Symposium

New insights into the pathophysiology of allergic rhinitis

Lanny Rosenwasser, M.D.
ABSTRACT The immune response to an allergen is dependent on an initial sensitization process, with future exposures triggering a two-part allergic response including an early and a late phase. The process by which an allergen is recognized as such, including which cell types and cytokines are involved in the sensitization process, has become clearer over the last several years. Similarly, the roles of the different preformed mediators responsible for many of the signs and symptoms of the early phase response have been elucidated. Recent work also has shed some light on the multitude of cells and mediators involved in the late-phase reactions, which can lead to priming and long-term inflammation. This article will discuss some of this recent work as well as review the basics behind all of the stages of the allergic response, especially as they apply to the nose and upper airway. (Allergy Asthma Proc 28:10 15, 2007; doi: 10.2500/aap.2007.28.2977) Key words: Allergen specific IgE, allergic rhinitis, cytokines, FoxP3, interleukins, late phase allergic response, Property of leukotrienes, mediators, natural killer T cells, regulatory T cells, TCR gamma delta cells skin, take up allergen by endocytosis, process it, and n the allergic response, initial sensitization involves activation of allergen-specific T cells that orchescopresent it along with human leukocyte antigen class trate the production of allergen-specific IgE, which is II molecules to CD4 T cells (Th2 lymphocytes), which the critical issue in allergic rhinitis. The modeling of are the major regulators.1 There are also newly recogthis disease in terms of allergic triggers involves an nized forms of these T cells that have become apparent analysis on an experimental basis of the early phase in the last few months in terms of playing a role in response, which is mast cell and basophil dependent, allergic responses, especially in asthma, as will be disand the late-phase response, in which allergic inflamcussed later in this article. mation and an influx of effector cells and immune cells In addition to interacting with the antigen-presenttake over in terms of the pathophysiology. Some of the ing cells during the activation process, CD4 T cells same components that are involved in the sensitization undergo clonal expansion and can interact with B cells process also may play a role postsensitization in terms as well through the production of soluble products of enhancing inflammation, especially with regard to such as cytokines and by direct cellular interactions in OceanSide the lymph nodes that lead to the secretion of IgE as the the late-phase response. This article will review some Publications of this in terms of what the potential mediators and B cells are induced to differentiate into plasma cells. IP: some mechanisms are and then will proceed to discuss 125.162.166.109 The subsequent binding of allergen-specific IgE to of the newer factors that might be playing a role in high-affinity receptors present on mast cells and badifferent aspects of allergic inflammation. sophils results in allergen priming.1,2 On the introduction of allergen into the body, antiOn reexposure to the allergen, cross-linking of the gen-presenting cells, which include macrophages and IgE molecules on the cell surface leads to opening of dendritic cells (DCs) similar to Langerhans cells in the calcium channels and activation of the cell. In the early phase response (the model for some of the immediate responses associated with allergic rhinitis), within 5 minutes the allergen causes degranulation of predomFrom the Department of Medicine, and Basic Science, University of MissouriKansas City School of Medicine, and the Division of Allergy and Immunology, Childrens inantly mast cells with the release of preformed mediMercy Hospital, Kansas City, Missouri ators1,3 including histamine, proteases, and some of the Presented at the Mid-Conference Symposium of the Eastern Allergy Conference, Naples, Florida, May 5, 2006 cytokines including TNF. These mediators initiate Supported by an unrestricted educational grant from Alcon Laboratories some of the symptoms related to early phase responses Address correspondence and reprint requests to Lanny Rosenwasser, M.D., University that are the general symptoms associated with allergic of MissouriKansas City School of Medicine, 2401 Gilman Road, Kansas City, MO 64108 rhinitis. Within 15 minutes there is synthesis of the E-mail address: lrosenwasser@cmh.edu various products of arachidonic acid metabolism inCopyright 2007, OceanSide Publications, Inc., U.S.A. cluding the cysteinyl leukotrienes, prostaglandins, and

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Figure 1. Early phase reaction.

