1q in NPs is suggested to be indicative of an ongoing inflammatory response in the nasal mucosa of these patients (21).

Innate immune recognition of pathogens by sinonasal epithelial cells may play an important role in the pathogenesis of chronic mucosal inflammation in rhinosinusitis (CRS) (22, 23). In Table 1, alterations in expression levels of several genes associated with immunopathogenesis in nasal mucosal or NP tissues are indicatives of an ongoing inflammation and impaired mucosal innate immunity in patients with CRS with or without NPs.

The general histopathological classification of NPs is eosinophil-dominated inflammation (80-90%), which appears to be a hallmark of Caucasian NPs (3). This statement is well supported by an increased expression of cytokines, chemokines and molecular markers, which are involved in the proliferation, migration, activation and survival of eosinophils (Table 2). In the literature, IL-5 and eotaxin are most frequently reported molecular markers in NPs, as they are essential for eosinophil development, activation and survival (3). The soluble IL-5Rα expression level was also found to be dramatically higher (up to 1,200 times) than IL-5 concentrations in NP (37).

In addition, infiltration of other types of inflammatory cells, especially lymphocytes and neutrophils, may also play an important role in the inflammatory process underlying the pathogenesis of NPs (38-40). In Table 2, increased expression levels of growth-related oncogene-alpha (GRO-alpha), stem cell factors (SCF) and C-C chemokine ligand 2 are associated with biological functions of neutrophils, mast cells and macrophages. Therefore, in NP studies, one may not rely solely on limited type of cells and number of molecular markers (e., g., IL-5 and eotaxin) as NP is a heterogeneous disease with complex pathogenic mechanisms involved.

Histomorphological characterisation of NP tissue reveals frequent epithelial damage, a thickened membrane, and oedematous to sometimes fibrotic stromal tissue, with a reduced number of vessels and glands, but virtually no neutral structure (3). Many genetic studies have resulted in an emphasis on the structure modification of the epithelium in NPs. Table 3 shows the changes in expression level of many important genes, which are associated with proliferations of nasal epithelial and endothelial cells, submucosal glandular cells, regulation of goblet cell mucins, tissue remodelling, angiogenesis, impaired electrolyte and water transport across the epithelial cells, epithelial barrier maintenance and repair, and etc. However, pathogenic mechanisms underlying the changes of these structural gene functions are not clear.

There are a number of genes which are involved in epithelial barrier maintenance and repair in the inflammatory state of chronic rhinosinusitis (CRS) with NPs. For example, carbonic anhydrase (CA) is a zinc metalloenzyme that participate in the biological processes of various fluid transporting epithelia, including ion and water transport. In this study, a decreased expression level of CA was found to be associated with impaired electrolyte and water transport across the epithelial cell, which will result in oedema of NP tissue (56). In another study, the level of epidermal growth factor receptor (EGFR) mRNA in human sinus mucosa was found to be statistically significantly increased compared with that in the healthy controls (57). It is therefore suggested by the authors that up-regulation of the EGFR cascade may have an important role regarding mucus production in the sinus mucosa of patients with CRS and CRS with NP associated with hyperplasia and metaplasia of epithelial goblet cells.

Epithelial differential and tissue remodelling is also reported to be involved in the development and pathogenic characterization of NPs. It was reported that an increased expression level of PDGF-B, TGF-beta1, and lower expressions of lumican and biglycan were found in NPs as compared to the healthy controls (Table 3). However, controversial results of TGF-beta1 expression level were also reported by other studies, where the expression levels of TGF-beta1 in NPs appeared to be low in NPs (Table 3).

Using a genome-wide expression microarray, some studies have reported a few genes with significant changes in expression profiles in NP tissue as compared to healthy controls (Table 4). However, the biological functions of some of these genes (e.g., plasma membrane intrinsic protein [PIP], deleted in malignant brain tumors 1 [DMBT1], Mammaglobin and CC10) underlying the pathogenic mechanisms of NP development are unclear and need to be investigated in future.

Mutation and differential expression of the ras family genes contributing to tumourigenesis either through the accumulation of mutations or by aberrant expression in a wide range of human cancers has been well demonstrated. However, a recent study found that K- and H-ras expression levels were elevated, whereas N-ras mRNA levels were lower in NPs and adjacent turbinates as compared to the healthy control tissues. K-ras mRNA levels were up-regulated in advanced-stage polyps, while N-ras levels were found elevated in small polyps (78). These findings suggest a potential key role for activated members of ras family genes in terms of their contribution to the development of NPs as well as to the hypertrophy of adjacent turbinates.

The presence of aspiring-intolerance in a patient with CRS with or without NPs is associated with a particularly persistent and treatment-resistant form of disease, coexisting usually with severe asthma and referred to as the "aspiring triad" (3). In a recent study, genome-wide expression microarray study was performed in 57 patients with three distinct phenotypes: 1) patients with chronic rhinosinusitis and sinonasal polyposis without a history of aspirin allergy (CRS group); 2) patients with chronic rhinosinusitis and sinonasal polyposis with a history of asthma and aspirin allergy (ASA group); and 3) patients with no history or clinical evidence of sinusitis, asthma, or aspirin allergy (control group) (79). This study was able to identify five genes (POSTN, MET, PIP, AZGP1, and PPP1R9B) that are likely to play a role in the pathogenesis of sinonasal polyps associated with CRS and ASA (Table 4).