Allergic Rhinitis and Conjunctivitis: Update on Pathophysiology

  • Jean-Baptiste Watelet
  • James I. McGill
  • Ruby Pawankar
  • Diana S. Church
  • Martin K. Church
Part of the Allergy Frontiers book series (ALLERGY, volume 3)


Our understanding of the development and mechanism(s) of allergic diseases has changed dramatically over the last 20 years. With the advent of genetic studies it has now become clear that the linear model, as defined by the allergic march, is no longer tenable. Instead, we must consider all allergies as complex multi-compartment models in which genes which control IgE production and also genes which govern other aspects of allergic disease, such as epithelium integrity, both play an important role. To explore such possibilities, this chapter asks four questions:

1. Is there any evidence of an abnormality in the conjunctival or nasal mucosa which would allow increased allergen penetration? Epithelial changes which are likely to facilitate allergen penetration are present in both allergic conjunctivitis and rhinitis, but they appear different. For example, epithelial PAR-2 expression is elevated in allergic rhinitis whereas in seasonal allergic conjunctivitis, many structural proteins, including E-cadherin, CD44, desmosomes, keratins K5/6, K7, K8, K13, K14, K18 and PAR-2 are all reduced. 2. What is known about the immunology of sensitization in allergic conjunctivitis and allergic rhinitis? Clearly, great strides are being made with respect to the biology of dendritic cells and T regulatory cells and to the possibility of local IgE production, but there is little evidence to suggest differences between the mechanisms of sensitization in the eye and nose. 3. What is the pattern of mediator release in the immediate allergic response and the development of allergic inflammation in allergic conjunctivitis and allergic rhinitis? The pattern of the early phase allergic response in the eye and nose seem similar. While an eosinophil dominated late phase response and allergic inflammation are present in allergic rhinitis, they are only present in the more severe forms of allergic conjunctivitis such as AKC and VKC. 4. Is there any evidence for clinically relevant persistent inflammation or organ remodelling in allergic conjunctivitis and allergic rhinitis? A sustained inflammation and tissue remodelling are well established in the lower airways in asthma where they contribute significantly to the symptoms. However, in upper airways, although there do appear to be functional changes in sensory neurone structure and function in the nose during prolonged allergen exposure, tissue damage seems to be more limited and overt remodelling does not appear to occur in allergic conjunctivitis and is questionable in allergic rhinitis.


Mast Cell Atopic Dermatitis Allergic Rhinitis Nasal Mucosa Allergy Clin Immunol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Blumenthal MN, Amos DB. Genetic and immunologic basis of atopic responses. Chest 1987;91:176S–84S.PubMedCrossRefGoogle Scholar
  2. 2.
    Wahn U. What drives the allergic march? Allergy 2000;55:591–9.PubMedCrossRefGoogle Scholar
  3. 3.
    ETAC Study Group. Allergic factors associated with the development of asthma and the influence of cetirizine in a double-blind, randomised, placebo-controlled trial: first results of ETAC. Early Treatment of the Atopic Child. Pediatr Allergy Immunol 1998;9:116–24.CrossRefGoogle Scholar
  4. 4.
    Warner JO. Future aspects of pharmacological treatment to inhibit the allergic march. Pediatr Allergy Immunol 2001;12(Suppl 14):102–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Lawrence R, et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001;29:175–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M. Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 2003;148:665–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Moffatt MF. SPINK5: a gene for atopic dermatitis and asthma. Clin Exp Allergy 2004;34:325–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Allen M, Heinzmann A, Noguchi E, Abecasis G, Broxholme J, Ponting CP, et al. Positional cloning of a novel gene influencing asthma from chromosome 2q14. Nat Genet 2003;35:258–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Lilly CM. Diversity of asthma: evolving concepts of pathophysiology and lessons from genetics. J Allergy Clin Immunol 2005;115:S526–S531.PubMedCrossRefGoogle Scholar
  10. 10.
    Van Eerdewegh P., Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, et al. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 25-72002;418:426–30.CrossRefGoogle Scholar
  11. 11.
    Holgate ST, Yang Y, Haitchi HM, Powell RM, Holloway JW, Yoshisue H, et al. The genetics of asthma: ADAM33 as an example of a susceptibility gene. Proc Am Thorac Soc 2006;3:440–3.PubMedCrossRefGoogle Scholar
  12. 12.
    Holgate ST, Davies DE, Powell RM, Howarth PH, Haitchi HM, Holloway JW. Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms. Eur Respir J 2007;29:793–803.PubMedCrossRefGoogle Scholar
  13. 13.
    Cullinan P, Harris JM, Newman Taylor AJ, Jones M, Taylor P, Dave JR, et al. Can early infection explain the sibling effect in adult atopy? Eur Respir J 2003;22:956–61.PubMedCrossRefGoogle Scholar
  14. 14.
    Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and atopy during childhood by allergen avoidance in infancy: a randomised controlled study. Thorax 2003;58:489–93.PubMedCrossRefGoogle Scholar
  15. 15.