Figure 2. Late-phase reaction.

flammatory cytokines, in particular TNF, IL-,1 and IL-6 platelet-activating factor.3,4 These processes contribute that are all part of the nasal inflammatory milieu.10 to the recruitment of other cells and the beginning of the late-phase response and also bring into play other Leukotrienes play a role in this, not just through an Property of factors including cytokines and the blood vessels, increase in mucous production, but also through a nerves, and mucous glands in the upper airway; all variety of other factors such as tachykinins. The cysteiplay a role in the generation of congestion, rhinorrhea, nyl leukotrienes themselves affect blood vessel physipruritus, and sneezing. In the early phase response, I ology so that transudation and edema are enhanced, have already mentioned how histamine is a major and, through an intermediate effect of neurokinins, player in terms of the preformed mediators affecting there also is sensitization of sensory C fibers so there is all of these symptoms,5 but, clearly, within 15 minutes an established role for leukotrienes in this process as these other materials including the leukotrienes and well.11 prostaglandins also can play a role in generating preOne of the things that becomes clear in the sensitidominantly congestion and rhinorrhea,6 8 although zation and elicitation phase is that T cells play a sigsome of the other factors may play a role in pruritus nificant role. All IgE production and eosinophilia in and sneezing. (Fig. 1). mammals are thymus dependent and T-cell depenIn the late-phase response, these early mediators are dent. The recognition of allergens by CD4 T-cell reinvolved in further recruitment of cells including the ceptor (TCR) T cells is the nub or the crux of the eosinophils, basophils, monocytes, macrophages, and sensitization and also the recall response and the prolymphocytes into the inflammatory milieu.9 There is Publicationscytokines in a variety of ways is a critical OceanSide duction of even more mediator release and an increase in symppart of this overall pathophysiological process. In the toms generally associated with congestion, but rhinorairways, IP: 125.162.166.109both in the upper and in the lower airways, rhea and sneezing can be part of the late-phase rethe ability of accessory cells, antigen-presenting cells, sponse as well (Fig. 2). The allergic response clearly is to interact with T cells in eliciting these responses is modeled in this way, but the actual disease depends on critical. Therefore, the Langerhans cells in the skin, or an ongoing development of the milieu that leads to the the equivalent of those cells; the DCs in the airway, tissue being primed for these kinds of responses with a including the nose and sinuses;and macrophages, neuvariety of triggers, even beyond allergens, that may trophils, eosinophils, basophils, mast cells, epithelium, play a role.9 The mediators that I have mentioned that endothelium, and even smooth muscle and fibroblasts are involved in inducing this inflammation include all under the right circumstance can interact with lymchemotactic mediators with both histamine and leukophocytes, in particular T cells, to activate them. The trienes having that characteristic, but chemokines are DCs are some of the most organized of these antigengenerated also, including eotaxin and RANTES, which presenting cells. Their growth and development from are strongly chemotactic. These all have different numbone marrow precursors depend on a variety of cytobers now, among the chemokines, for their nomenclakines including granulocyte macrophage colony-stimture. I will refer to the recent publication in the Miniulating factor, IL-3, IL-4, IL-1, and TNF,12 and they can Primer, in the Journal of Allergy and Clinical Immunology, be divided into two subsets: the DCs type 1 (DC-1), which John Steinke has published and that has the which are capable of inducing Th1-type T cells and newer nomenclature for the chemokines and the inDC-2, which induce Th2 type of lymphocytes, CD4

