Allergic Conjunctivitis: Update on Its Pathophysiology and Perspectives for Future Treatment

  • Stefano Bonini
  • Roberto Sgrulletta
  • Marco Coassin
  • Sergio Bonini
Part of the Allergy Frontiers book series (ALLERGY, volume 3)


The ocular surface mucosa is constantly exposed to allergens and, therefore, highly susceptible for developing allergic reactions. Allergic conjunctivitis is among the most common diseases faced by ophthalmologists and it has been traditionally divided in four categories based on clinical presentation: seasonal and perennial allergic conjunctivitis, the two milder forms, and vernal and atopic keratoconjunctivitis, the two most severe forms often characterized by corneal involvement. Although they may present with different grades of severity, all four classes of allergic conjunctivitis share common symptoms such as ocular redness, itching and tearing, and they are all characterized by inflammatory reaction and eosinophil infiltration of the conjunctiva. However, while seasonal and perennial allergic conjunctivitis are characterized by a well-defined pathogenesis, with a typical type I hypersensitivity reaction, vernal and atopic keratoconjunctivitis feature more complex pathogenetic mechanisms: in the former, specific sensitization is not found in many patients and the disease typically regresses with puberty; in the latter, patients have atopic dermatitis or eczema from childhood, but develop ocular symptoms only later in life. Considering the variety of clinical presentations and the diverse pathophysiology characterizing the different forms of allergic conjunctivitis, several therapeutic options are available and newer therapies with immunomodulatory agents are under consideration in recent and ongoing clinical trials. In this chapter we will describe in detail the pathophysiology of ocular allergy, the mechanisms of action of all the available treatments, and the perspectives for future therapies that have been introduced by recent findings in clinical and basic research studies.


Mast Cell Ocular Surface Allergic Conjunctivitis Ocular Allergy Corneal Fibroblast 


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  1. 1.
    Phipatanakul W. Allergic rhinoconjunctivitis:epidemiology. Immunol. Allergy Clin. North Am., 2005. 25(2): 263–281.PubMedCrossRefGoogle Scholar
  2. 2.
    Weeke ER. Epidemiology of hay fever and perennial allergic rhinitis. Monogr. Allergy, 1987. 21: 1–20.PubMedGoogle Scholar
  3. 3.
    Foster CS. The pathophysiology of ocular allergy: current thinking. Allergy, 1995. 50(21 Suppl): 6–9; discussion 34–38.PubMedCrossRefGoogle Scholar
  4. 4.
    Ehlers WH, Donshik PC. Allergic ocular disorders: a spectrum of diseases. Clao J., 1992. 18(2): 117–124.PubMedGoogle Scholar
  5. 5.
    MC Gill JI, Church MK, Anderson DF, Bacon A. Allergic eye disease mechabism. Br. J. Ophthalmol., 1998. 82: 1203–1214.PubMedCrossRefGoogle Scholar
  6. 6.
    Bielory L. Allergic and immunology disorders of the eye. Part II: ocular allergy. J. Allergy Clin. Immunol., 2000. 106: 1019–1032.PubMedCrossRefGoogle Scholar
  7. 7.
    Foster C. The pathophysiology of ocular allergy: current thinking. Allergy, 1995. 50: 6–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Dart JK, Monnickendan M, Prasad J. Perennial allergic conjunctivitis: definition, clinical characteristic and prevalance. A comparison with seasonal allergic conjunctivitis. Trans. Ophthalmol. Soc. UK, 1986. 105: 513–520.PubMedGoogle Scholar
  9. 9.
    Bonini S, Bucci MG et al. Allergen dose response and late symptoms in a human model of ocular allergy. J. Allergy Clin. Immunol., 1990. 86: 869–876.PubMedCrossRefGoogle Scholar
  10. 10.
    Ono SJ. Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. J. Allergy Clin. Immunol., 2005. 115: 118–122.PubMedCrossRefGoogle Scholar
  11. 11.
    Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. J. Allergy Clin. Immunol., 2005. 115: 118–122.PubMedCrossRefGoogle Scholar
  12. 12.