    McGill JI, Holgate ST, Church MK, Anderson DF, Bacon A. Allergic eye disease mechanisms. Br J Ophthalmol 1998;82:1203–14.PubMedCrossRefGoogle Scholar
  16. 16.
    Salib RJ, Howarth PH. Remodelling of the upper airways in allergic rhinitis: is it a feature of the disease? Clin Exp Allergy 2003;33:1629–33.PubMedCrossRefGoogle Scholar
  17. 17.
    Watelet JB, Van ZT, Gjomarkaj M, Canonica GW, Dahlen SE, Fokkens W, et al. Tissue remodelling in upper airways: where is the link with lower airway remodeling? Allergy 2006;61:1249–58.PubMedCrossRefGoogle Scholar
  18. 18.
    Senol M, Ozcan A, Kandi B, Karaca S, Aki T, Bayram N. Incidence of atopic stigmata and prick test results in patients with asthma, allergic rhinitis and conjunctivitis. Asian Pac J Allergy Immunol 2006;24:105–9.PubMedGoogle Scholar
  19. 19.
    Gradman J, Wolthers OD. Allergic conjunctivitis in children with asthma, rhinitis and eczema in a secondary outpatient clinic. Pediatr Allergy Immunol 2006;17:524–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Herbert CA, Holgate ST, Robinson C, Thompson PJ, Stewart GA. Effect of mite allergen on permeability of bronchial mucosa. Lancet 3-11-1990;336:1132.CrossRefGoogle Scholar
  21. 21.
    Herbert CA, King CM, Ring PC, Holgate ST, Stewart GA, Thompson PJ, et al. Augmentation of permeability in the bronchial epithelium by the house dust mite allergen Der p1. Am J Respir Cell Mol Biol 1995;12:369–78.PubMedGoogle Scholar
  22. 22.
    Stewart GA, Lake FR, Thompson PJ. Faecally derived hydrolytic enzymes from Dermatophagoides pteronyssinus: physicochemical characterisation of potential allergens. Int Arch Allergy Appl Immunol 1991;95:248–56.PubMedGoogle Scholar
  23. 23.
    Petersen A, Grobe K, Schramm G, Vieths S, Altmann F, Schlaak M, et al. Implications of the grass group I allergens on the sensitization and provocation process. Int Arch Allergy Immunol 1999;118:411–3.PubMedCrossRefGoogle Scholar
  24. 24.
    Wan H, Winton HL, Soeller C, Tovey ER, Gruenert DC, Thompson PJ, et al. Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions. J Clin Invest 1999;104:123–33.PubMedCrossRefGoogle Scholar
  25. 25.
    Widmer F, Hayes PJ, Whittaker RG, Kumar RK. Substrate preference profiles of proteases released by allergenic pollens. Clin Exp Allergy 2000;30:571–6.PubMedCrossRefGoogle Scholar
  26. 26.
    Robinson C, Baker SF, Garrod DR. Peptidase allergens, occludin and claudins. Do their interactions facilitate the development of hypersensitivity reactions at mucosal surfaces? Clin Exp Allergy 2001;31:186–92.PubMedCrossRefGoogle Scholar
  27. 27.
    Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38:441–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, az-Lacava A, et al. Loss-offunction variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006;118:214–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, et al. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol 2006;118:3–21.PubMedCrossRefGoogle Scholar
  30. 30.
    Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 2005;129:550–64.PubMedGoogle Scholar
  31. 31.
    Zeissig S, Burgel N, Gunzel D, Richter J, Mankertz J, Wahnschaffe U, et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn's disease. Gut 2007;56:61–72.PubMedCrossRefGoogle Scholar
  32. 32.
    Xaio C, Bedke M, Holgate ST, Davies DE, Puddicombe SM. Bronchial epithelial barrier integrity is altered in asthma but not normal subjects, independent of atopy. Am J Respir Crit Care Med. ATS Abstracts, San Francisco Meeting, A886. 2007. Ref Type: Abstract.Google Scholar
  33. 33.
    Hughes JL, Lackie PM, Wilson SJ, Church MK, McGill JI. Reduced structural proteins in the conjunctival epithelium in allergic eye disease. Allergy 2006;61:1268–74.PubMedCrossRefGoogle Scholar
  34. 34.
    Bacon AS, Ahluwalia P, Irani AM, Schwartz LB, Holgate ST, Church MK, et al. Tear and conjunctival changes during the allergen-induced early- and late-phase responses. J Allergy Clin Immunol 2000;106:948–54.PubMedCrossRefGoogle Scholar
  35. 35.
    Alattia JR, Tong KI, Takeichi M, Ikura M. Cadherins. Methods Mol Biol 2002;172:199–21.PubMedGoogle Scholar
  36. 36.
    Leir SH, Baker JE, Holgate ST, Lackie PM. Increased CD44 expression in human bronchial epithelial repair after damage or plating at low cell densities. Am J Physiol Lung Cell Mol Physiol 2000;278:L1129–L1137.PubMedGoogle Scholar
  37. 37.