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toxin, and a variety of other cytokines. The Th2 CD4 T cells are the ones that are predominantly active in allergic rhinitis, allergic diseases, and asthma, in which class II major histocompatibility complex and a peptide derived from allergens activate these cells. They are critically important in antibody synthesis and, in particular, for IgE isotype switch and the eventual production of IgE and they make a set of cytokines that includes IL-4, IL-5, IL-9, and a variety of other cytokines that are active in this Th2 arm of immunity.13,14 There is a group of cells called TCR- cells that have neither CD4 nor CD8 on their surface and are involved in epithelial defense. They are present in the nose, but they also are present in the lungs and in the gastrointestinal tract, and they are restricted not to the MHC molecules but to a molecule on the surface of the Figure 3. Antigen-presenting cells in atopic disease. macrophages called CD1.15 Heat shock proteins, lipids, and glycolipids are the general targets for specificity of lymphocytes (Fig. 3).12 These are the cells that are these -cells and they have a much more restricted critically important to the allergen recognition. They range of potential interactions, but a variety of potenplay a role predominantly in allergen or antigen captial Property of antigens have characteristics that might trigger ture and presentation to the T cells and how they these kinds of cells in an allergic reaction. function in the tissues depends on the milieu in which The old suppressor cells ( 20 30 years ago) have they interact and develop. Therefore, in addition to the been reborn in the past 7 or 8 years as regulatory T effects of cytokines mentioned previously, DC precurlymphocytes, and these cells are thought to be imporsors develop into DC-1 cells if there is a milieu that is tant even in the induction of the potential benefits of rich in Il-12. If the milieu is rich in the prostaglandin immunotherapy. A group in Switzerland with Cezmi product, prostaglandin E2, then DC-2type DCs are Akdis and Kurt Blaser has shown, e.g., in bee venom developed. If the DC-2 interacts with the T helper cell immunotherapy that these cells get activated and exprecursor in a milieu that includes IL-4, then differenpanded.16 They are regulatory cells and they are called tiation into Th2 cells occurs. If the DC-1 cell interacts T-reg cells. They express TGF- and IL-10. Originally, with the T helper cell precursor in a milieu that is rich it was thought that perhaps the secretion of these cyin IL-12, then the interferon producing Th1 cells are tokines was critical for their suppressive effects, but in produced.12 So, it is clear that the milieu and the type reality it is just their expression that may be a marker of cytokines and inflammatory mediators that these of how they act as suppressive cells in that the actual cells interact and swim around are very important in production of these cytokines does not seem to correterms of profiling the kind of response that will de- Publications OceanSide late with the potential inhibition or suppression of velop into an antigen or allergen. other cells and it may be mediated by these kinds of Among the T lymphocytes that are involved in recells directly interacting with target T cells, which IP: 125.162.166.109 sponses, there are CD8 , TCR- type mature T cells would be the standard CD4 helper cells as discussed that are restricted to class 1 MHC and allergen-derived previously. These cells have not only CD4 on their peptides.13 Generally, these are types of T cells that are surface but the T-cell activation antigen CD25. This is active in cytotoxicity and it is generally not allergen one protein that is part of the complex that interacts as that is the critical issue here but endogenous infections a receptor for IL-2; therefore, it is a sign of activation; with viruses and other kinds of potential targets for but not all CD4 or CD25 T lymphocytes can be T delayed-type hypersensitivity using CD8 T cells. In regulatory cells. They have to express these cytokines the past, these were thought to be the suppressor cells, and they have to use a unique transcription factor but new facts have become clear about this immunocalled FoxP3 to have this regulatory effect. In regard to regulatory cell that used to be known as a suppressor immunodeficiency, FoxP3 defects have been identified cell 10 20 years ago. There also is the Th1-type CD4 in certain groups of severe combined immune defiT cell that has a standard TCR and can be restricted to ciency and other immune deficiencies.17 So, not only is a peptide that could be derived from an allergen and this an important factor for the regulation of IgE prothat mediates generally delayed-type hypersensitivity duction, but it is also a potential marker or target for in host defense and not antibody synthesis.13 The set of the development of immunodeficiency. cytokines that is generally the product of these kinds of In a recent publication in the New England Journal, the differentiated cells includes interferon , IL-2, lymphogroup at Childrens Hospital in Boston (Dale Umetsus