    Bonini S, Bonini S, Bucci MG, Berruto A, Adriani E, Balsano F, Allansmith MR. Allergen dose response and late symptoms in a human model of ocular allergy. J. Allergy Clin. Immunol., 1990. 86: 869–876.PubMedCrossRefGoogle Scholar
  13. 13.
    Bonini S, Bonini S, Lambiase A, Marchi S, Pasqualetti P, Zuccaro O, Rama P, Magrini L, Juhas T, Bucci MG. Vernal keratoconjunctivitis revisited: a case series of 195 patients with long-term follow up. Ophthalmology, 2000. 107(6): 1157–1163.PubMedCrossRefGoogle Scholar
  14. 14.
    Bonini S, Bonini S, Lambiase A, Magrini L, Rumi C, Del Prete G, Schiavone M, Rotiroti G, Onorati P, Rutella S. Vernal keratoconjunctivitis: a model of 5q cytokine gene cluster disease. Int. Arch. Allergy Immunol., 1995. 107(1–3): 95–98.PubMedGoogle Scholar
  15. 15.
    Bonini S, Coassin M, Aronni S, Lambiase A. Vernal keratoconjunctivitis. Eye, 2004. 18(4): 345–351.PubMedCrossRefGoogle Scholar
  16. 16.
    Bonini S, Lambiase A, Schiavone M, Centofanti M, Palma LA, Bonini S. Estrogen and progesteron receptors in vernal Keratoconjunctivitis. Ophthalmology, 1995. 102: 1374–1279.PubMedGoogle Scholar
  17. 17.
    Bonini S. Atopic keratoconjunctivitis. Allergy, 2004. 59(78 Suppl): 71–73.PubMedCrossRefGoogle Scholar
  18. 18.
    Sarac O, Erdener U, Irkec M, Us D, Gungen Y. Tear exotin levels in giant papillary conjunctivitis associated with ocular prosthesis. Ocul. Immunol. Inflamm., 2003. 11: 223–230.PubMedCrossRefGoogle Scholar
  19. 19.
    Allansmith MR. Vernal conjunctivitis. In: The Eye and Immunology, ed. C.V.M. Company, St. Louis, 1982. pp. 118–124.Google Scholar
  20. 20.
    Bonini S, Lambiase A, Sgrulletta R, Bonini S. Allergic chronic inflammation of the ocular surface in vernal keratoconjunctivitis. Curr. Opin. Allergy Clin. Immunol., 2003. 3(5): 381–387.PubMedCrossRefGoogle Scholar
  21. 21.
    Bonini S, Pierdomenico R, Bonini S. Levocabastine eye drops in vernal conjunctivitis. Eur. J. Ophthalmol., 1995. 5(4): 283–284.PubMedGoogle Scholar
  22. 22.
    D'Angelo G, Lambiase A, Cortes M, Sgrulletta R, Pasqualetti R, Lamagna A, Bonini S. Preservative-free diclofenac sodium 0.1% for vernal keratoconjunctivitis. Graefes Arch. Clin. Exp. Ophthalmol., 2003. 241(3): 192–195.PubMedCrossRefGoogle Scholar
  23. 23.
    Bonini S, Magrini A, Rotiroti G, Lambiase A, Tomassini M, Rumi C, Bonini S. The eosinophil and the eye. Allergy, 1997. 52(34 Suppl): 44–47.PubMedCrossRefGoogle Scholar
  24. 24.
    Allansmith MR, Greiner JV, Baird RS. Number of inflammatory cells in normal conjunctiva. Am. J. Ophthalmol., 1978. 86: 250–259.PubMedGoogle Scholar
  25. 25.
    Allansmith MR, Baird RS, Greiner JV. Vernal conjunctivitis and contact lens-associated giant papillary conjunctivitis compared and contrasted. Am. J. Ophthalmol., 1979. 87: 545–555.Google Scholar
  26. 26.