    Miyake K, Underhill CB, Lesley J, Kincade PW. Hyaluronate can function as a cell adhesion molecule and CD44 participates in hyaluronate recognition. J Exp Med 1-71990;172:69–75.CrossRefGoogle Scholar
  38. 38.
    Roche WR, Montefort S, Baker J, Holgate ST. Cell adhesion molecules and the bronchial epithelium. Am Rev Respir Dis 1993;148:S79–S82.PubMedGoogle Scholar
  39. 39.
    Shahana S, Jaunmuktane Z, Asplund MS, Roomans GM. Ultrastructural investigation of epithelial damage in asthmatic and non-asthmatic nasal polyps. Respir Med 2006;100:2018–28.PubMedCrossRefGoogle Scholar
  40. 40.
    Pitz S, Moll R. Intermediate-filament expression in ocular tissue. Prog Retin Eye Res 2002;21:241–62.PubMedCrossRefGoogle Scholar
  41. 41.
    Ryder MI, Weinreb RN. Cytokeratin patterns in corneal, limbal, and conjunctival epithelium. An immunofluorescence study with PKK-1, 8.12, 8.60, and 4.62 anticytokeratin antibodies. Invest Ophthalmol Vis Sci 1990;31:2230–4.PubMedGoogle Scholar
  42. 42.
    Kasper M, Moll R, Stosiek P, Karsten U. Patterns of cytokeratin and vimentin expression in the human eye. Histochemistry 1988;89:369–77.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang M, Liu Z, Xie Y. The study on the expression of keratin proteins in pterygial epithelium. Yan Ke Xue Bao 2000;16:48–52.PubMedGoogle Scholar
  44. 44.
    Galou M, Gao J, Humbert J, Mericskay M, Li Z, Paulin D, et al. The importance of intermediate filaments in the adaptation of tissues to mechanical stress: evidence from gene knockout studies. Biol Cell 1997;89:85–97.PubMedCrossRefGoogle Scholar
  45. 45.
    Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, et al. Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. J Allergy Clin Immunol 2001;108:797–803.PubMedCrossRefGoogle Scholar
  46. 46.
    Kawabata A, Kawao N. Physiology and pathophysiology of proteinase-activated receptors (PARs): PARs in the respiratory system: cellular signaling and physiological/pathological roles. J Pharmacol Sci 2005;97:20–4.PubMedCrossRefGoogle Scholar
  47. 47.
    Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R. Proteinase-activated receptors. Pharmacol Rev 2001;53:245–82.PubMedGoogle Scholar
  48. 48.
    Asokananthan N, Graham PT, Stewart DJ, Bakker AJ, Eidne KA, Thompson PJ, et al. House dust mite allergens induce proinflammatory cytokines from respiratory epithelial cells: the cysteine protease allergen, Der p 1, activates protease-activated receptor (PAR)-2 and inactivates PAR-1. J Immunol 15-10-2002;169:4572–8.Google Scholar
  49. 49.
    Hollenberg MD. Physiology and pathophysiology of proteinase-activated receptors (PARs): proteinases as hormone-like signal messengers: PARs and more. J Pharmacol Sci 2005;97:8–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Reed CE, Kita H. The role of protease activation of inflammation in allergic respiratory diseases. J Allergy Clin Immunol 2004;114:997–1008.PubMedCrossRefGoogle Scholar
  51. 51.
    Asano-Kato N, Fukagawa K, Okada N, Dogru M, Tsubota K, Fujishima H. Tryptase increases proliferative activity of human conjunctival fibroblasts through protease-activated receptor-2. Invest Ophthalmol Vis Sci 2005;46:4622–6.PubMedCrossRefGoogle Scholar
  52. 52.
    Vliagoftis H, Befus AD, Hollenberg MD, Moqbel R. Airway epithelial cells release eosinophil survival-promoting factors (GM-CSF) after stimulation of proteinase-activated receptor 2. J Allergy Clin Immunol 2001;107:679–85.PubMedCrossRefGoogle Scholar
  53. 53.
    D'Agostino B, Roviezzo F, De PR, Terracciano S, De NM, Gallelli L, et al. Activation of protease-activated receptor-2 reduces airways inflammation in experimental allergic asthma. Clin Exp Allergy 2007;37:1436–43.PubMedGoogle Scholar
  54. 54.
    Vergnolle N, Hollenberg MD, Sharkey KA, Wallace JL. Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw. Br J Pharmacol 1999;127:1083–90.PubMedCrossRefGoogle Scholar
  55. 55.
    Aslam A, Buckley MG, Wilson SJ, Howarth PH, Hollenberg MD, Walls AF. Protease activated receptor-2 (PAR-2) expression is increased in the bronchial epithelium of asthmatics. Clin Exp Allergy 2002;32:1384; Clin Exp Allergy 32, 1384, 2002. Ref Type: Abstract.Google Scholar
  56. 56.
