Nasal hyperreactivity and inflammation in allergic rhinitis

The history of allergic disease goes back to 1819, when Bostock described his own ‘periodical affection of the eyes and chest’, which he called ‘summer catarrh’. Since they thought it was produced by the effluvium of new hay, this condition was also called hay fever. Later, in 1873, Blackley established that pollen played an important role in the causation of hay fever. Nowadays, the definition of allergy is ‘An untoward physiologic event mediated by a variety of different immunologic reactions’. In this review, the term allergy will be restricted to the IgE-dependent reactions. The most important clinical manifestations of IgE-dependent reactions are allergic conjunctivitis, allergic rhinitis, allergic asthma and atopic dermatitis. However, this review will be restricted to allergic rhinitis. The histopathological features of allergic inflammation involve an increase in blood flow and vascular permeability, leading to plasma exudation and the formation of oedema. In addition, a cascade of events occurs which involves a variety of inflammatory cells. These inflammatory cells migrate under the influence of chemotactic agents to the site of injury and induce the process of repair. Several types of inflammatory cells have been implicated in the pathogenesis of allergic rhinitis. After specific or nonspecific stimuli, inflammatory mediators are generated from cells normally found in the nose, such as mast cells, antigen-presenting cells and epithelial cells (primary effector cells) and from cells recruited into the nose, such as basophils, eosinophils, lymphocytes, platelets and neutrophils (secondary effector cells). This review describes the identification of each of the inflammatory cells and their mediators which play a role in the perennial allergic processes in the nose of rhinitis patients.

produced by the effluvium of new hay, this condition was also called hay fever. Later, in 1873, Blackley established that pollen played an important role in the causation of hay fever.
In 1902 Portier and Richet described the development of anaphylaxis in dogs a few minutes after reinjection with anemone toxine. By this experiment they demonstrated that, in this case, immunity was not protective but damaging to the individual. Arthus observed in 1903 that after repeated injections with substances which had not caused any reaction the first time, the injected tissues became inflamed. Von Pirquet 2 noted that under some conditions, patients, instead of developing immunity, had an increased reactivity to repeated exposure with foreign substances. By putting together the Greek words 'allos' meaning different or changed, and 'ergos' meaning work or action, he introduced in 1906 the term allergy. Both immunity and hypersensitivity were thought to have similar underlying immunologic mechanisms. Later, in 1923, Coca and Cooke proposed the term atopy for the clinical forms of allergy, manifested by hay fever and asthma, in which 'the individuals as a group possess a peculiar capacity to become sensitive to certain proteins to which their environment and habits of life frequently expose them'. Thus, (C) 1996 Rapid Science Publishers Mediators of Inflammation Vol 5 1996 79 ship between exposure to the antigen and occursance. Social interaction is limited and there is an rence of the lesion, and (3) identification of the impact on emotional well-being. 4 In addition to immunologic mechanism involved in the illness, the costs of medication, health seeeices and sick In this review, the term allergy will be absence, the loss in personal income contributes restricted to the IgE-dependent reactions. The to the economic impact of rhinitis. To measure most important clinical manifestations of IgE-the influence of nasal symptoms on day-to-day dependent reactions are allergic conjunctivitis, life, rhinitis quality of life (QOL) questionnaires 14 allergic rhinitis, allergic asthma and atopic derma-have been developed. Juniper et al. 4 demontitis. However, this review will be restricted to strated that QOL deteriorated after allergen expoallergic rhinitis, sure (pollen season) and increased after symptomatic treatment.

Allergic Rhinitis
Reactions of Nasal Mucosa on Allergen Exposure Epidemiology: Allergic rhinitis is the most common manifestation of the IgE-mediated disor-Most studies concerning the pathophysiology ders, with a prevalence ranging from 2 to 20%. of allergic rhinitis have been performed in The prevalence of allergic rhinitis seems to be patients with seasonal rhinitis. The effect of increasing. In a study performed in Swedish army pollen exposure on the nasal mucosa can be recruits, the prevalence of hay fever increased determined during the natural pollen season or from 4.4% in 1971 to 8.4% in 1981. The preva-by nasal challenge models performed outside the lence of allergic skin test reactivity, i.e. atopy, pollen season. In nasal allergen challenge studies, increased from 39% to 50% in a community well-known amounts of standardized allergen are sample in the USA of individuals of all ages for a administered into the nose. In most studies, mean of 8 years. 12 Since skin reactivity and allernasal challenges are used to investigate the gic disease are associated; this suggests that the pathophysiology of allergic rhinitis. However, one prevalence of allergic rhinitis is also increasing, should keep in mind that the mode of exposure is not natural and that in a short time high con-Clinical aspects of allergic rhinitis: According to centrations of allergens are administered to elicit the international consensus rhinitis is defined as a clear nasal response instead of continuous an inflammation of the nasal mucosa characterexposure to lower and variable amounts of aller-gens. The problem of monitoring nasal response pollen in his nose. This recurrence of symptoms during natural exposure is the variable and has been termed the late phase reaction. 