    Di Gioacchino M, Cavallucci E, Di Sciascio MB, Di Stefano F, Verna N, Lobefalo L, Crudeli C, Volpe AR, Angelucci D, Cuccurullo F, Conti P. Increase in CD45R0 + cells and activated eosinophils in chronic allergic conjunctivitis. Immunobiology, 2000. 201: 541–551.PubMedGoogle Scholar
  27. 27.
    Tai PC, Spry CJF, Peterson C, Venge P, Olsson I. Monoclonal antibodies distinguish between storage and secreted form s of eosinophil cationic protein. Nature, 1984. 309: 182–184.PubMedCrossRefGoogle Scholar
  28. 28.
    Trocme SD, Kephart GM, Allansmith MR, Bourne WM, Gleich GJ. Conjunctivasl deposition of eosinophil granule major basic protein in vernal keratoconjunctivitis and contact lens associated giant papillary conjunctivitis. Am. J. Ophthalmol., 1989. 108: 57–63.PubMedGoogle Scholar
  29. 29.
    Udell IJ, Gleich GJ, Allansmith MR, Ackerman SJ, Abelson MB. Eosinophil granule major basic protein and Charcot-Leyden crystal protein in human tears. Am. J. Ophthalmol., 1981. 92: 824–828.PubMedGoogle Scholar
  30. 30.
    Leonardi A, Borghesan F, Faggian D, Secchi AG, Plebani M. Eosinophil cationic protein in teras of normal subjects and patients affected by vernal keratoconjunctivitis. Allergy, 1995. 50: 610–613.PubMedCrossRefGoogle Scholar
  31. 31.
    Montan PG, Van Hage-Hamsten M, Zetterstorm O. Sustained eosinophil cationic protein release into tears after a single high-dose conjunctival allergen challenge. Clin. Exp. Allergy, 1996. 26: 1125–1130.PubMedCrossRefGoogle Scholar
  32. 32.
    Trocme SD, Hallaberg CK, Gill KS, Gleich GJ, Tyring SK, Brysk MM. Effects of eosinophil granule proteins on human corneal epithelial cell viability and morphology. Invest. Ophthalmol. Vis. Sci., 1997. 38: 593–599.PubMedGoogle Scholar
  33. 33.
    Li Q, Fukuda K, Lu Y, Nakamura Y, Chikama T, Kumagai N, Nishida T. Enhancement by neutrophils of collagen degradation by corneal fibroblast. J. Leukoc. Biol., 2003. 74: 412–419.PubMedCrossRefGoogle Scholar
  34. 34.
    Trocme SD, Leiferman KM, George T, Bonini S, Foster CS, Smit EE, Sra SK, Grabowski LR, Dohlman CH. Neutrophil and eosinophil participation in atopic and vernal keratoconjunctivitis. Curr. Eye Res., 2003. 26(6): 319–325.PubMedCrossRefGoogle Scholar
  35. 35.
    Cameron JA. Shield ulcers and plaques of the cornea in vernal keratoconjunctivitis. Ophthalmology, 1995. 102: 985–993.PubMedGoogle Scholar
  36. 36.
    Saitu T, Fukuchi T, Tazawa H, Sakaue F, Sawaguchi S, Iwata K. Histopathology of corneal plaque in vernal keratoconjunctivitis. Jpn. J. Ophthalmol. Soc., 1993. 97: 201–209.Google Scholar
  37. 37.
    Nakajima T, Matsumoto K, Suto H, Tanaka K, Ebisawa M, Tomita H, Yuki K, Katsunuma T, Akasawa A, Hashida R, Sugita Y, Ogawa H, Ra C, Saito H. Gene expression screening of humanamast cels and eosinophil using high-density oligonucleotide probe arrays: abundant expression of major basic protein in mast cells. Blood, 2001. 98: 1127–1134.PubMedCrossRefGoogle Scholar
  38. 38.
    Rothenberg M. Eosinophilia. N. Engl. J. Med., 1998. 338: 1592–1600.PubMedCrossRefGoogle Scholar
  39. 39.
    Fernandez HN, Henson PM, Otani A, Hugli TE. Chemotactic response to human C3a and C5a anaphylatoxins. Evaluation of C3a and C5a leukotaxis in vitro and under stimulated in vivo conditions. J. Immunol., 1978. 120: 109–115.PubMedGoogle Scholar
  40. 40.