    Nagata H, Motosugi H, Sanai A, Suzuki H, Ohno K, Numata T, et al. Enhancement of submicroscopic damage of the nasal epithelium by topical allergen challenge in patients with perennial nasal allergy. Ann Otol Rhinol Laryngol 2001;110:236–42.PubMedGoogle Scholar
  57. 57.
    Lee HM, Kim HY, Kang HJ, Woo JS, Chae SW, Lee SH, et al. Up-regulation of protease-activated receptor 2 in allergic rhinitis. Ann Otol Rhinol Laryngol 2007;116:554–8.PubMedGoogle Scholar
  58. 58.
    Dinh QT, Cryer A, Trevisani M, Dinh S, Wu S, Cifuentes LB, et al. Gene and protein expression of protease-activated receptor 2 in structural and inflammatory cells in the nasal mucosa in seasonal allergic rhinitis. Clin Exp Allergy 2006;36:1039–48.PubMedCrossRefGoogle Scholar
  59. 59.
    Dinh QT, Cryer A, Dinh S, Trevisani M, Georgiewa P, Chung F, et al. Protease-activated receptor 2 expression in trigeminal neurons innervating the rat nasal mucosa. Neuropeptides 2005;39:461–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Runswick S, Mitchell T, Davies P, Robinson C, Garrod DR. Pollen proteolytic enzymes degrade tight junctions. Respirology 2007;12:834–42.PubMedCrossRefGoogle Scholar
  61. 61.
    Wan H, Winton HL, Soeller C, Taylor GW, Gruenert DC, Thompson PJ, et al. The transmembrane protein occludin of epithelial tight junctions is a functional target for serine peptidases from faecal pellets of Dermatophagoides pteronyssinus. Clin Exp Allergy 2001;31:279–94.PubMedCrossRefGoogle Scholar
  62. 62.
    Takano K, Kojima T, Go M, Murata M, Ichimiya S, Himi T, et al. HLA-DR- and CD11cpositive dendritic cells penetrate beyond well-developed epithelial tight junctions in human nasal mucosa of allergic rhinitis. J Histochem Cytochem 2005;53:611–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Kobayashi N, Dezawa M, Nagata H, Yuasa S, Konno A. Immunohistochemical study of E-cadherin and ZO-1 in allergic nasal epithelium of the guinea pig. Int Arch Allergy Immunol 1998;116:196–205.PubMedCrossRefGoogle Scholar
  64. 64.
    Benson M, Svensson PA, Adner M, Caren H, Carlsson B, Carlsson LM, et al. DNA micro-array analysis of chromosomal susceptibility regions to identify candidate genes for allergic disease: a pilot study. Acta Otolaryngol 2004;124:813–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Kusunoki T, Okafuji I, Yoshioka T, Saito M, Nishikomori R, Heike T, et al. SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. J Allergy Clin Immunol 2005;115:636–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. J Allergy Clin Immunol 2005;115:118–22.PubMedCrossRefGoogle Scholar
  67. 67.
    Keane-Myers AM, Miyazaki D, Liu G, Dekaris I, Ono S, Dana MR. Prevention of allergic eye disease by treatment with IL-1 receptor antagonist. Invest Ophthalmol Vis Sci 1999;40:3041–6.PubMedGoogle Scholar
  68. 68.
    Bundoc VG, Keane-Myers A. IL-10 confers protection from mast cell degranulation in a mouse model of allergic conjunctivitis. Exp Eye Res 2007;85:575–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Fokkens WJ, Bruijnzeel-Koomen CA, Vroom TM, Rijntjes E, Hoefsmit EC, Mudde GC, et al. The Langerhans cell: an underestimated cell in atopic disease. Clin Exp Allergy 1990;20:627–38.PubMedCrossRefGoogle Scholar
  70. 70.
    Godthelp T, Holm AF, Fokkens WJ, Doornenbal P, Mulder PG, Hoefsmit EC, et al. Dynamics of nasal eosinophils in response to a nonnatural allergen challenge in patients with allergic rhinitis and control subjects: a biopsy and brush study. J Allergy Clin Immunol 1996;97:800–11.PubMedCrossRefGoogle Scholar
  71. 71.
    Fokkens WJ, Vroom TM, Rijntjes E, Mulder PG. Fluctuation of the number of CD-1(T6)positive dendritic cells, presumably Langerhans cells, in the nasal mucosa of patients with an isolated grass-pollen allergy before, during, and after the grass-pollen season. J Allergy Clin Immunol 1989;84:39–43.PubMedCrossRefGoogle Scholar
  72. 72.
    Till SJ, Jacobson MR, O'Brien F, Durham SR, Kleinjan A, Fokkens WJ, et al. Recruitment of CD1a + Langerhans cells to the nasal mucosa in seasonal allergic rhinitis and effects of topical corticosteroid therapy. Allergy 2001;56:126–31.PubMedCrossRefGoogle Scholar
  73. 73.