29 To unknown level and spectrum of allergen content, define the late phase reaction in the nose is diffi-Several methods have been used to perform cult. Mygind et aL could not detect late phase nasal allergen challenges. Connel115 developed a reactions by means of symptom scores. Since it quantitated challenge with ragweed pollen. Later, is hard for patients to estimate their nasal standardized liquid allergen extracts were develpatency, and late phase responses are mainly oped, which can be insufflated into the nose or characterized by nasal blockage and to a lesser can be administered by filter paper discs or by extent by mild rhinorrhoea, this might show the special equipment like the 'nasal pool problems detecting clinical late phase responses. device'. <7 When estimating nasal obstruction by rhino-Nasal response to allergen challenge can be manometry, a recurrence of nasal blockage could determined by different methods. Usually, the be demonstrated. In other studies late phase symptomatic response is monitored by the reactions were determined by measurement of number of sneezes, the amount of secretion, and nasal obstruction and analysis of nasal lavage nasal blockage. Sneezing and itchiness are the fluid. results of a central reflect elicited in the sensory We demonstrated both an immediate and a nerve endings in the nasal mucosa. Sneezing and late phase reaction by symptom scores when the itchiness can also be subjectively measured by nasal mucosa of perennial allergic rhinitis symptom scoring. Nasal blockage is the result of patients were challenged with a house dust mite pooling of blood in the capacitance vessels of extract. 2 the mucosa, and to some degree the result of tissue oedema. It can be assessed subjectively by Nasal priming.. In the 1960s Connell described means of symptom scoring. An objective estima-a phenomenon known as nasal primingrepetition of nasal blockage can be made by methods tive exposure to allergen causes an increased such as rhinomanometry, s nasal peak flow sensitivity to allergens. This has been demondetermination, 19 acoustic rhinometry 2 and rhi-strated with repetitive exposures to a pollen-rich nostereometry. 21 Nasal secretion can be assessed natural environment as well as by repetitive nasal by weighing the blown secretion or by measurprovocation with allergen. This effect was coning the volume of secretion collected in a funnel firmed by others by nasal challenge studies. 4 equipped tube or syringe while the subject is However, the exact processes resulting in nasal bending her/his head forwards. Several scoring priming remain unclear. In perennial rhinitis the methods have been developed: visual analogue priming phenomenon has only been examined scales, combined symptom scores taking nasal in one study. 5 This Dutch study demonstrated blockage, secretion and sneezes 22 and a combian increased threshold sensitivity to house dust nation of all signs and symptoms. 2 Nasal mite challenge in autumn, compared to spring response can also be monitored by analysis of months, corresponding with the peak of house nasal biopsies, 24 brushes, 25 smears, 6 or dust mite levels between August and October. lavages. 27 Immediate allergic reaction.. When the nasal Allergen-induced Nasal Hyperreactivity mucosa of patients with allergic rhinitis is Hyperreactivity can be described as a clinical exposed to allergen, allergen activates mast cells feature characterized by an exaggerated response and basophils by bridging two or more IgE of the nasal mucosa to everyday stimuli molecules on their surfaces. After being activated (perfume, tobacco smoke, change of temperathese cells produce and release biochemical ture) as estimated by history (clinical hyperreacmediators. 7 Gomez et a/. 27 and Fokkens et al. 28 tivity). In comparison to allergens, these stimuli demonstrated in biopsy studies an increased perare nonspecific, that is, they can affect the nasal centage of degranulated mast cells at the surface mucosa of any individual, albeit to a different of the nasal mucosa after nasal pollen challenge, extent. By analogy to challenge studies in bron-The released substances act on the local cells, chial asthma, rhinitis patients were challenged vessels and sensory nerve endings, leading to with histamine and methacholine to measure nasal itching, sneezing, rhinorrhoea and nasal nonspecific nasal hyperreactivity. 6 Gerth van blockage in this immediate allergic reaction.
Wijk et al. 7 demonstrated that the amount of secretion and the number of sneezes in response Late allergic reaction: Blackley in 1873 was the to histamine challenge were associated with the first to describe the recurrence of symptoms clinical hyperreactivity assessed by a hyperreactivseveral hours after the introduction of grass ity score. It was also demonstrated that assess-ment of the number of sneezes and the amount of secretion is more appropriate in distinguishing Allergic Rhinitis: A Model to Study patients from healthy subjects in terms of repro-Airway Inflammation? ducibility and estimation of clinical hyperreactiv-Asthma and allergic rhinitis are common disity compared with assessment of nasal airway orders, with a high socio-economic impact and resistance after histamine challenge. 8 the cause of much morbidity. Many studies have In patients with allergic rhinitis, part of the been performed concerning the pathophysiologisymptoms is due to exposure to nonspecific cal mechanisms. Such studies are easier to stimuli. Repetitive exposure to allergen not only perform in the nose, as this is readily accessible, increases sensitivity allergens, but also to non-and biopsies and lavages accompanied by less specific stimuli. Borum et al. 9 demonstrated risk and discomfort to the patient. It would that in patients with seasonal allergic rhinitis therefore be easy if studies evaluating the pathothe nasal response to histamine and methachophysiology and therapeutic intervention of line increased during the pollen season. Aller-asthma were to be replaced by a study of the gen challenge also increased nasal response to nasal mucosa. However, the upper and lower histamine and methacholine. 4 In contrast, airways are not entirely similar since some of the repeated challenges with histamine or methasymptoms in asthma are caused by contraction choline do not increase nasal responsiveness to of smooth muscle tissue, resulting in bronchohistamine, constriction.
In a few studies evaluating the effect of topical Repetitive allergen challenge causes an corticosteroids, effective anti-inflammatory drugs, increased sensitivity to allergen and nonspecific nasal hyperreactivity was reduced, 4 which might stimuli. This phenomenon was first described for indirectly give evidence of the involvement of the lower airways 46 and could also be explored inflammation in this process. This is confirmed in the nose. 4 In the lower airways, the late by our recent work on perennial allergic rhini-phase response to allergen challenge was found tis. 42 Gerth van Wijk et al. found that in perento be associated with inflammation and bronchial nial allergic rhinitis patients nasal reactivity to hyperreactivity, 47 suggesting that inflammation is histamine was associated with clinical symptoms involved in the pathogenesis of hyperreactivity. and the sensitivity to everyday stimuli.