    Goetzl EJ, Gorman RR. Chemotattic and chemokinetic stimulation of human eosinophil nad neutrophil polymorphonuclear leukocytes by 12-L-Hydroxy-5,8,10-heptadecatrienoic acid (HHT). J. Immunol., 1978. 120: 526–531.PubMedGoogle Scholar
  41. 41.
    Goetzl EJ. mediators of immediate hypersensitivityderived from arachidonic acid. N. Engl. J. Med., 1980. 303: 822–825.PubMedGoogle Scholar
  42. 42.
    Baggiolini M. Chemokines and leukocyte traffic. Nature, 1998. 392: 565–568.PubMedCrossRefGoogle Scholar
  43. 43.
    Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotkin A, Schall TJ. A new class of membrane vound-chemokine with a CX3C motif. Nature, 1997. 385: 640–644.PubMedCrossRefGoogle Scholar
  44. 44.
    Dorner B, Muller S, Entshalden F, Schroder JM, Franke P, Kraft R, Friedl P, Clark-Lewis I, Kroczek RA. Purification, structural analysis, and function of natural ATAC, a cytokine secreted by CD8 + T cells. J. Biol. Chem., 1997. 272: 8817–8823.PubMedCrossRefGoogle Scholar
  45. 45.
    Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu. Rev. Immunol., 1997. 15: 675–705.PubMedCrossRefGoogle Scholar
  46. 46.
    Teran LM, Noso N, Carroll M, Davies DE, Holgate S, Schroder JM. Eosinophil recruitment following allergen challenge is associated with the release of the chemokine RANTES into asthmatic airways. J. Immunol., 1996. 157: 1806–1812.PubMedGoogle Scholar
  47. 47.
    Venge J, Lampinen M, Hakansson L, Rak S, Venge P. Identification of IL-5 and RANTES as the major eosinophil chemoattractants in the asthmatic lung. J. Allergy Clin. Immunol., 1996. 97: 1110–1115.PubMedCrossRefGoogle Scholar
  48. 48.
    Nagase H, Yamaguci M, Jibiki S, Yamada H, Ohta K, Kawasaki H, Yoshie O, Yamamoto K, Morita Y, Hirai K. Eosinophil chemotaxis by chemokines: a study by a simple photometric assay. Allergy, 1999. 54: 944–950.PubMedCrossRefGoogle Scholar
  49. 49.
    Sabroe I, Hartnell A, Jopling LA, Bel S, Ponath PD, Pease IE, Collins PD, Williams TJ. Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways. J. Immunol., 1999. 162: 2946–2955.PubMedGoogle Scholar
  50. 50.
    Ochi H, Hirani WM, Yuan Q, Friend DS, Austen KF, Boyce JA. Thelper cell type 2 cytokinemediated comitogenic responses and CCR3 expression during differentiation of human mast cells in vitro. J. Exp. Med., 1999. 190: 267–280.PubMedCrossRefGoogle Scholar
  51. 51.
    Romagnani P, De Paulis A, Beltrame C, Annunziato F, Dente V, Maggi E, Romagnani S, Marone G. Tryptase-chymasedouble-positive human mast cells express the eotaxin receptor CCR3 and are attracted by CCR3-binding chemokines. Am. J. Pathol., 1999. 155: 1195–1204.PubMedGoogle Scholar
  52. 52.
    Forssmann U, Uguccioni M, Loetscher P, Dahinden CA, Langen H, Thelen M, Baggiolini M. Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. J. Exp. Med., 1997. 185: 2171–2176.PubMedCrossRefGoogle Scholar
  53. 53.
    Uguccioni M, Mackay CR, Ochensberger B, Loetscher P, Rhis S, LaRosa GJ, Rao P, Ponath PD, Baggiolini M, Dahinden CA. High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines. J. Clin. Invest., 1997. 100: 1137–1143.PubMedCrossRefGoogle Scholar
  54. 54.
