الفهرس 
Innate ImmunityOnly 14 pages are availabe for public view
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Abstract
syndrome associated with persistent inflammation of the mucosa of the nose and paranasal sinuses. The definition of CRS is intentionally inclusive, encompassing, for example, both the polypoid (CRSwNP) and non polypoid (CRSsNP) forms of the disease but does not address causation or etiology. Objective evidence for mucosal inflammation using nasal endoscopy and/or computerized tomography (CT) is required for confirmation of the diagnosis.
Historically, CRSsNP was considered to result from an incompletely treated case of acute infectious rhinosinusitis resulting in chronic infection. CRSwNP was considered a distinct, non infectious disorder of unclear etiology, perhaps related to atopy.
Over the last decade, two dominant hypotheses attempted to broadly explain CRS etiology as a response to common intranasal organisms: the Alternaria ‘fungal hypotheses’and staphylococcus aureus ‘superantigen hypotheses’. These current prevailing theories have focused interest on identification of the predominant, presumably microbial, agents inciting CRS rather than searching for a putative defect(s) in the host response. Data confirming either fungi or staphylococci as the primary antigenic or etiologic agent triggering CRS are limited, however, and clinical success with either antifungal or antibiotics has unimpressive. Furthermore, these two classes of organisms can be identified in nasal lumen of a high percentage of normal people without CRS, indicating that disease expression will manifest only in susceptible individuals. from this perspective, CRS may be viewed as analogous to inflammatory bowel disease, where in tolerance mechanisms toward commensal organism are impaired.
The shifting emphasis away from environmental and microbial agents toward identifying host susceptibility is well established in other chronic inflammatory disease involving epithelial surfaces such as atopic dermatitis, asthma and inflammatory bowel disease. Theoretically, the primary susceptibility could reside in the host acquired immune system, such as in Tcell subsets for example, but epidemiologic research into CRS suggests that its incidence is not strongly correlated with other inflammatory condition outside the airway, suggesting that susceptibility specific to the airway epithelium is more likely.
The respiratory epithelium now is known to be involved in innate immunity. The innate immune system comprises cells and their associated mechanisms that provide the first line of defense against pathogens through genetically encoded pathways with limited specificity for molecular structures. In addition to the physical barrier and pathogen clearing effects of the mucociliary clearance system, sinonasal mucosa has been shown to express a vast arsenal of antimicrobial molecules.
Research on the innate immune system over the years had focused on a number of large topics. The first topic was the diverse role of (airway) epithelium in the innate defense. The second topic was the activity of different receptors by which cells can detect the outside environment, and the third was the action of secreted mediators that fight off potential threats.
The sinonasal mucosa serves as site of interface with inhaled irritants, aero-allergens, commensal organisms and pathogens. Mucociliary clearance and apical junctional complexes (AJCs) between epithelial cells comprise a mechanical barrier between host and environment. In CRS evidence for barrier disruption includes significantly diminished tight junction proteins and increased ion permeability when compared with normal controls. Recent studies demonstrated that SPINK5 which encodes the protein LEKT1, a protease inhibitor involved in maintaining epithelial barrier function, is significantly decreased.
Toll-like receptors (TLRs) have been at the forefront of research into innate immunity. As such, they are best described family of receptors by which cells can detect microorganisms in their environment. Also in CRS related research, there has been great interest in these receptors as triggers of innate immune reactions. However, recent findings show that we probably need to broaden our view. One of the first negative results comes from the field of TLR2, in which despite previous observations of a link between lower expression of TLR2 and difficult-to-treat CRS none of the investigated polymorphisms in the TLR2 gene could be linked to the disease. Interestingly, one possible explanation is that we should not consider one receptor or one trigger in isolation. Although the design of the study would have been better with the inclusion of more than one concentration of stimuli.
In general, earlier studies of CRS did not demonstrate consistent alterations in the expression of antimicrobial molecules, with increased levels reported in some molecules, whereas others are reportedly decreased. Recent studies suggested that the S100 proteins might play a significant role in mediating some forms of CRS. The S100 proteins have multiple effects on cell differentiation and barrier function and several members (e.g. S100A7, S100A8 and S100A9) act as antimicrobial proteins with direct antibacterial and antifungal effects. Taken together, these studies suggest that diminished S100 protein in sinonasal epithelial cells may predispose to development of CRS, possibly through increased microbial colonization or diminished wound healing.
One study focuses on SNPs within a member of SERPIN family. This family of proteins is named after the proteins’ability to inhibit the protease activity of serine protease.One of the important target molecules of SERPIN-A1 is the elastase produced by neutrophils after exposure to bacterial superantigens or allergens and could therefore contribute to the ongoing inflammation in CRS. Indeed, one of the SNPs investigated was linked to a nearly sixfold increase in the risk of developing CRS. Whether this mutation had consequence for the activity of SERPIN-A1 or its secretion was not investigated.
An important inducer of innate immune responses is the cytokine IL-22 that is secreted by Th17 and Th1 cells and activates epithelial cells via the IL-22 receptors (IL22R). In CRSwNP, the levels of IL22R1 were found to be significantly decreased in nasal polyposis when compared with controls, suggesting a diminished IL-22 response in CRSwNP. This provides an interesting paradigm in which decreased IL-22R on nasal epithelial cells may impair innate immune responses in CRSwNP.
In the study of CRS etiology, most interest still centers on identification of putative inciting microbial agents, likely reflecting an earlier era when sinonasal disease was primarily infectious in nature. Comparatively few studies on CRS etiology have focused on host defects, despite recent acceptance that CRS is best considered an inflammatory disease. Although the evidence for the hypothesis that innate immune barrier function is compromised in CRS is currently very limited, it places the current controversies in rhinology in a framework consistent with modern concepts of complex genetic disorders and chronic mucosal inflammatory disease in general.