    Bachert C, Behrendt H, Nosbusch K, Hauser U, Ganzer U. Possible role of macrophages in allergic rhinitis. Int Arch Allergy Appl Immunol 1991;94:244–5.PubMedGoogle Scholar
  74. 74.
    Francis JN, Lloyd CM, Sabroe I, Durham SR, Till SJ. T lymphocytes expressing CCR3 are increased in allergic rhinitis compared with non-allergic controls and following allergen immunotherapy. Allergy 2007;62:59–65.PubMedCrossRefGoogle Scholar
  75. 75.
    Jutel M, Akdis M, Budak F, ebischer-Casaulta C, Wrzyszcz M, Blaser K, et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol 2003;33:1205–14.PubMedCrossRefGoogle Scholar
  76. 76.
    Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, et al. Relation of CD4 + CD25 + regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 21-2-2004;363:608–15.CrossRefGoogle Scholar
  77. 77.
    Malmhall C, Bossios A, Pullerits T, Lotvall J. Effects of pollen and nasal glucocorticoid on FOXP3 +, GATA-3 + and T-bet + cells in allergic rhinitis. Allergy 2007;62:1007–13.PubMedCrossRefGoogle Scholar
  78. 78.
    Lee JH, Yu HH, Wang LC, Yang YH, Lin YT, Chiang BL. The levels of CD4 + CD25 + regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin Exp Immunol 2007;148:53–63.PubMedGoogle Scholar
  79. 79.
    Xu G, Mou Z, Jiang H, Cheng L, Shi J, Xu R, et al. A possible role of CD4 + CD25 + T cells as well as transcription factor Foxp3 in the dysregulation of allergic rhinitis. Laryngoscope 2007;117:876–80.PubMedCrossRefGoogle Scholar
  80. 80.
    Siewert C, Menning A, Dudda J, Siegmund K, Lauer U, Floess S, et al. Induction of organ-selective CD4 + regulatory T cell homing. Eur J Immunol 2007;37:978–89.PubMedCrossRefGoogle Scholar
  81. 81.
    Ahluwalia P, Anderson DF, Wilson SJ, McGill JI, Church MK. Nedocromil sodium and levocabastine reduce the symptoms of conjunctival allergen challenge by different mechanisms. J Allergy Clin Immunol 2001;108:449–54.PubMedCrossRefGoogle Scholar
  82. 82.
    Anderson DF, MacLeod JD, Baddeley SM, Bacon AS, McGill JI, Holgate ST, et al. Seasonal allergic conjunctivitis is accompanied by increased mast cell numbers in the absence of leucocyte infiltration. Clin Exp Allergy 1997;27:1060–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Trocme SD, Kephart GM, Allansmith MR, Bourne WM, Gleich GJ. Conjunctival deposition of eosinophil granule major basic protein in vernal keratoconjunctivitis and contact lens-associated giant papillary conjunctivitis. Am J Ophthalmol 15-7-1989;108:57–63.Google Scholar
  84. 84.
    Foster CS, Rice BA, Dutt JE. Immunopathology of atopic keratoconjunctivitis. Ophthalmology 1991;98:1190–6.PubMedGoogle Scholar
  85. 85.
    Trocme SD, Leiferman KM, George T, Bonini S, Foster CS, Smit EE, et al. Neutrophil and eosinophil participation in atopic and vernal keratoconjunctivitis. Curr Eye Res 2003;26:319–25.PubMedCrossRefGoogle Scholar
  86. 86.
    Bradding P, Feather IH, Wilson S, et al. Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. J Immunol 1993;151:3853–65.PubMedGoogle Scholar
  87. 87.
    Pawankar R, Okuda M, Hasegawa S, et al. Interleukin-13 expression in the nasal mucosa of perennial allergic rhinitis. Am J Respir Critical Care Med 1995;152:2059–67.Google Scholar
  88. 88.
    Pawankar R, Ra C. Heterogeneity of mast cells and T cells in the nasal mucosa. J Allergy Clin Immunol 1996;98:249–62.CrossRefGoogle Scholar
  89. 89.
    Pawankar R, Takizawa R, Saito H, et al. RANTES can regulate mast cell migration into the allergic nasal epithelium [abstract]. J Allergy Clin Immunol 2002;101:153.Google Scholar
  90. 90.
    Lilly CM, Nakamura H, Kesselman H, et al. Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids. J Clin Invest 1997;99:1767–73.PubMedCrossRefGoogle Scholar
  91. 91.
    Li L, Xia Y, Nguyen A, et al. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. J Immunol 1999;162:2477–87.PubMedGoogle Scholar
  92. 92.
    Sekiya T, Miyamasu M, Yamaguchi M, Pawankar R, et al. Inducible expression of a Th2typeCCchemokine, thymus-and activation regulated chemokine (TARC) by human bronchial epithelial cells. J Immunol 2000;165:2205–13.PubMedGoogle Scholar
  93. 93.