Several studies have been performed to deter-The exact mechanism of nasal hyperactivity is mine whether similar associations could also be unknown. Several hypotheses with respect to the shown in patients with allergic rhinitis. However, mechanisms underlying hyperreactivity have been in. studies performed in pollinosis patients tested advanced. (1) Increased epithelial permeability, outside the pollen season, no relation was found which would lead to an increased accessibility between nasal hyperreactivity and late nasal for stimuli to sensory nerve endings, vessels and response, 4 between nasal hyperreactivity and 4O nasal glands. An indirect support to this hypothactivation of eosinophils, or between nasal esis has been delivered by Buckle and Cohen, 43 priming and late nasal response. 49 who demonstrated that topically applied 125I-In contrast, in a study with rhinitis patients albumin penetrates better into the nasal mucosa allergic to house dust mite, an association of allergic rhinitis patients compared with healthy between nasal responsiveness to allergen and subjects. However, in more recent studies there pre-existent nasal hyperreactivity was found, 42'5 is little evidence that the nasal epithelium suffers a finding more in agreement with data from the much damage in acute or chronic allergic rhini-lower airways. So this subpopulation might be tis. 24 (2) Increase sensitivity of sensory nerve more suitable to study the association between endings would induce an exaggerated response nasal hyperreactivity, nasal inflammation and the to normal stimuli. No firm data are available to late phase response and might serve as a better confirm this theory. (3) Imbalance of the auto-model to study airway inflammation. nomic nerve regulation caused by changes of the neuroreceptors in the nasal mucosa. Megen et Histopathology a/. 44 demonstrated an increased sensitivity and a decreased number of muscarinic receptors in the The histopathological features of allergic nasal mucosa of allergic subjects. Increased preinflammation involve an increase in blood flow sence of the neuropeptide substance P or dimin-and in vascular permeability leading to plasma ished levels of vasoactive intestinal peptide (VIP) exudation and the formation of oedema. In addimight contribute to hyperreactivity. Until now, tion, a cascade of events occurs which involves a evidence for this hypothesis has only been variety of inflammatory cells. These inflammatory demonstrated in the lower airways. 45 cells migrate under the influence of chemotactic agents to the site of injury and induce the Histamine, 52 Adenosine, 57 Tryptase, 58 Chymase, 59  process of repair. Several types of inflammatory cells have been implicated in the pathogenesis of allergic rhinitis. What remains unclear is how the different cellular components interact with each other to induce the pathological symptoms of allergic rhinitis, and the relationship between the inflammatory infiltration, cellular activation and hyperreactivity still need to be established. After specific or nonspecific stimuli, inflammatory mediators are generated from cells normally found in the nose, such as mast cells, antigenpresenting cells and epithelial cells (primary effector cells) and from cells recruited into the nose, such as basophils, eosinophils, lymphocytes, platelets and neutrophils (secondary effector cells). This review describes the identification of each of the inflammatory cells and their mediators which play a role in the perennial allergic processes in the nose of rhinitis patients.

Cells in Allergic Rhinitis
The cells involved in allergic rhinitis, together with their products (arachidonic acid metabolites, cytokines, and others) are given in Table 1.

Primary effector cell.
Mast cells. Human mast cells can be characterized by the presence of tryptase on the one hand (MC) or tryptase and chymase (MCTc) on the other. More than 95% of the epithelial mast cells and 75% of the subepithelial mast cells in human airways are of the MCT-subtype. 5 Binding of allergen to specific IgE molecules on mast cells leads to secretion of mediators. 42 Mast cell-derived mediators can be divided into two main categories: pre-formed or granule-associated mediators and the newly formed or membrane-derived mediators.
Mast cells have been implicated in the pathogenesis of allergic diseases ever since histamine was localized to these cells. The number of mast cells in the nasal mucosa is increased in allergic rhinitis. 28 Elevated levels of mast cell mediators are present in the nasal lavage fluid 17 after experimental allergen challenge and chalenge with cold dry air, and experimental application of mast cell mediators to the nasal mucosa produces symptoms of rhinitis. Several studies have demonstrated that the amount of mast cells in the epithelial layer is increased after allergen exposure, which can be interpreted as Langerhans cells were found in the epithelium shift of cells from the lamina propria to the and lamina propria of the nasal mucosa and epithelium or proliferation of precursor cells in higher amounts of Langerhans cells were the epithelium. '4 Borres demonstrated that detected in nasal biopsies of allergic patients metachromatic cells can be found superficially in compared with controls. 28 During the grassthe nasal mucosa 5-24 h after allergen challenge, pollen season, the nasal epithelium of patients with a correlation between the amount of cells with an isolated grass-pollen allergy demonand symptom score. 5 strated more Langerhans cells than before or Mast cells are multifunctional cells which can after the season. 7 play more than one role and can contribute to the chronic inflammation underlying allergic dis-Epithelial cells. Epithelial cells play an important eases by producing a number of immunomodurole in the defence of the airways and in inflamlatory and proinflammatory cytokines and matory processes, but it seems to be more than mediatrs. a protective barrier. Immunohistochemical studies of human lung tissue have reported that Antigen-presenting cells. Responses to most antiepithelial cells have the ability to express the gens require processing of the antigen by HLA-DR antigens, suggesting that these cells play antigen-presenting cells (APC), because T-cells an important role in the antigen presentation and ordinarily recognize antigens only together with immunoregulation. major histocompatibility complex (HMC; human The epithelial layer in the airways is enriched leukocyte antigen HLA-DR,-DQ,-DP) antigens on with nerve endings which contain tachykinins, the surface of other cells. These MHC proteins such as substance P, which is chemotactic for are expressed on the surface cell membrane of neutrophils 8 and monocytes, sv and potentiates macrophages, dendritic cells in lymphoid tissue, phagocytosis and lysosomal enzyme release by Langerhans cells in the skin and the nose, neutrophils and macrophages. 