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Table 1 IL generations and families important to allergy. New information that allergists should know about ILs First Generation IL-4 IL-2 IL-12 IL-1 IL-10 IFN? Second Generation IL-13, IL-9 IL-15, IL-17 IL-18,IL-23,IL-27 IL-18 Third Generation IL-25 IL-21, IL-25 IL-32, IL-33 IL-19,IL-20,IL-22,IL-24,IL-26,IL-28,IL-29 IL-28, IL-29

activity associated with that first generation group of group) published a study in asthma in which he identified in a small number of patients ( 14 patients), the cytokines. So, e.g., IL-4, IL-13, and IL-9 were somewhat predominance of a certain variant of T cells called overlapping in terms of the activities, and now there is natural killer T (NKT) cells, which are highly expressed a third generation in this new millennium that has in asthma18; and the extension here that requires a leap been identified predominantly by genomics, in which of faith at this particular point is that similar NKT cells there are a variety of activities that mimic what the first may be present at other sites of allergic inflammation generations do. In addition, a whole variety of these including the skin and perhaps the nose, but theseProperty ofin the 20 series are a part of the IL-10 family and are ILs TCR restricted and invariant so they have limited repthere are variants in the IL-10 receptor that give these ertoires of the TCRs. CD4 T cells that react to allervariants in ligands that have been identified. Almost all gens have a wide variety of specificities that interact of these, from IL-19 to IL-29, seem to have less activity with all of the potential allergens you may encounter, than IL-10 in terms of the ability to fight viral infections whereas these have a very restricted repertoire of what or suppress other cytokines, which were some of the they will react to. Some of them, and in particular the basic things that IL-10 did, but then there are a couple NKT cells that are active in asthma, are CD4 and like of other ILs that that are of importance as well. Another the -cells they are restricted to CD1b on the antigengroup of cytokines that is of interest is the IL-17 fampresenting cells and that means that, probably, the ily.21 There are actually six of these cytokines, IL-17, A, ligands that activate this are not the standard allergens; B, C, D, E, and F. IL-17E is actually the same as IL-25 they are probably proteins or lipids that have affinity and that is the one that is associated with Th2 cell for CD1. This may mean that in some groups of paactivation and it is involved with eosinophilia and tients with either nonallergic rhinitis or asthma these airway responsiveness both in animal models in the more unusual T cells may be the dominant kind of mouse and in humans. The genetics of the IL-17 family inflammatory cells rather than the standard CD4 T have been linked to asthma and allergic proclivities in cells (which was the point of the editorialOceanSide Publications that Barry family studies done in a variety of settings and popuKay wrote in the same New England Journal regarding lations ranging from Japan to here in the United 19 this article ). These NKT cells that were reported by IP: 125.162.166.109 States.22 There is another group of cytokines that is part the group at Boston Childrens Hospital have a greater of the extended IL-1 family that seems to be very proclivity and propensity to produce IL-4 and IL-13 interesting and is called IL-33 and it seems to have a and they produce much less interferon , explaining specific proclivity for activating Th2 T cells.23 New how they potentially may play a role in the inflammaresearch reports regarding IL-33 are highly anticipated. tion associated with responses. Of particular interest is the possible contribution to Therefore, although we heard about allergies in the pruritus of allergic rhinitis of IL-31. This is a major America and unmet needs on a clinical level previousmediator of atopic dermatitis in both humans and ly,20 in this study, some of the unmet needs in the field mice. It was discovered in mice by a biotech company of pathophysiology are identified. First, I will review in Seattle, but in February its potential role in atopic new information that the allergist should know about dermatitis was confirmed by the group at National ILs. ILs are grouped as first-, second-, and third-genJewish with Don Leung and Mark Boguniewicz,24 eration cytokines (Table 1). The earliest ones such as which indicates this unique cytokine seems to be the IL-4 and IL-2 were associated with particular functions mediator of pruritus in both animal models and in in terms of inducing IgE, activating T cells, inducing patients with atopic dermatitis. It is produced by CD3 interferon, or being proinflammatory such as IL-1. In cutaneous lymphocyte antigen-positive T lymphocytes the 1990s a whole group of other cytokines were identified that had similar if not exactly the same spectra of and it would be interesting to see if some of the pru-