    Naclerio RM, Proud D, Togias AG, Adkinson NF, Jr., Meyers DA, Kagey-Sobotka A, et al. Inflammatory mediators in late antigen-induced rhinitis. N Engl J Med 11-71985;313:65–70.CrossRefGoogle Scholar
  94. 94.
    Naclerio RM, Meier HL, Kagey-Sobotka A, Adkinson NF, Jr., Meyers DA, Norman PS, et al. Mediator release after nasal airway challenge with allergen. Am Rev Respir Dis 1983;128:597–602.PubMedGoogle Scholar
  95. 95.
    Wagenmann M, Baroody FM, Cheng CC, Kagey-Sobotka A, Lichtenstein LM, Naclerio RM. Bilateral increases in histamine after unilateral nasal allergen challenge. Am J Respir Crit Care Med 1997;155:426–31.PubMedGoogle Scholar
  96. 96.
    Juliusson S, Holmberg K, Baumgarten CR, Olsson M, Enander I, Pipkorn U. Tryptase in nasal lavage fluid after local allergen challenge. Relationship to histamine levels and TAME-esterase activity. Allergy 1991;46:459–65.PubMedGoogle Scholar
  97. 97.
    Rasp G, Hochstrasser K. Tryptase in nasal fluid is a useful marker of allergic rhinitis. Allergy 1993;48:72–4.PubMedCrossRefGoogle Scholar
  98. 98.
    Wagenmann M, Schumacher L, Bachert C. The time course of the bilateral release of cytokines and mediators after unilateral nasal allergen challenge. Allergy 2005;60:1132–8.PubMedCrossRefGoogle Scholar
  99. 99.
    Sim TC, Grant JA, Hilsmeier KA, Fukuda Y, Alam R. Proinflammatory cytokines in nasal secretions of allergic subjects after antigen challenge. Am J Respir Crit Care Med 1994;149:339–44.PubMedGoogle Scholar
  100. 100.
    Bachert C, Hauser U, Prem B, Rudack C, Ganzer U. Proinflammatory cytokines in allergic rhinitis. Eur Arch Otorhinolaryngol 1995;252(Suppl 1):S44–S49.PubMedCrossRefGoogle Scholar
  101. 101.
    Jeffery PK. Remodeling and inflammation of bronchi in asthma and chronic obstructive pulmonary disease. Proc Am Thorac Soc 2004;1:176–83.PubMedCrossRefGoogle Scholar
  102. 102.
    An SS, Bai TR, Bates JH, Black JL, Brown RH, Brusasco V, et al. Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma. Eur Respir J 2007;29:834–60.PubMedCrossRefGoogle Scholar
  103. 103.
    Funayama Y, Sasaki I, Naito H, Fukushima K, Matsuno S, Masuda T. Remodeling of vascular wall in Crohn's disease. Dig Dis Sci 1999;44:2319–23.PubMedCrossRefGoogle Scholar
  104. 104.
    Meijer MJ, Mieremet-Ooms MA, van der Zon AM, van DW, van Hogezand RA, Sier CF, et al. Increased mucosal matrix metalloproteinase-1, -2, -3 and -9 activity in patients with inflammatory bowel disease and the relation with Crohn's disease phenotype. Dig Liver Dis 2007;39:733–9.PubMedCrossRefGoogle Scholar
  105. 105.
    Brandtzaeg P. The changing immunological paradigm in coeliac disease. Immunol Lett 15-6-2006;105:127–39.CrossRefGoogle Scholar
  106. 106.
    Bacon AS, McGill JI, Anderson DF, Baddeley S, Lightman SL, Holgate ST. Adhesion molecules and relationship to leukocyte levels in allergic eye disease. Invest Ophthalmol Vis Sci 1998;39:322–30.PubMedGoogle Scholar
  107. 107.
    Shimizu A, Tepler I, Benfey PN, Berenstein EH, Siriganian RP, Leder P. Human and rat mast cell high-affinity immunoglobulin E receptors: characterization of putative alpha-chain gene products. Proc Natl Acad Sci USA 1988;85:1907–11.PubMedCrossRefGoogle Scholar
  108. 108.
    Kuster H, Zhang L, Brini AT, MacGlashan Jr DW, Kinet J-P. The gene and cDNA for the high affinity immunoglobulin E receptor β chain and expression of complete human receptor. J Biol Chem 1992;18:12782–87.Google Scholar
  109. 109.
    Kuster H, Thompson H, Kinet J-P. Characterization and expression of the gene for the human Fc receptor gamma subunit. Definition of a new gene family. J Biol Chem 1990;265:6448–52.PubMedGoogle Scholar
  110. 110.
    Blank U, Ra C, Kinet J-P. Characterization of truncated α chain products from human, rat and mouse high affinity receptor for immunoglobulin E. J Biol Chem 1991;266:2639–45.PubMedGoogle Scholar
  111. 111.
    Hakimi J, Seals C, Kondas JA, Pettine L, Danho W, Kochan JP. The α subunit of the human IgE receptor (FceRI) is sufficient for high affinity IgE binding. J Biol Chem 1990;265:22079–85.PubMedGoogle Scholar
  112. 112.
