allergic rhinitis, chronic rhinosinusitis and asthma

REVIEW

CURRENTOPINION Allergic rhinitis, chronic rhinosinusitis and asthma:

unravelling a complex relationship

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1068-9508 � 2013 Wolters Kluwer

Harsha H. Kariyawasam and Giuseppina Rotiroti

Purpose of review

Allergic rhinitis, chronic rhinosinusitis (CRS) and asthma have a high worldwide prevalence and confer asignificant socioeconomic burden. This article reviews the recent advances in allergic rhinitis, CRS andasthma with view to understanding the upper and lower airway as one system.

Recent findings

Allergic rhinitis, CRS and asthma demonstrate strong epidemiological coassociation, and early life riskfactors for upper airway disease are now apparent. The absence of demonstrable peripheral IgE does notstrictly classify airway disease as nonallergic. Excess mucosal inflammation with immune dysregulation is acommon feature to all. An important role for innate immunity is now apparent and offers prospects of noveltherapeutic approaches in the future. A role for bacterial superantigens is also emerging in all threediseases. Genetic studies highlight common associations between allergic rhinitis, CRS and asthma.

Summary

Whether such overlapping pathological findings reflect a manifestation of the same disease but in relationto the different airway locations in individuals with genetic predisposition remains unknown, althoughlikely. This continues under investigation and debate. The current research priorities are to understand whatkey events predispose to both upper and lower airway disease together and the critical immunologicalfactors that establish and sustain airway inflammation.

Keywords

allergic rhinitis, asthma, chronic rhinosinusitis, disease overlap, immunopathogenesis

Allergy and Medical Rhinology Section, Royal National Throat Nose EarHospital, UCLH NHS Foundation Trust, University College London,London, UK

Correspondence to Harsha H. Kariyawasam, PhD, MBBS, Allergy andMedical Rhinology Section, Royal National Throat Nose and Ear Hospital,330 Gray’s Inn Road, London WC1X 8DA, UK. Tel: +44 207 915 1674;fax: +44 207 915 1674; e-mail: [email protected]

Curr Opin Otolaryngol Head Neck Surg 2013, 21:79–86

DOI:10.1097/MOO.0b013e32835ac640

INTRODUCTION

The airway is a continuous structure that extendsfrom the nasal vestibule to the alveolar units of thelung. Its mucosal surface is constantly exposed tothe outside world. It is thus highly adapted in its roleas first defence against diverse environmentalinsults, whether from irritants, allergens or micro-organisms. The airway must mount a rapid andeffective mucosal response against such harmfulagents when needed, whilst at the same time regu-lating the extent of such mucosal activation, termi-nating such reactions appropriately. This defenceresponse is instigated using the highly effectiveinnate and adaptive arms of the immune system,dysregulation of which is implicated in the patho-genesis and sustenance of allergic rhinitis, chronicrhinosinusitis (CRS) and asthma. The strong coex-istence of allergic rhinitis and CRS with asthma andthe common overlap in immunopathology suggeststhese diseases are related. They may thereforebenefit from similar immunomodulatory thera-peutic approaches. Recent findings that highlight

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common factors in the upper and lower airway inrelation to allergic rhinitis, CRS and asthma areevaluated.

EPIDEMIOLOGY

Epidemiological studies provide insight into thefactors that may predispose to disease and highlightsignificant associations. Despite the close associ-ation of rhinitis and CRS with asthma, along withthe greater prevalence of more symptomatic asthmain individuals with associated upper airway disease,

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KEY POINTS

� Allergic rhinitis, CRS and asthma commonly coexistand share mechanisms by which disease predispositionand propagation may occur.

� Current classification of disease as allergic andnonallergic is too simplistic, given local mucosal IgE isfound in allergic rhinitis, CRS and asthma.

� The innate immune system is increasingly recognizedas having a dominant drive for airway disease, withthe ability to not only augment established inflammationbut also to bypass classic inflammatory pathways.

� Local mucosal factors such as bacterial superantigensare emerging as potent airway inflammatoryenhancement cofactors.