    Sallusto F, Mackay CR, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 1997. 277: 2005–2007.PubMedCrossRefGoogle Scholar
  55. 55.
    Quackenbush EJ, Wershil BK, Aguirre V, Gutierrez-Ramos JC. Eotaxin modulates myelopoiesis and mast cell development from embryonic hematopoietic progenitors. Blood, 1998. 92: 1887–1897.PubMedGoogle Scholar
  56. 56.
    De Paulis A, Annunziato F, Di Gioia L, Romagnani S, Carfora M, Beltrame C, Marone G, Romagnani P. Expression of the chemokine receptor CCR3 on human mast cells. Int. Arch. Allergy Immunol., 2001. 124: 146–150.PubMedCrossRefGoogle Scholar
  57. 57.
    Hochstetter R, Dobos G, Kimmig D, Dulkys Y, Kapp A, Elsner J. The CC chemokine receptor 3 CCR3 is functionally expressed on eosinophils but not on neutrophils. Eur. J Immunol., 2000. 30: 2759–2764.PubMedCrossRefGoogle Scholar
  58. 58.
    Healt H, Qin S, Rao, Wu L, LaRosa G, Kassam N, Ponath PD, Mackay CR. Chemokine receptor usage by human eosinophils. The importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J. Clin. Invest., 1997. 99: 178–184.CrossRefGoogle Scholar
  59. 59.
    Kitaura M, Nakajima T, Imai T, Harada S, Combadiere C, Tiffany HL, Murphy PM, Yoshie O. Molecular cloning of human eotaxin, an eosinophil selective CC chemokin, an identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3. J. Biol. Chem., 1996. 271: 7725–7730.PubMedCrossRefGoogle Scholar
  60. 60.
    Ponath PD, Qin S, Post TW, Wang J, Wu L, Gerrard NP, Newman W, Gerard C, Mackay CR. Molecular cloning characterization of a human eotaxin receptor expressed selectivity on eosinophils. J. Exp. Med., 1996. 183: 2437–2448.PubMedCrossRefGoogle Scholar
  61. 61.
    Daugherty BL, Siciliano SJ, DeMartino JA, Malkowitz L, Sirotina A, Springer MS. Cloning, expression, and characterization of the human eosinophil eotaxin receptor. J. Exp. Med., 1996. 183: 2349–2354.PubMedCrossRefGoogle Scholar
  62. 62.
    Conroy DM, Williams TJ. Eotaxin and the attraction of eosinophils to the asthmatic lung. Respir. Res., 2001. 2(3): 150–156.PubMedCrossRefGoogle Scholar
  63. 63.
    Maggi E, Biswas P, Del Prete G, Parronchi P, Macchia D, Simonelli C, Emmi L, De Carli M, Tiri A, Ricci M et al., Accumulation of Th-2-like helper T cells in the conjunctiva of patients with vernal conjunctivitis. J. Immunol., 1991. 146: 1169–1174.PubMedGoogle Scholar
  64. 64.
    Leonardi A, DeFranchis G, Zancanaro F, Crivellari G, De Paoli M, Plebani M, Secchi AG. Identification of local Th2 and Th0 lymphocytes in vernal conjunctivitis by cytokine flow cytometry. Invest. Ophthalmol. Vis. Sci., 1999. 40: 3036–3040.PubMedGoogle Scholar
  65. 65.
    Kumagai N, Fukuda K, Ishimura Y, Nishida T. Synergistic induction of eotaxin expression in human keratocytes by TNF-a and IL-4 or IL-13. Invest. Ophthalmol. Vis. Sci., 2000. 41: 1448–1453.Google Scholar
  66. 66.
    Fukuda K, kumagai N, Fujitsu Y, Nishida T. Fibroblasts as local immune modulators in ocular allergic disease. Allergol. Int., 2006. 55(2): 121–129.PubMedCrossRefGoogle Scholar
  67. 67.
    Leonardi A, Borghesan F, De Paoli M, Plebani M, Secchi AG. Procollagens and inflammatory cytokine concentrations in tarsal and limbal vernal keratoconjunctivitis. Exp. Eye Res., 1998. 67: 105–112.PubMedCrossRefGoogle Scholar
  68. 68.