    Kinet J-P, Blank U, Ra C, White K, Metzger H, Kochan J. Isolation and characterization of the β-subunit cDNAs coding for the of the high affinity receptor for immunoglobulin E. Proc Natl Acad Sci USA 1993;85:6483–7.CrossRefGoogle Scholar
  113. 113.
    Benhamou M, Gutkind JS, Robbins KC, Siriganian RP. Tyrosine phosphorylation coupled to an IgE receptor mediated signal transduction and histamine release. Proc Natl Acad Sci USA 1990;87:5327–32.PubMedCrossRefGoogle Scholar
  114. 114.
    Connelly PA, Farrell CA, Marenda JM, Conklyn MJ, Showell HJ. Tyrosine phosphorylation is an early signalling event common to Fc receptor crosslinking in human neutrophils and rat basophilic leukemia cells (RBL-2H3). Biochem Biophys Res Commun 1991;177:192–99.PubMedCrossRefGoogle Scholar
  115. 115.
    Kawakami T, Inagaki N, Takei M, et al. Tyrosine phosphorylation is required for mast cell activation through FceRI cross linking. J Immunol 1992;175:1285–92.Google Scholar
  116. 116.
    Dombrowicz D, Flamand V, Brigman KK, Koller BH, Kinet J-P. Abolition of anaphylaxis by targeted disruption of the high affinity immunoglobulin E receptor α chain gene. Cell 1993;75:969–76.PubMedCrossRefGoogle Scholar
  117. 117.
    Pawankar R, Okuda M, Yssel H, et al. Nasal mast cells in perennial allergic rhinitis exhibit increased expression of the FcepsilonRI,CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J Clin Invest 1997;99:1492–99.PubMedCrossRefGoogle Scholar
  118. 118.
    Yamaguchi M, Lantz CS, Oettgen HC, et al. IgE enhances mouse mast cell FceRI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions. J Exp Med 1997;185(4):663.PubMedCrossRefGoogle Scholar
  119. 119.
    Saito H, Nakajima T, Tachimoto H. Upregulation of the FceRIα by IgE molecules on human cultured mast cells and basophils. J Allergy Clin Immunol 1997;99(1): S103.Google Scholar
  120. 120.
    Pawankar R, Ra C. IgE-IgE receptor mast cells axis in allergy. Clin Exp Allergy 1998;28:6–11.PubMedCrossRefGoogle Scholar
  121. 121.
    Pawankar R. Revisting the roles of mast cells and its relation to local IgE synthesis. Am J Rhinol 2001;14:309.CrossRefGoogle Scholar
  122. 122.
    Durham SR, Gould HJ, Thienes CP, et al. Expression of epsilon germ-line gene transcripts and mRNA for the epsilon heavy chain of IgE in nasal B cells and the effects of topical corticosteroid. Eur J Immunol 1997;27(11):2899.PubMedCrossRefGoogle Scholar
  123. 123.
    Pawankar R, Yamagishi S, Takizawa R, Yagi T. Local IgE synthesis: its functional significance and strategy for new therapy. J Rhinol 2000;39:69.Google Scholar
  124. 124.
    Ciprandi G, Buscaglia S, Pesce G, Pronzato C, Ricca V, Parmiani S, et al. Minimal persistent inflammation is present at mucosal level in patients with asymptomatic rhinitis and mite allergy. J Allergy Clin Immunol 1995;96:971–9.PubMedCrossRefGoogle Scholar
  125. 125.
    Naito K, Takeda N, Yokoyama N, Ibata K, Ishihara M, Senoh Y, et al. The distribution of eosinophil cationic protein positive eosinophils in the nasal mucosa of the nasal allergy patients. Auris Nasus Larynx 1993;20:197–204.PubMedGoogle Scholar
  126. 126.
    Berger G, Bernheim J, Ophir D. Epithelial shedding of the inferior turbinate in perennial allergic and nonallergic rhinitis: a riddle to solve. Arch Otolaryngol Head Neck Surg 2007;133:78–82.PubMedCrossRefGoogle Scholar
  127. 127.
    Gleich GJ, Flavahan NA, Fujisawa T, Vanhoutte PM. The eosinophil as a mediator of damage to respiratory epithelium: a model for bronchial hyperreactivity. J Allergy Clin Immunol 1988;81:776–81.PubMedCrossRefGoogle Scholar
  128. 128.
    Amin K, Rinne J, Haahtela T, Simola M, Peterson CG, Roomans GM, et al. Inflammatory cell and epithelial characteristics of perennial allergic and nonallergic rhinitis with a symptom history of 1 to 3 years' duration. J Allergy Clin Immunol 2001;107:249–57.PubMedCrossRefGoogle Scholar
  129. 129.
    Watanabe K, Kiuna C. Epithelial damage of nasal mucosa in nasal allergy. Ann Otol Rhinol Laryngol 1998;107:564–70.PubMedGoogle Scholar
  130. 130.