� Understanding upper and lower airway disease as onesystem is an urgent research priority, as emergingtherapeutic approaches may be effective for allergicrhinitis, CRS and asthma together.

Nose and paranasal sinuses

how different sinonasal phenotypes relate to exactasthma phenotypes remains unknown. In a postal-based survey with over 18 000 responses, the find-ings were that greater the prevalence of rhinitis andCRS symptoms singly or together, the higher wasthe association of more symptomatic asthma [1].Also, separate environmental influences such asmould or mould risk (home water damage), pollu-tants and dust exposure predisposed to a higherodds ratio (OR) for asthma with CRS rather thanallergic rhinitis alone. Symptom expression inasthma was different in relation to the coexistentsinonasal clinical type, with CRS associated withmore difficult asthma symptoms, prompting theauthors to speculate how different upper airwayphenoendo types may relate to asthma subtypes.More work is needed to take forward such ideas, butthis observation would appear to support previousfindings that asthmatics with associated CRS ratherthan allergic rhinitis declare more asthma-relatedpoor quality of life (QOL) [2]. The recent demon-stration of the parallel existence of severe asthmawith difficult more-extensive CRS, albeit associatedwith potential disease-modifying factors of nasalpolyps and allergic sensitization [3], may furthersupport the concept of bidirectional upper andlower airway inflammation demonstrated pre-viously in allergic rhinitis [4,5].

No real data on early life predisposing factors forallergic rhinitis in relation to disease incidence havepreviously been available. Using a questionnaire-based survey in 8486 individuals at baseline and9 years apart, useful information on the naturalhistory of rhinitis in Europe and independent

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predictors of disease has been obtained [6&

]. Earlychildhood risk of allergic rhinitis decreases in chil-dren with exposure to siblings or day school, whilstfarm upbringing was associated with less rhinitis inadolescence. Individuals with a maternal history ofsmoking in pregnancy and early childhood demon-strated consistently increased risk of rhinitis as didindividuals with a family history of allergic disease[6

&

]. A separate study, using a Swedish birth cohortfrom 1973 to 2009, showed that a low gestationalage at birth rather than the degree of foetal growthled to less allergic rhinitis later on [7

&

]. The authorshere hypothesize this may be as a result of earlierexposure to microbes that confers immunologicalprotection. Such studies bring us closer to perhapsinitiating preventive measures for high-risk individ-uals in the future and allow further hypotheses onmechanistic and therapeutic approaches to bedeveloped. These studies provide growing supportfor the ‘hygiene hypothesis’ for allergic rhinitis asestablished in asthma. Interestingly, a recent pro-spectively performed study showed that being bornand raised on a farm significantly reduced the oddsrisk ratio for asthma, whereas atopic status had noassociation [8]. Also, a detailed study demonstratesthat diversity of microbial exposure is inverselyrelated to the risk of asthma [9

&&

]. Thus, earlymicrobial exposure may be an early life determinantfor both allergic rhinitis and asthma developmentand airway immune intolerance as such is verymuch influenced by environmental factors.

CRS is subdivided into with (CRSwNP) and with-out nasal polyps (CRSsNP) subtypes. Epidemiolog-ical CRS data is sparse. It is only recently that theoverall European prevalence of CRS using the EP3OSdiagnostic criteria [10] has been determined at10.9% of the population, with an excess of smokersin this group [11]. The first population-based surveyto definitely show the strong association of CRS withasthma, particularly when allergic rhinitis coexists,was recently published [12

&

]. Also, nonallergic CRSis associated with late-onset nonallergic asthma,both being airway phenotypes that are moredifficult to treat.

CRSwNP and asthma are commonly seentogether. In fact, lower airway dysfunctionsuggesting an underlying asthma phenotype hasbeen shown to be present in CRSwNP even whenovert clinical asthma has not been declared [13]. Itwould be helpful to undertake longitudinal studiesin such ‘asymptomatic’ individuals to determine thetime course to active asthma development if everand see whether upper airway intervention modu-lates such progression. Overall, these recent studiesconfirm the strong coexistence of CRS in asthmaand would suggest overlapping disease mechanisms.