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Table 2 Common symptoms of allergic rhinitis and their mediators Symptoms Tickling Itching Nose rubbing Allergic salute Sneezing Nasal congestion Stuffy nose Mouth breathing Snoring Runny nose Postnasal drip Throat clearing Histamine X X X X X X X X X X X X Prostaglandins X X X X X X X X X X X X X X X X X X X X Leukotrienes Bradykinin PAF

PAF platelet-aggregating factor. Source: Adapted from American Academy of Allergy, Asthma and Immunology. The Allergy Report. Allergy Report Task Force with chairs Harold S. Nelson, MD, and Gary S. Rachelefsky, MD. Vol. 2: Diseases of the Atopic Diathesis. Milwaukee, WI: AAAAI, 6, 2000. ritus one gets in the nose might be due to the same lead to hyperresponsiveness in the nose. That hypercytokine. responsiveness can either resolve or it can lead to Only IL-l through IL-33 have been defined. IL-30, complications and persistent symptoms. Figuring out a may play an important role in the activation of eosinway to interrupt this process will be a critical issue not ophils. Some transplantation investigators on the basic just for immediate relief but also in trying to get from science of transplantation identified a cytokine that 60% satisfaction with current treatments (Allergies in they termed IL-50 because they were going to name it America Report, Healthstar Communications, Inc., the highest number. Therefore, I think that is about 2006: www.myallergiesinamerica.com; Sept. 13, 2006) what the limit will be for the interleukins, but this is a to closer to 90 or 95%. There are unmet needs not just reperfusion injury specific cytokine that probably is in the issue of the burden of the disease or its treatgoing to be the cap, the limit of the interleukins bement, but also in its pathophysiology, because they are cause there are not any newer genes that have not been all linked. Allergen responses trigger upper airway discovered, so the cytokines probably end about there. responses through IgE-mediated mast cell activation as In terms of allergic rhinitis, in Table 2, the symptoms the initial phase, and a complex cascade related to this listed are associated with the mediators, both common two-phase response results in a variety of different preformed mediators and short-term mediators that Publications OceanSide cells and mediators being recruited. Repeated allergen get generated during allergen exposure. You can see exposure leads to persistent hyperresponsiveness and the relative contribution of some of these mediators to inflammation in the upper airway. Despite how much IP: 125.162.166.109 some of these symptoms based on the some of the we know, there still are unknown pathophysiological ways in which one could put this together (Table 2). factors that need to be discovered. The source of this information was The Allergy Report (The Allergy Report is a component of the American Academy of Allergy, Asthma and Immunologys AllerREFERENCES gic Disorders: Promoting Best Practice initiative: at www. 1. Young MC. Rhinitis, sinusitis, and polyposis. Allergy Asthma Proc 19:211218, 1998. theallergyreport.com; Sept. 5, 2006) and there is some 2. Naclerio RM. Allergic rhinitis. N Engl J Med 325:860 869, 1991. limitation as to how strong the data are regarding how 3. Frieri M. Inflammatory issues in allergic rhinitis and asthma. much of this is due to which mediator. Allergy Asthma Proc 26:163169, 2005 Needless to say, inhibition or enhancement related to 4. Jordan TR, Rasp G, Pfrogner E, and Kramer MF. An approach all of these mediators would be a goal toward reaching of immunoneurological aspects in nasal allergic late phase. Allergy Asthma Proc 26:382, 2005. the unmet needs issue that was addressed previously 20 5. Mygind N and Dahl R. Challenge tests in nose and bronchi: in this issue of the Proceedings and may be the basis Pharmacological modulation of rhinitis and asthma. Clin Exp for some of the potential treatments that will be disAllergy 26:S39 S43, 1996. 25 cussed in additional articles in this issue. 6. Bisgaard H, Olsson P, and Bende M. Effect of leukotriene D4 on In summary, the late-phase response and priming nasal mucosal blood flow, nasal airway resistance, and nasal secretion in humans. Clin Allergy 16:289 297, 1986. generated by immune responses and inflammation can

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