    Leonardi A, Brun P, Tavolato M, Plebani M, Abatangelo G, Secchi AG. Tumor necrosis factor-alpha (TNF-a) in seasonal allergic conjunctivitis and vernal keratoconjunctivitis. Eur. J. Ophthalmol., 2003. 16: 606–610.Google Scholar
  69. 69.
    Fujishima H, Takeuchi T, Shinozaki N, Saito I, Tsubota K. Measurement of IL-4 in tears of patients with seasonal allergic conjunctivitis and vernal keratoconjunctivitis. Clin. Exp. Immunol., 1995. 102: 395–398.PubMedCrossRefGoogle Scholar
  70. 70.
    Yokoi K, Yokoi N, Kinoshita S. Impairment of ocular surface epithelium barrier function in patients with atopic dermatitis. Br. J. Ophthalmol., 1998. 82: 797–800.PubMedCrossRefGoogle Scholar
  71. 71.
    Cubitt CL, Tang Q, Monteiro CA, Lausch RN, Oakes JE. IL-8 gene expression in cultures of human corneal epithelial cells and keratocytes. Invest. Ophthalmol. Vis. Sci., 1993. 34: 3199–3206.PubMedGoogle Scholar
  72. 72.
    Barton K, Monroy DC, Nava A, Pflugfelder SC. Inflammatory cytokines in the tears of patients with ocular rosacea. Ophthalmology, 1997. 104: 1868–1874.PubMedGoogle Scholar
  73. 73.
    Vesaluoma M, Teppo AM, Gronhagen-Riska C, Tervo T. Increased release of tumour necrosis factor-a in human tear fluid after excimer laser induced corneal wound. Br. J. Ophthalmol., 1997. 81: 145–149.PubMedCrossRefGoogle Scholar
  74. 74.
    Nakajima H, Sano H, Nishimura T, Yoshida S, Iwamoto I. Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. J. Exp. Med., 1994. 179: 1145–1154.PubMedCrossRefGoogle Scholar
  75. 75.
    Ebihara N, Yokoyama T, Kimura T, Nakayasu K, Okumura K, Kanai A, Ra C. Anti VLA-4 monoclonal antibody inhibits eosinophil infiltration in allergic conjunctivitis model of guinea pig. Curr. Eye Res., 1999. 19: 20–25.PubMedCrossRefGoogle Scholar
  76. 76.
    Kumagai N, Fukuda K, Fujitsu Y, Nishida T. Expression of functional ICAM-1 on cultured human keratocytes induced by tumor necrosis factor-alpha. Jpn. J. Ophthalmol., 2003. 47(2): 134–141.PubMedCrossRefGoogle Scholar
  77. 77.
    Kumagai N, Fukuda K, Fujitsu Y, Nishida T. Synergistic effect of TNF-a and either IL-4 or IL-13 on VCAM-1 expression by cultured human corneal fibroblasts. Cornea, 2003. 22: 557–561.PubMedCrossRefGoogle Scholar
  78. 78.
    Meerschaert J, Vrtis RF, Shikama Y, Sedgwick JB, Busse WW, Mosher DF. Engagement of a4b7 integrins by monoclonal antibodies or ligands enhances survival of human eosinophils in vitro. J. Immunol., 1999. 163: 6217–6227.PubMedGoogle Scholar
  79. 79.
    Nagata M, Sedgwick JB, Vrtis R, Busse WW. Endothelial cells upregulate eosinophil superoxide generation via VCAM-1 expression. Clin. Exp. Allergy, 1999. 29: 550–561.PubMedCrossRefGoogle Scholar
  80. 80.
    Tsuruta R, Cobb RR, Mastrangelo M, Lazarides E, Cardarelli PM. Soluble vascular cell adhesion molecule (VCAM)-Fc fusion protein induces leukotriene C4secretion in platelet-activating factor-stimulated eosinophils. J. Leukoc. Biol., 1999. 65: 71–79.PubMedGoogle Scholar
  81. 81.