88 Substance P is Kupffer cells in the liver, microglial cells in the 89 n h mitogenic for T-lymphocytes and s 'mu a es 'scentral nervous system tissue, epithelial cells and tamine release by mast cells. 9 It also stimulates B-cells. B-cells are relatively poor activators of Tairway epithelial ion transport, 9 causes airway cells when presenting antigens, possible because smooth muscle contraction 92 and stimulates subsuch T-cells require activating factors such as mucosal-gland secretion. 9 interleukins which B-cells fail to provide. There-Although damage of the epithelial layer causes fore, it is believed that macrophages or Langeran increased permeability to antigens, exposure hans cells probably play the dominant role as of sensory nerve fibres and actuation of local APCs in the initial or primary immune response reflex mechanisms, changes in osmolarity of the whereas B-cells may dominate in the memory or bronchial surface lining fluid and a decreased 67 68 secondary response. production of epithelial relaxant factors, 45 this Macrophages play a central role in host has not been demonstrated in the nose. Epithedefence, which includes ingesting and killing lial cells may play an important role in the local invading organisms/antigens and releasing a recruitment, differentiation, and survival of number of factors involved in host defence and inflammatory migrating cells, 94 and contribute to inflammation. Macrophages possess low affinity the pathologic and clinical events which occur in IgE receptors and after binding of IgE they will allergic rhinitis. release mediators. 9 Although macrophages are the most common cell type residing in the lumen of the lower Secondary effector cells: airways, little is known about the presence and Basophils. The blood basophil count increases pathogenic implications of macrophages in the during the pollen season, suggesting that basoupper airways. Both local allergen challenge and philopoiesis may be influenced by environmental natural exposure increase the number of macro-factors, such as allergens, 95 but this has not been phages on the mucosal surface during the confirmed by others. Several studies have immediate as well as late phase reactions, indicat-demonstrated that the amount of basophils in ing that macrophages are involved in the inflam-the mucus and in the nasal lavage fluid is matory processes of allergic rhinitis. 8 increased 4-11 h after allergen exposure, which It is important to note that the undoubtedly can be interpreted as a shift of cells to the super- 96 effective antigen-presenting ability of pulmonary ficial layers of the mucosa. interstitial dendritic cells may be limited to the It has been suggested that basophils play an interstitial lung-compartment. 79 This is in conimportant role in the late phase of the allergic trast with other investigators, who found that process, based on their release of lipid media-tors. 92 However, whether basophils are asso-Due to their ability to produce these inflammaciated with hyperresponsiveness is not known, tory mediators, neutrophils could play an important role in allergic rhinitis, although the role of Eosinophils. In vitro experiments have shown neutrophils is still unclear. 25 An increased influx that eosinophil-derived enzymes are capable of of neutrophils is measured in nasal lavages of degrading mast cell products, such as histamine rhinitis patients after exposure to ozone. 126 and leukotrienes. 2' Eosinophils have cytoplasmic granules which contain cytotoxic pro-Monocytes/macrophages. The tissue macrophages teins, which can stimulate upregulation of arise either by immigration of monocytes from intercellular adhesion molecule-1 (ICAM-1) on the blood (probably the predominant mechanhuman nasal epithelial cells, which suggests a ism) or by proliferation of precursors in local positive feedback mechanism in which the prosites. During differentiation of monocytes to ducts released from migrating eosinophils might macrophages, the azurophilic peroxidase-containpromote additional human nasal epithelial celling cytoplasmic granules are lost and lysosymes leukocyte adherence. 4 containing hydrolytic enzymes become promi-The role of eosinophilic inflammation in nent. Although monocytes produce myeloperoxiallergy has been studied most thoroughly in the dase, macrophages do not. 2r Their role in pathogenesis of the airway inflammatory rhinitis has already been outlined on page 84.

marrow-derived lymphocytes (B-cells) and
A relationship between the influx of eosino-natural-Miler (NK)-cells. Moreover, the presence phils into the nasal mucosa and allergic rhinitis or absence of certain cell surface markers has was noted 5 and during asymptomatic periods, been used to delineate stages of differentiation, the eosinophils were absent from the nasal secrestates of cellular activation and functionally distions.
There are numerous factors, like GMtinct subsets of lymphocytes. After direct interac-CSF, PAF and lymphocyte chemotactic factor tion with antigen, B-cells can differentiate into (LCF), which have been shown to be chemotactic plasma cells, which can secrete large amounts of for eosinophils, to prolong eosinophil progenitor all immunoglobulin subclasses, including IgE. multiplication, maturation and differentiation. v After the same exposure to antigen, some B-cells The eosinophils are probably derived, in part, can differentiate to memory B-cells which are from progenitors at the site of inflammation, responsible for the rapid recall response which, in turn, are derived from the bone marrow observed after re-exposure to antigens previously via the circulation. The role of the eosinophil in recognized by the immune system. In addition to perennial rhinitis has been rather less intensively producing immunoglobulin, B-cells can secrete studied than in seasonal rhinitis. It has been certain mediators, so-called lymphokines, such as shown that the number of eosinophils is IL-6 that affect the growth and differentiation of increased in the biopsies and secretions com-B-cells and other lymphocytes. In with the formation of T-lymphoblasts and the response to bacterial lipopolysaccharides and secretion of soluble mediators, such as IL-4 and cytokines, such as IL-1, TNF and IFNq,, endothe-IL-5 which augment to help B-cells to respond lial cells become adhesive for neutrophils. 2 A and regulate the IgE production. 28 large number of chemotactic factors can recruit Two functional subclasses of murine T-helper neutrophils to sites of tissue inflammation. Celluclones have been described and are commonly lar sources of factors chemotactic for neutrophils designated Tm and TH2 .129 The murine Tininclude bacteria, macrophages, lymphocytes, pla-lymphocytes produce dominantly IL-2, IFN-, and telets and mast cells.