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Volume 21 � Number 1 � February 2013

Upper airway disease and asthma Kariyawasam and Rotiroti

CLASSIFICATION OF DISEASECurrent thinking considers rhinitis, CRS and asthmaas syndromes rather than exact disease entities, withdistinct clinical phenotypes and biological endo-types. Both rhinitis and asthma are broadly dividedinto allergic and nonallergic rhinitis (NAR) subtypesbased on demonstration of IgE to an aeroallergencompatible with a history of symptoms on exposure.Recent findings demonstrate that this classificationis not strictly correct, being far too simplistic. Inindividuals with no demonstration of skin or bloodIgE to allergen, excess nasal and bronchial mucosalIgE has been demonstrated previously, although theexact antigenic specificity of such IgE has so far beenspeculative [14]. It has now been shown that aproportion of individuals with NAR have localmucosal IgE production to an array of allergens thatcan provoke symptoms on allergen challenge [15

&&

].Such rhinitis is being classified now with the newterm local allergic rhinitis (LAR). The prevalence ofthese new LAR phenotypes needs to be determinedand whether they will respond to immunotherapyas a therapeutic intervention remains unknown.Nonallergic asthmatics have also been shown todemonstrate increased bronchial house dust mite(HDM) specific IgE recently, although allergen chal-lenge failed to provoke asthma [16]. The emergingrole for local mucosal IgE in CRS and the implica-tions for CRS classification are discussed later.

ADAPTIVE IMMUNITY

In allergic rhinitis, CRS and asthma, antigen-specificIgE production, mast cell activation with degranu-lation and eosinophilia are the key findings [17].Previous studies have failed to analyse upper andlower airway biopsies from the same volunteertogether. The analysis of nasal and bronchial bio-psies in the same individual with allergic rhinitisand asthma demonstrated similar numbers of mastcells, eosinophils, neutrophils and CD3þ T cells,confirming parallel upper and lower inflammationin the same airway [18].

So far, the focus has been in relation to under-standing the airway adaptive immune system(Fig. 1). Allergen sensitization to aeroallergens suchas HDM begins in childhood with the production ofallergen-specific IgE. The most simplistic concept isthat such IgE on mast cells recognizes allergen andleads to mast cell degranulation which initiates aseries of inflammatory cascades. This then rapidlymanifests as disease symptoms with repetitive aller-gen exposure leading to a chronic disease state(Fig. 1). Allergen sensitization occurs via antigen-presenting cells called dendritic cells. These cells arefound in association with the airway epithelium and

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submucosa, but will have migrated from the bonemarrow in response to signals from the airway inrelation to injury and activation of the epitheliumby microbes, irritants and after antigen sensitiz-ation. Allergen is actively taken up by dendritic cellsand presented to naı̈ve T cells that undergo polar-ization to immune subtypes based on coexistentimmune signals. The selective expansion of naı̈veT cells into predominantly Th2 cells that secrete animportant group of cytokines which include inter-leukin (IL)-4 (for IgE isotype class switching on Bcells and Th2 cell survival), IL-5 (eosinophil devel-opment, recruitment and survival), IL-9 (mast cellmaturation) and IL-13 (promotion of allergicinflammation and mucus production) is consideredfundamental to disease pathogenesis in allergic rhi-nitis and asthma, and important roles in CRS arenow apparent.

Specific roles for other T-cell subtypes such asTh1 (associated with more bacterial or viral infec-tion related immunity), Th9 (Th2 cell differen-tiation) and Th17 (neutrophilic inflammation) areemerging in airway disease. Although early reportsindicate increased numbers of Th17 cells in bothserum and nasal tissue in allergic rhinitis, therelationship to pathogenesis of allergic rhinitis isnot understood [19]. In the CRSsNP subgroup, Th1dominance with a more significant neutrophilicinflammation is common along with a cytokineprofile of excess IFN-g, IL-1, IL-3, IL-6 and IL-8(neutrophil chemoattractant) that reflect a moreTh1 T-cell immune response [20]. Late-onset non-allergic neutrophilic asthma with excess IL-8 expres-sion can be associated with this CRS phenotype, andboth diseases are often poorly responsive to cortico-steroids but may respond to macrolide antibiotics[10,21]. The exact role for Th17 cells in asthma isstill unknown, but may contribute to neutrophil-driven, steroid-resistant severe asthma.