    Montero MP, Blanco E, Matta Campos JJ, Gonzalez EA, Guidos FG, Tinajeros Castaneda OA. Nasal remodeling in patient with perennial allergic rhinitis. Rev Alerg Mex 2003;50:79–82.Google Scholar
  131. 131.
    Chanez P, Vignola AM, Vic P, Guddo F, Bonsignore G, Godard P, et al. Comparison between nasal and bronchial inflammation in asthmatic and control subjects. Am J Respir Crit Care Med 1999;159:588–95.PubMedGoogle Scholar
  132. 132.
    Berger G, Marom Z, Ophir D. Goblet cell density of the inferior turbinates in patients with perennial allergic and nonallergic rhinitis. Am J Rhinol 1997;11:233–6.PubMedCrossRefGoogle Scholar
  133. 133.
    Malekzadeh S, Hamburger MD, Whelan PJ, Biedlingmaier JF, Baraniuk JN. Density of middle turbinate subepithelial mucous glands in patients with chronic rhinosinusitis. Otolaryngol Head Neck Surg 2002;127:190–5.PubMedCrossRefGoogle Scholar
  134. 134.
    Tos M, Morgensen C. Nasal glands in nasal allergy. Acta Otolaryngol 1977;83:498–504.PubMedCrossRefGoogle Scholar
  135. 135.
    Sanai A, Nagata H, Konno A. Extensive interstitial collagen deposition on the basement membrane zone in allergic nasal mucosa. Acta Otolaryngol 1999;119:473–8.PubMedCrossRefGoogle Scholar
  136. 136.
    Matovinovic E, Solberg O, Shusterman D. Epidermal growth factor receptor – but not histamine receptor – is upregulated in seasonal allergic rhinitis. Allergy 2003;58:472–5.PubMedCrossRefGoogle Scholar
  137. 137.
    Wu X, Myers AC, Goldstone AC, Togias A, Sanico AM. Localization of nerve growth factor and its receptors in the human nasal mucosa. J Allergy Clin Immunol 2006;118:428–33.PubMedCrossRefGoogle Scholar
  138. 138.
    van Toorenenbergen AW, Gerth van WR, Vermeulen AM. Allergen-induced matrix metalloproteinase-9 in nasal lavage fluid. Allergy 1999;54:293–4.PubMedCrossRefGoogle Scholar
  139. 139.
    Kirmaz C, Ozbilgin K, Yuksel H, Bayrak P, Unlu H, Giray G, et al. Increased expression of angiogenic markers in patients with seasonal allergic rhinitis. Eur Cytokine Netw 2004;15:317–22.PubMedGoogle Scholar
  140. 140.
    Sarin S, Undem B, Sanico A, Togias A. The role of the nervous system in rhinitis. J Allergy Clin Immunol 2006;118:999–1016.PubMedCrossRefGoogle Scholar
  141. 141.
    Pawankar R, Inflammatory mechanisms in allergic rhinitis. Curr Opin Allergy Clin Immunol. 2007;7(1):1–4.PubMedCrossRefGoogle Scholar
  142. 142.
    Fontanari P, Zattara-Hartmann MC, Burnet H, Jammes Y. Nasal eupnoeic inhalation of cold, dry air increases airway resistance in asthmatic patients. Eur Respir J 1997;10:2250–4.PubMedCrossRefGoogle Scholar
  143. 143.
    O'Hanlon S, Facer P, Simpson KD, Sandhu G, Saleh HA, Anand P. Neuronal markers in allergic rhinitis: expression and correlation with sensory testing. Laryngoscope 2007;117:1519–27.PubMedCrossRefGoogle Scholar
  144. 144.
    Fang SY, Shen CL, Ohyama M. Distribution and quantity of neuroendocrine markers in allergic rhinitis. Acta Otolaryngol 1998;118:398–403.PubMedCrossRefGoogle Scholar
  145. 145.
    Heppt W, Dinh QT, Cryer A, Zweng M, Noga O, Peiser C, et al. Phenotypic alteration of neuropeptide-containing nerve fibres in seasonal intermittent allergic rhinitis. Clin Exp Allergy 2004;34:1105–10.PubMedCrossRefGoogle Scholar
  146. 146.
    Sanico AM, Philip G, Proud D, Naclerio RM, Togias A. Comparison of nasal mucosal responsiveness to neuronal stimulation in non-allergic and allergic rhinitis: effects of capsaicin nasal challenge. Clin Exp Allergy 1998;28:92–100.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Jean-Baptiste Watelet
    • 1
  • James I. McGill
    • 2
  • Ruby Pawankar
    • 3
  • Diana S. Church
    • 2
  • Martin K. Church
    • 2
  1. 1.Department of Otorhinolaryngology and Head and Neck SurgeryGhent University HospitalBelgium
  2. 2.Infection, Inflammation and Repair Research DivisionSouthampton General HospitalSouthamptonUK
  3. 3.Nippon Medical SchoolBunkyo-kuJapan

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