TNF-a, and they are thought to be involved in delayed-type hypersensitivity reactions and in the participate in the pathogenesis in the allergic synthesis of IgM and some IgG subclasses. The disease. murine TH2-lymphocytes, on the other hand, have been shown to synthesize IL-3, IL-4, IL-5, IL-Products of Allergic Inflammation 6, IL-8, IL-10, and also TNFand are thought to be important in allergic-type inflammatory reac-The role of each product itself is complex and tions and defence against parasites. In their interactions are even more complex. The humans, atopic allergic disorders seem to be most important features of the products relevant related with the activation of T-helper lympho-for rhinitis are reviewed in the following paracytes with a type 2 cytokine secretion profile, a graphs. Non-atopic T lymphocytes resembled murine Inflammatory products may have a large spec-Tra-cells. The atopics' TI2-cells were excellent trum of effects on a variety of target cells in the helper cells for IgE induction and the non-atopic airways, which are relevant in rhinitis. Some of Tin-cells were cytolytic, with activity towards them lead directly and indirectly to contraction autologous antigen presenting cells, of smooth muscle or enhance muscle tone, via Cytotoxic/suppressor T-cells (Tc/s), expressing secondary mediators or neuronal substances.
the surface protein CD8, have the ability to kill They may also lead to oedema of the airways other cells that are perceived as foreign, for and exudation of plasma into the lumen. These example virus-infected cells. These Tc/s cells inflammatory products can attract and activate recognize peptide antigens bound to class I inflammatory cells which thereafter can release MHC molecules on the cell surface of the target mediators themselves, consequently leading to cell, whereafter the target cell is destroyed by the on-going inflammation. Tc/s-cell.
A few studies have shown that T-cell subsets Histamine.. Histamine may be released by change in bronchoalveolar fluid and peripheral a number of immunologic substances, such as blood from asthmatic patients. 2 The produc-IgE, antigen and cytokines, and non-immunotion of IFN-y, IL-4 and IL-5 is enhanced in asthlogic substances, such as anaphylatoxins, matics, showing an increased activity of TIpeptides (e.g. substance P), drugs (e.g. opiates), cells. and physical stimuli. After release from the It was recently demonstrated in biopsies from storage granules, histamine rapidly diffuses allergic patients and nonallergic controls that into the surrounding tissues, and changes in there were no differences between the number blood concentration may be detected within of T-helper cells and cytotoxic T-cells in the minutes. 44 epithelium, but a higher number of activated T-Released histamine interacts with specific cells expressing CD4 was found in the allergic receptors on target cells. To date, three subtypes group in the lamina propria. Following a local of histamine receptors have been characterized: allergen challenge of the nose, an increased H, H 2 and H receptors. The first physiologic number of CD4 + T-helper cells were found in action of histamine to be described was smooth the nasal submucosa. 4 muscle contraction. 45 In vitro blockade of smooth muscle contraction by histamine H Platelets. The role of platelets in inflammatory receptor antagonists has clearly demonstrated reactions is not as well defined as that of neutro-that this effect is mediated predominantly via the phils, eosinophils, macrophages or mast cells. An H receptor subtype. 146 In human airways increased number of platelets have been smooth muscle contraction in response to histaobserved at the sites of the reaction in asthma mine causes bronchoconstriction. 4 Histamine after allergen challenge. 15 Cooperation of plateincreases vascular permeability to macromolelets with basophils and/or mast cells was cules by the formation of intercellular gaps in reported in the release of histamine during the postcapillary venules. 48 Histamine affects antigen challenge of asthmatics, which resulted in both the quantity and viscosity of mucus secrea potentiated six-fold increase of histamine tion, mediated via H2149 and H 5 receptors, release. respectively. The chemotactic activity of eosino- 151 152 A significant increase in platelet volume and a phils and neutrophils may be increased by shorter life-span (2-3 days)of platelets was histamine and the antigen-induced histamine 5 noticed in patients with allergic rhinitis compared release from basophils is controlled. Histamine with controls. v A potential role of platelet also modulates immunoglobulin synthesis, which release compounds in the development of includes interference with the maturation of delayed responses in allergic patients has been antigen-stimulated B-cells, 54 suppressing antiproposed. These findings suggest that platelets body secretion from plasma cells, .55 and modu-lating immunoglobulin production of mature Eicosanoids: Free arachidonic acid may be enzymononuclear cells. 56 matically oxygenated by two major pathways: Nasal challenge of rhinitis patients with hista-cyclooxygenase and lipoxygenase. The prostamine induces nasal blockage, measured by nasal glandins and thromboxane are generated airway resistance (NAR), and is accompanied by through the cyclooxygenase pathway and leukodose-dependent sneezing and rhinorrhoea. 36 A trienes are derived via the lipoxygenase pathway. greater change in NAR is found in rhinitis patients compared with controls, suggesting non-Cyclooxygenase metabolites. Cyclooxygenase specific hyperreactivity of the upper airways, 5 (COX) products have effects on bronchial which is in contrast with other investigations, in smooth muscle and vessels. PGF2 and PGD2 are which an equal effect of histamine provocation potent bronchoconstrictors. 6 PGD2 also has on NAR in patients and controls was found. 8 vasoactive properties, causing increase in pul-Thus, histamine derived from mast cells and monary arterial pressure. 162 TxA 2 has bronchoacting via H and H2 receptors is responsible for constrictor properties, stimulates airway much of the sneezing, nasal blockage and rhinor-smooth muscle cell proliferation, 164 and causes rhoea during the early response to nasal allergen vasoconstriction and platelet aggregation. 65 challenge. Increased concentrations of histamine PGE2 and PGI2 are bronchoand vasodilators. 62 are found in nasal washings of rhinitis patients However, inhaled PGI2 may have bronchoconimmediately after allergen provocation. 48 Also strictor properties in some mild allergic asthduring the late phase response histamine, matics, 6 this paradox has not been resolved. released from basophils, is found in increased PGD2, PGE2 and PGI2 inhibit platelet aggregaconcentrations in nasal washings. 