CRSwNP is a more distinct immunologicaldisease. Th2 dominance with excess IL-5 (tissueeosinophilia) and increased IL-4 and IL-13 expres-sion is observed, and aspirin-sensitive asthma is adistinct association with this CRS phenotype [22].Studies so far have not shown any increase of Th17cells in either CRSsNP or CRSwNP in nasal tissuefrom a European population [22]. This is surprisingas CRSwNP has a high bacterial burden and IL-17 isimportant in immune defence to extracellularbacteria and augments inflammation. In contrast,Chinese polyp tissue expresses IL-17 in excess,regardless of coexistent or dominant eosinophilicinflammation [23,24]. The reasons for such differ-ences are unclear, but important to understandto allow functional understanding of CRS endo-types. Bronchial biopsies from such patients with


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Airway mucosa

Innate immunityAdaptive immunity

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etic

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Excess IgE

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Immunopathogenesis Disease

FIGURE 1. Summary of current immunological pathways common to AR, CRS and asthma. 1a. Antigen-presenting cells calleddendritic cells (DCs) take up antigen and present processed antigen peptide in the context of MHC Class II to naı̈ve T cellswhich undergo differentiation to T-cell subtypes based on other immunological cofactors. Th2 cells interact with B cells togenerate antigen-specific IgE (termed allergen sensitization) that can bind mucosal mast cells (MCs). 1b. Allergen impaction ofthe mucosal surface leads to solubilization and diffusion to sites of MCs, where cross-linking of two or more high affinity(FceRI) IgE receptors leads to MC activation and subsequent degranulation and release of mediators. This leads to acutesymptoms and further enhancement of underlying chronic inflammation. 2. Overlapping T-cell-driven mucosal pathwaysprobably converge to determine disease phenotypes and endotypes. Tissue eosinophilia and mucosal IgE production oftendominate, but a role for neutrophilic inflammation is emerging. 3. Increased activation of epithelium via the TLR system andgeneration of potent cytokines such as TSLP, IL-25 and IL-33 can lead to signalling to submucosal inflammatory cells in apowerful manner and is believed to drive disease independent of adaptive immune pathways. Innate lymphoid cells (ILCs) thatare particularly responsive to such cytokines have at least been confirmed in CRSwNP. 4. Local factors such as bacterialsuperantigens can promote further local inflammation and enhance the generation of mucosal IgE. 5. On the basis of exactgenetic predisposition and environmental factors along with exact mucosal local factors, AR, CRS and asthma can manifest.AR, allergic rhinitis; TLR, toll-like receptor; TSLP, thymic stromal lymphopoietin.


coexistent asthma looking for Th17 cells in particu-lar will be important as it may allow us to under-stand the role these important cells play in asthma.

INNATE IMMUNITY

Several innate immunological signalling pathwaysand cytokines have been identified that augmentairway adaptive immunity and thus inflammation(Fig. 1). Epithelial toll-like receptors (TLRs) are nowincreasingly relevant and recognize structurallyconserved molecules derived from microbes calledpathogen-associated molecular patterns (PAMPs).Recognition by TLRs can directly activate immunecell responses.Thymic stromal lymphopoietin (TSLP)



is predominantly derived from epithelium and aug-ments Th2 inflammation by selectively upregulatingthe costimulatory molecule OX40L ligand on den-dritic cells leading to potent Th2 stimulation. Otherrecently discovered important Th2-augmentingcytokines are IL-33 and IL-25. Epithelium generatesTSLP, IL-25 and IL-33 in response to epithelial injuryor activation by the TLR system. IL-25 enhances Th2responses alongside TSLP. TSLP, IL-25 and IL-33 areproduced as a first line of defence against infection,thus leading to potent enhancement of allergicinflammation, acting as a ‘bridge’ between innateand adaptive airway mucosal immunity.