96 tion. 5 PGF2a, PGE2 and PGI2 are potent inducers of cough, perhaps through stimulation of Tryptase: Dog mast cell tryptase has been irritant receptors and C-fibres. -.6 PGE2 inhibits reported to increase the contractile response of phagocytosis, mediator function and cytotoxicity canine bronchial smooth muscle strips to hista-of macrophages, chemotaxis of macrophages mine and other agonists. This effect appeared to and neutrophils and several lymphocyte funcbe dependent on the enzymatic activity and was tions. 68 prevented by H1 receptor antagonists and voltage COX has two isoforms: COX1 and COX2. dependent Ca 2+ channel blockers. This observa-COX1 is constitutively expressed and involved in tion has not been confirmed with human tissues, prostaglandin synthesis in cellular 'housekeeping but raises the possibility that tryptase could con-functions'. COX2 expression is inducible and tribute to bronchial hyperreactivity. Tryptase has involved in inflammatory processes. 69 COX2 is been found to increase vascular permeability, expressed in lung tissue, but whether COX2 when injected into guinea-pig skin and stimulate plays a role in rhinitis is not known. neutrophil accumulation. 5s Increased concentrations of PGD2 and TxA2 In rhinitis, comparatively little attention has were found in bronchoalveolar lavage fluid gfter been paid to the contribution of proteases in antigen-induced bronchoconstriction in atopic disease pathogenesis. However, the recent develasthmatics. 17 In addition to constrictor/dilator opment of sensitive procedures for the detection properties, prostanoids have also been demonof proteases from mast cells, and the discovery strated to induce airway hyperreactivity in of their potent biologic effects has provoked asthma. 71 interest in the potential of these enzymes to act PGD2 was released into nasal secretions during as major mediators of allergic disease. 159 the immediate response to nasal challenge with Increased levels of proteases have been detected pollen anen, though not during the late phase in the nasal secretions of rhinitis patients. Provoresponse. Only a release of PGD2 during the cation of acute rhinitis with allergen or cold dry immediate allergic response to allergen challenge air is associated with the rapid release of mast of perennial allergic rhinitis patients was 42 173 cell tryptase as well as histamine and other found.' In another study with allergic rhinitis mast-cell-derived mediators into nasal fluid. 6 In patients, increased concentrations of PGD2 were nasal lavage fluid of perennial allergic rhinitis reported to occur within minutes of an allergenpatients levels of tryptase were elevated only induced early nasal response. 14 during the immediate phase reaction to provocation with house dust mite extract. 32'42 Tryptase Lipoxygenase metabolites. LTC4, LTD4 and LTE4 may thus participate in many of the processes have potent bronchoconstrictor properties, and of rhinitis and deserves attention beyond its role increase microvascular permeability in the as a marker for mast cell activation in the airways and decrease blood pressure. 75 LTB 4 is airways, a potent chemoattractant for neutrophils and monoc.es, but is less effective for eosino-Nasal challenge with PAF induced nasal obstrucphils. v LTB4 also stimulates the release of lysotion, rhinorrhoea and itching in allergic rhinitis somal ene.s from macrophages and patients, but no increase in histamine levels was neutrophils, ncreases vascular permeability observed in nasal lavages. No changes were seen and releases oxygen radicals from neutrophils. rs after challenge with lyso-PaF. 196 Topical nasal 5-and 15-HETE modestly contracted human application of PAF induced an increase in eosbronchial muscle, r9 and HETEs are chemotactic inophils in the nasal lavage fluid and brushes of for neutrophils and eosinophils. s Neutrophils allergic rhinitis patients, but did not produce any are degranulated by 5-and 12-HETE. m changes in methacholine-induced secretory Increased concentrations of LTC4, LTD4 and responsiveness. 9v Thus, PAF may have patho-LTE4 were found in nasal lavages of rhinitis genetic and clinical relevance in allergic rhinitis. patients allergic to ragweed during allergeninduced early nasal response. v4 During the Eosinophil-derived granule proteins.. Activation of immediate allergic reaction to allergen provoca-granulocytes, including eosinophils, can result in tion of perennial allergic rhinitis patients an the release of granule contents, providing the increase of cysteinyl leukotrienes was found. 42 '73 cells with a very potent mechanism of inflamma-As a consequence of their activity, the eicosa-tory action. Degranulation of these cationic pronoids have been implicated as potential canditeins has been correlated to several of the dates in the pathogenesis of rhinitis, symptoms of asthma and rhinitis and hyperresponsiveness. MBP is toxic to many mamma-Platelet activating factor: PAF is a potent in vitro lian cells, such as human lung epithelium, 198 and activator of eosinophil, platelet, neutrophil, induces mast cell and basophil histamine release. monocyte and macrophage chemotaxis and The EPO can stimulate mast cell secretion, 99 superoxide anion production, and an activator of inactivate mediators of immediate hypersensitivthe release of arachidonic acid metabolites, such ity, 2 and is cytotoxic to various target cells. ECP as LTC4, by neutrophils, eosinophils and macro-can inhibit T-lymphocyte proliferation in a nonphages.  PAF has been shown to be a cytotoxic fashion, but the mechanisms involved potent mucus secretagogue for human airways in are unclear. 2m vitro 5 and to stimulate the secretion of chloride ions and, thus, allow the movement of water Eosinophil cationic protein. Motojima et al. 202 toward the lumen. 8 Basophils are activated by found that ECP caused dope-dependent damage PAF and, thereafter, release histamine and LTC4 to guinea-pig tracheal epithelium in vitro. by a rise in calcium influx. 87 Intravenous injec-However, ECP had no effect on bronchoconstrictions of PAF to guinea-pigs leads to a bronchotor or airway hyperresponsiveness of cynomolgus constriction and hypotension 88 as well as monkeys. 2 bronchial hyperreactivity to serotonin, 189 hista-Increased serum levels of ECP occur in allermine or acetylcholine. 9 In humans PAF induces gen-provoked asthma. 24 Elevated levels of ECP bronchial hyperreactivity to methacholine in non-have been found in bronchoalveolar lavage fluid asthmatics. 9 This is in contrast with other inves-of asthmatics obtained during the late phase tigators, who found that PAF failed to induce reaction after allergen-inhalation challenge of hyperreactivity to methacholine in normal subasthmatics, as well as in unchallenged patients 192 193 jects and asthmatic patients, with chronic asthma.
Lyso-PAF-acether, but almost no PAF was sig-In both allergic and nonallergic rhinitis nificantly increased in nasal secretions from allerincreased serum levels of ECP are obseed. 122 gic patients in the immediate reaction to antigen Lavage fluid from allergic rhinitis patients showed challenge. 94 In a study with perennial allergic marked elevations of ECP after segmental bronrhinitis patients a 15-fold increase from baseline chial antigen challenge. 25 In nasal lavage fluid of of PAF after allergen provocation was demonperennial allergic rhinitis patients levels of ECP strated, which tended to decrease after treatment were elevated only during the late phase reaction with a corticosteroid. 42'7 Topical pretreatment to provocation with house dust mite with PAF of seasonal allergic rhinitis patients extract. 2'42'2 An increased number of eosinoinduced only minor changes in nasal respiratory phils and raised levels of ECP were found on the peak flow rate and symptom score as compared nasal mucosal surface during natural allergic rhiwith placebo. However, it induced an increase in nitis patients. 27 These changes were not accomresponsiveness of the nasal vasculature to allerpanied by an increased secretory responsiveness 20 gen challenge, measured as increased symptoms of the nasal mucosa to methacholine. In the and nasal peak flow, but other parameters, such lavage fluid of the patients with a late phase reacas sneezes and secretion remained identical. 95 tion, a significant eosinophilia was found, com-pared with controls and those patients who only tion of bone marrow precursors into eosinophils demonstrated early responses. This suggested and supports the growth of eosinophilic cell that eosinophils and their mediators might be lines and induction of cytotoxic T-cells. IL-5 involved in the development of the late phase enhances eosinophil development and differenreaction, tiation 219 and prolongs survival of eosinophils. 22 IL-5 can alter functional and immunologic prop-Cytokines: Cytokines modulate reactions of the erties of eosinophils. Data from patients with host to foreign antigens or injurious agents by eosinophil-related disorders suggest that IL-5 proregulating the growth, mobility and differentia-duces 'activated' eosinophils. 22 It has been tion of leukocytes and other cells. Normal resting observed that IL-5 increases eosinophil, but not cells must be stimulated to produce cytokines, neutrophil, adherence to vascular endothelium 222 and therefore usually no cytokines are normally and IL-5 is chemotactic for eosinophils. 223 Eosipresent in serum. Many cytokines are simulta-nophils can be primed by IL-5 for chemotaxis neously produced by activated cells, towards PaF. 224 Some cytokines have direct histamine-releasing Although the T-lymphocyte is considered to be properties, such as IL-3, GM-CSF and IL-1 from a major source of IL-5, eosinophils contribute to bas,ophils and mast cells. 29 Cytokines can prime the production of IL-5 in allergic airway inflambasophils for enhanced histamine release in mation. 225 This raises the possibility of an autoresponse to other secretagogues, such as anti-IgE crine mechanism whereby stimulated eosinophils and FMLP. This priming effect has been documay both release and respond to cytokines, such mented for IL-1-3,2'2, IL-5, 98 IL-11, GM-CSF 22 as IL-5. Thus, there is the potential for a self-perand IFN-7. 213 Some of these priming cytokines, petuating cycle, with continuous eosinophil infilsuch as IL-5, also upregulate adhesion molecules tration and activation and consequently chronic in nasal mucosa, including E selectin, P selectin, inflammation. ICAM-1, ICAM-2 and vcam-1. 214 The inducible In humans, elevated serum IL-5 was noted in expression of these molecules on endothelium symptomatic asthmatics in association with actidirects the focal adherence of leukocytes to vated T-lymphocytes and eosinophilia. 226 In allerendothelium for extravasation at sites of inflamgic rhinitis patients, IL-5 levels were elevated 48 h mation, after antigen challenge and found to correlate Several investigators have suggested that cyto-strongly with eosinophil number, eosinophil kines may contribute to the occurrence of degra-granule proteins and LTC4 levels. 25 IL-5 levels nulation of cells in bronchial mucosa of were increased in nasal lavages during both the asthmatics. 25 Durham et al. 216 showed with in immediate and the late phase response to allersitu hybridization messenger ribonuclear acid gen challenge of perennial allergic rhinitis (mRNA) for IL-3, IL-4, IL-5 and GM-CSF in nasal patients. Treatment with a corticosteroid biopsies 24 h after allergen challenge, which is decreased the evoked IL-5 levels in the late phase 42 206 correlated with the number of activated T-cell reaction.