Out of an analysis of 98 candidate genes, TSLPgene polymorphisms demonstrate the greatest




statistical significance with asthma [25] and similarassociations are emerging in allergic rhinitis [26].TSLP is linked to severity of allergic disease and inrecent meta-analysis has been associated withasthma along with IL-33 [27]. TSLP expression dis-tinguishes severe asthma cohorts [28]. Interestingly,TSLP receptor is highly expressed in both CRS sub-types, indicating that the two main forms of CRS arenot Th2-immunologically distinct as previouslythought [29

&

] and highlights the overall immaturityof our understanding in this disease.

IL-33 and its receptor ST2 expression is increasedin allergic rhinitis epithelial cells [30]. T cells andmast cells also have a high density of ST2 expression.Thus, individuals with high IL-33 expression havethe potential to rapidly induce Th2 cell expansionand release cytokines. IL-33 knockout mice fail todemonstrate allergic rhinitis in a murine model ofallergen-induced allergic rhinitis [31

&&

] and CRSwNPpatients with recalcitrant disease express high levelsof epithelial IL-33 [32].

An exciting finding in CRSwNP is the presenceof a relatively large population of novel innatelymphoid cells (ILCs) responsive to IL-25 andIL-33 leading to production of excess amounts ofthe key Th2 cytokine IL-13 [33

&&

]. These cells are ofgreat interest as they can potentially link innateimmunity to cell-mediated, Th2-driven inflam-mation. Furthermore, they may allow the airwaymucosa to completely bypass the adaptive immunesystem. A mouse model of asthma highlights thecritical role such cells and cytokines may play in anasthmatic airway in that these cells have beenshown to induce disease independent of thetraditional Th2 pathway [34

&

,35&

]. The race to findsuch ILC populations in the allergic rhinitis andasthmatic airway is intense, as they may providethe link pathway by which innate immunity toallergen or infection drives airway disease. Targetingmolecules that are upstream of adaptive immunitymay be more effective than current approaches.

IMMUNE DYSREGULATION

As well as proinflammatory Th cell subset suppres-sion, self-antigen tolerance and nonresponse toenvironmental antigens is maintained by activeimmune regulation by T cells termed T regulatorycells (Tregs). Tregs expressing the transcription fac-tor forkhead box protein 3 (FoxP3) represent aparticular subtype. Suppression of Th2 responsesto allergen by Tregs may be defective in seasonalallergic rhinitis [36] and CRSwNP tissue demon-strates minimal FoxP3þ cells [22]. Bronchial lavage[37] and blood [38] from asthmatics show reducednumbers and impaired function of such cells. Thus,



these diseases all demonstrate a common theme ofimpaired immune regulation. Allergen provocationincreases Foxp3þ Treg cells in a highly proliferativestate in the nose, probably as part of inflammatoryresolution events [39]. It will be important to knowif such cells have impaired regulatory function.Strategies by which induction of immune regulationcan be achieved are still unknown, but helpful tounderstand as this may offer novel therapeuticintervention possibilities.

Vitamin D is a potent immunomodulatory hor-mone and may promote Treg cell function as well asimproving steroid responsiveness in inflammatorydisease [40]. Observational studies in allergic rhinitisand asthma demonstrate Vitamin D deficiencyin disease cohorts [41]. A causal role is not yetdemonstrated and overall the results are conflicting.For example in children, serum 25-hydroxyvitaminD3 deficiency was associated with sensitization toragweed and oak on serum IgE analysis to 17 aller-gens, but serum vitamin D levels did not predict theprevalence of actual rhinitis symptoms [42]. Theadults failed to show any relationship of VitaminD levels to either IgE sensitization or rhinitis symp-toms. Similar conflicting findings are shown inasthma [43]. It is likely that there are other con-founding factors restricting such studies from defin-ing a clear disease association with Vitamin D.Studies in CRS also suggest Vitamin D levels aredeficient in CRSwNP rather than CRSsNP [44] andmay be relevant to disease pathogenesis, but theseare early findings. Vitamin D replacement cannot berecommended with confidence until the resultsof clinical trials demonstrating safety and clinicalefficacy are available.