Application of recombinant human and eosinophils. In addition to the work in nasal IL-5 onto the nasal mucosa of patients allergic to mucosal tissue, attempts have been made to pollen increased the numbers of eosinophils, quantitate cytokines in nasal secretions following epithelial cells, ECP and IgA in the nasal lavage antigen challenge. 2v In general, little success has fluid. Also the number of eosinophils in both the been reported in nasal lavages, with some cyto-epithelium and lamina propria as well as in the kines such as IL-113, IL-2 and IL-6 being detect-lumens of the blood vessels in the nasal mucosa able in higher levels than prechallenge fluids were increased. The response to histamine was only in a subset of allergic subjects. Increased also enhanced after the application. 227 levels of IL-113 and GM--CSF have been detected by using strips of filter paper to collect secre-Nitric oxide.. NO generated by intact endothelium tions from the nose. 217 Of these cytokines, IL-5 is not only induces smooth-muscle relaxation, but highly important, because IL-5 alone is capable of also appears to serve to inhibit further adhesion inducing eosinophil degranulation in the absence and aggregation of normal platelets, which sugof a ligand and greatly enhancing ligand-stimugests protective effects against inflammation. 228 lated eosinophil degradation. 2 NO has the ability to suppress leukocyte adherence and T-lymphocyte proliferation and to regu- 229 Interleukin-5. IL-5 promotes the proliferation late the mitogen responses. NO can modulate and differentiation of B-cells and promotes the the release of histamine from mast cells. 23 antibody production by B-cells, particularly, of NO has been shown to be a potent bronchothe IgA isotype. IL-5 has modest mitogenic effects dilator in isolated guinea-pig trachea smooth on T-cells. In addition, it induces the differentia-muscle and in humans, xv8 Probably, NO mediates airway smooth muscle relaxation by inhibiting the release of acetylcholine from nerve terminals. 2 NO also leads to the production of cP. 232 The products of NO are extremely cytotoxic. Because epithelial damage is related to the development of bronchial hyperreactivity, 233 NO may be greatly responsible for hyperresponsiveness in asthmatics. This is supported by Golden, who found that inhalation of nitrogen dioxide and ozone increases bronchial reactivity in healthy humans 234 and by Barnes, who suggested that free oxygen radicals from inflammatory cells increases the breakdown of NO, thus leading to exaggeration of the cholinergic reflex bronchoconstriction. 231 Inhalation of ozone of allergic rhinitis patients caused an increase in symptoms after allergen challenge. Also, an increase in nasal lavage neutrophils, eosinophils, mononuclear cells and epithelial cells was observed. The histamine and albumin concentration in lavage fluid increased on the ozone exposure day. NO metabolites (measured as nitrite + nitrate) were present in nasal lavage fluid of both controls and perennial allergic rhinitis patients. 42'235 However, the level gradually increased with time and treatment with fluticasone propionate did not affect initial production of NO nor production following provocation with allergen. These findings do not suggest that NO is associated with rhinitis nor hyperreactivity.

Pharmacotherapy
Antihistamines, corticosteroids, mast cell stabilizers, decongestants and anticholinergics are the major topical drugs used in the treatment of allergic rhinitis. Although H1 antihistamines are effective in controlling sneezing, pruritus and rhinorrhea, they are not useful for alleviating congestion. Some H1 receptor antagonists (terfenadine, cetirizine) inhibit mediator release from basophils and mast cells and decrease recruitment of inflammatory cells. Intranasal corticosteroids, such as fluticasone propionate, may be the most effective treatment of rhinitis. They decrease vasodilatation, oedema and inflammation and decrease symptoms, including nasal blockage. Mast cell stabilizers constitute a class of drugs, such as cromolyn sodium, that prevent degranulation and mediator release from mast cells. Cromolyn is more helpful for sneezing, rhinorrhoea and nasal itching, than for nasal obstruction. Nasal decongestants (vasoconstrictor sympathomimetic agents) reduce blood flow, oedema and blanching of the nasal mucosa.
They are very effective for short-term use to increase nasal airway patency, but they do not improve rhinorrhea, sneezing or nasal pruritis. The anticholinergic ipratropium bromide has been shown to be effective for perennial allergic rhinitis.  Concluding Remarks Several inflammatory cells, such as mast cells, basophils, lymphocytes and eosinophils and their mediators released after specific or nonspecific stimuli, have been demonstrated during the nasal allergic processes. Although some of these mediators, such as histamine, prostaglandins and leukotrienes may be biologically active in allergic rhinitis, the role of others, such as PAF, IL-5 and nitric oxide still needs clarification. The interaction between these different cellular components to induce the clinical symptoms of allergic rhinitis remains unclear. Also the relationship between the inflammatory infiltration, cellular activation and hyperreactivity needs further establishment. We have particularly reviewed the role of tryptase, as a marker of activated mastcells, ECP, as a marker of activated eosinophils, and further more histamine, LTC4/D4/E4, PGD2, PAF, IL-5 and NO, which may be involved in the immediate and late phase nasal reaction to allergen challenge, in hyperreactivity and in therapeutic intervention. Intranasal corticosteroid is the most effective treatment of allergic rhinitis, because not only are the symptoms improved but nasal inflammation is also decreased.