AIRWAY SUPERANTIGENS

Nonallergic asthma is found in excess in CRS,particularly with CRSwNP, and the extent of sino-nasal disease correlates with asthma severity. Anemerging explanation for such association of diseaseis the airway superantigen hypothesis [45]. Super-antigens direct nonspecific activation of T cells,resulting in polyclonal T-cell expansion with mas-sive cytokine release and directly stimulate B-cellproliferation. In addition, superantigens can induceimmunoglobulin class-switching to IgE and the pro-duction of allergen-specific IgE in mucosal B cells.Intense mucosal inflammation independent oftraditional allergen-driven pathways can be estab-lished. Bacteria are an important source of super-antigen. A role for superantigens in allergic rhinitisin relation to local IgE and mucosal events wasrecognized some years ago [46]. Such local IgEproduction, in relation to Staphylococcus aureus



C


enterotoxin (SAE) superantigens in particular, alongwith a functional role in disease pathogenesis hasalso been established for CRSwNP [47] and this IgEwas recently shown to be functional [48

&

]. As withlocal IgE in LAR, asthma and CRSwNP, phenotypesof CRS with negative skin and blood allergen IgE alsodemonstrate excess sinonasal mucosal IgE-encodingtranscripts [49]. It may be that local IgE has a func-tional role in CRSsNP also, that so far has not beenconsidered. Recent meta-analysis of nine clinicalstudies confirms an increased prevalence of S. aureusexposure or SAE IgE positivity in allergic rhinitis andasthma, with an OR of 2.4 and 3.3, respectively [50].In fact, serum IgE SAE rather than inhalant allergenIgE is a predictor of asthma severity with a very highOR of 11.09 [51

&&

]. This is important as it points to acommon disease overlap mechanism in relation tosuperantigen drive of airway inflammation relevantto both CRS and asthma [51

&&

]. Overall what thesestudies demonstrate is that in allergic rhinitis, CRSand asthma phenotypes without an obvious IgE-mediated mechanism, local mucosal IgE-mediatedpathways are present and probably functionallymore important than previously considered. A com-mon role for bacterial superantigen-driven, localIgE-mediated disease may be relevant, particularlyin relation to more severe airway inflammatory dis-ease. Thus, strict definition of allergic or nonallergicdisease based on skin or serum IgE positivity can nolonger be applied and a future change in classifi-cation terminology will be needed. Given theemerging role for bacterial superantigens, antimi-crobial treatments which so far have had limitedsuccess in CRS and asthma may re-emerge as aneffective disease intervention.

EPITHELIAL BARRIER FUNCTION

Loss of epithelial barrier function can lead to bothmucosal vulnerability and greater penetration byallergens, microbes and pollutants, predisposingto an activated epithelial state and sustained sub-mucosal inflammation. Restoration of tissue integ-rity offers a novel therapeutic approach. Defectivebarrier function is demonstrated in allergic rhinitis,CRS and asthma.

Intercellular tight junctions are the principalcomponents of the epithelial paracellular per-meability barrier. Epithelial cells in both asthmaand CRSwNP demonstrate inadequate tight junctionstructure and function [52,53]. IL-4 (a Th2 cytokine)and IFN-g (innate cytokine) can further disrupt suchintegrity [54]. Such intrinsic airway vulnerability isexacerbated by environmental factors that furthercompromise barrier integrity. For example, the cys-teine proteinase allergen Der p 1 from faecal pellets of



the HDM Dermatophagoides pteronyssinus disruptstight junctions. Recent data on nasal lavage bio-markers indicative of epithelial permeability corre-lated with HDM IgE sensitization in allergic rhinitis[55], suggesting that defects in epithelial barrierrelated to IgE are indeed relevant to allergic rhinitisand allergic asthma, and most probably CRS wherelocal IgE mechanisms are implicated.

Although clinical observations show viral infec-tion can exacerbate both allergic rhinitis and CRS,definite mechanistic studies are not available. Viraldouble-stranded RNA (dsRNA) is a potent trigger forantiviral immune responses via sensors such as theTLR system. Interestingly, synthetic dsRNA (poly-inosinic: polycytidylic acid) induces marked dis-ruption of airway epithelial barrier structure andfunction in vivo via a TLR-3 pathway [56]. Suchdefective barrier induction mechanism may berelevant to the association of airway viral infectionwith allergic airway sensitization.

GENE ASSOCIATION STUDIES

Genomewide association studies (GWAS) are limitedin rhinitis, but data so far implicate genes associatedwith immune regulation, Th2 inflammation andinnate immunity. In nearly 4000 individuals withseasonal allergic rhinitis, disease significantly associ-ated with polymorphisms in LLRC32 (leucine-richrepeat containing 32) which is critical for tetheringtransforming growth factor (TGF)-b to the T regulat-ory cell surface [57

&

,58]. TGF-b isoforms are potentregulators of inflammation and tissue repair. LLRC32is also associated with increased allergic asthma riskreaching genomewide significance [59]. Polymor-phisms near the genes for TMEM232 (transmem-brane protein 232) and SLC25A46 (solute carrierfamily 25 member 46) also significantly associatedwith allergic rhinitis and are relevant given the pro-ximity of this region to regulation of TSLP expressionon chromosome 5. Using a candidate-gene approach,TSLP,TLR-6and NOD1 (nucleotide-binding oligome-rization domain containing 1) had an associationP value less than 10�4. TLR and NOD both havepotent roles in innate immunity in defence againstinfection at the epithelial level. Infections areassociated with exacerbation of allergic disease andthus understanding the innate response to microbesmay allow development of disease intervention. Arecent murine model suggests that TLR-6 may beprotective against asthma pathogenesis [60] andone can speculate TLR-6 will confer similar functionin the nose. NOD receptor expression is modulated inboth SAR [61] and CRSwNP [62] during allergenseason or steroid treatment, respectively, suggest-ing a functional role in disease. Further work to




understand the important roles of such innate epi-thelial signalling pathways is underway.

GWAS studies are lacking in CRS and a candi-date-gene approach in several CRS phenotypes (witha focus on refractory CRS) has failed so far to identifyany single causative gene. Studies have mainlylooked at genes related to innate immunity anddownstream immune regulation. Given the limita-tions inherent to such methods, the data so far areinteresting but limited. Studies implicate multipledefects in innate immune recognition mechanismssuch as the TLR system and regulatory pathways.The genes evaluated are summarized in the reviewby Mfuna-Endam et al. [63]. It is relevant thatprevious GWAS in asthma also highlight diseasesusceptibility genes that have function in innateimmunity and local tissue integrity [64].

THERAPEUTIC INTERVENTION

Trials of potential disease intervention with novelbiologics, previously considered in asthma, have nowbeen extended to allergic rhinitis and CRS. Whilstanti-IL-13 therapy failed to attenuate disease symp-toms in an allergen challenge model of allergicrhinitis, subanalysis suggests that individuals withexcess IL-13 have a trend towards attenuation ofsymptoms [65]. An anti-IL-5 pilot study directed atattenuating eosinophilic inflammation in CRSwNPdemonstrates significant improvement in disease[66

&&

]. As with the above allergic rhinitis study,whether anti-IL-13 therapy is effective in clinicalasthma remains unanswered [67], but it may be thatdisease subtypes with excess IL-13 are those thatrespond. Future planned studies must phenoendo-type volunteers more rigorously. One very successfultherapeutic approach in asthma has been anti-IgEtherapy and given the established or emerging role ofIgE-driven pathways in allergic rhinitis and CRS, onewould speculate significant therapeutic impactwith such intervention. Anti-IgE studies are eagerlyawaited.

CONCLUSION

Recent work highlights common disease associationsand overlapping mechanisms in allergic rhinitis, CRSand asthma. Further studies are needed to take for-ward these early findings. Information from carefullyselected clinical phenotypes with sampling fromboth the upper and lower airway together with func-tional studies is needed. ENT surgeons must workalongside allergists and pulmonologists at both thebench and the bedside in the future.

Acknowledgements

None.



Conflicts of interest

There are no conflicts of interest.

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allergic rhinitis, chronic rhinosinusitis and asthma

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