    Wynn TA. IL-13 effector functions. Annu. Rev. Immunol., 2003. 21: 425–456.PubMedCrossRefGoogle Scholar
  82. 82.
    Gauchat JF, Lebman DA, Coffman RL, Gascan H, de Vries JE. Structure and expression of germline e transcripts in human B cells induced by interleukin 4 to switch to IgE production. J. Exp. Med., 1990. 172: 463–473.PubMedCrossRefGoogle Scholar
  83. 83.
    Vita, N, Lefort S, Laurent P, Caput D, Ferrara P. Characterization and comparison of the interleukin 13 receptor with the interleukin 4 receptor on several cell types. J. Biol. Chem., 1995. 270: 3512–3517.PubMedCrossRefGoogle Scholar
  84. 84.
    Schnyder B, Lugli S, Feng N, Etter H, Lutz RA, Ryffel B, Sugamura K, Wunderli-Allenspach H, Moser R. Interleukin-4 (IL-4) and IL-13 bind to a shared heterodimeric complex on endothelial cells mediating vascular cell adhesion molecule-1 induction in the absence of the common gchain. Blood, 1996. 87: 4286–4295.PubMedGoogle Scholar
  85. 85.
    Doucet C, Brouty-Boye D, Pottin-Clemenceau C, Jasmin C, Canonica GW, Azzarone B. IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts. Int. Immunol., 1998. 10: 1421–1433.PubMedCrossRefGoogle Scholar
  86. 86.
    Van der Velden VHJ, Naber BAE, Wierenga-Wolf AF, Debets R, Savelkoul HFJ, Overbeek SE, Hoogsteden HC, Versnel MA. Interleukin 4 receptors on human bronchial epithelial cells. An in vivo and in vitro analysis of expression and function. Cytokine, 1998. 10: 803–813.PubMedCrossRefGoogle Scholar
  87. 87.
    Lai SY, Molden J, Liu KD, Puck JM, White MD, Goldsmith MA. Interleukin-4-specific signal transduction events are driven by homotypic interactions of the interleukin-4 receptor a subunit. EMBO J., 1996. 15: 4506–4514.PubMedGoogle Scholar
  88. 88.
    Fujiwara H, Hanissian SH, Tsytsykova A, Geha RS. Homodimerization of the human interleukin 4 receptor a chain induces Ce germline transcripts in B cells in the absence of the interleukin 2 receptor g chain. Proc. Natl. Acad. Sci. USA, 1997. 94: 5866–5871.PubMedCrossRefGoogle Scholar
  89. 89.
    Reichel M, Nelson BH, Greenberg PD, Rothman PB. The IL-4 receptor a-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression. J. Immunol., 1997. 158: 5860–5867.PubMedGoogle Scholar
  90. 90.
    Harada N, Higuchi K, Wakao H, Hamasaki N, Izuhara K. Identification of the critical portions of the human IL-4 receptor a chain for activation of STAT6. Biochem. Biophys. Res. Commun., 1998. 246: 675–680.PubMedCrossRefGoogle Scholar
  91. 91.
    Matsukura S, Stellato C, Plitt JR, Bickel C, Miura K, Georas SN, Casolaro V, Schleimer RP. Activation of eotaxin gene transcription by NF-k B and STAT6 in human airway epithelial cells. J. Immunol., 1999. 163: 6876–6883.PubMedGoogle Scholar
  92. 92.
    Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for the development of Th2 cells. Immunity, 1996. 4: 313–319.PubMedCrossRefGoogle Scholar
  93. 93.
    Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S. Essential role of Stat6 in IL-4 signalling. Nature 1996. 380: 627–630.PubMedCrossRefGoogle Scholar
  94. 94.
    Abu El-Asrar AM, Struyf S, AL-Kharashi SA, Missotten L, Van Damme J, Geboes K. Chemokines in the limbal form of vernal keratoconjunctivitis. Br. J. Ophthalmol., 2000. 84: 1360–1366.PubMedCrossRefGoogle Scholar
  95. 95.
    Abu El-Asrar AM, Struyf S, AL-Kharashi SA, Missotten L, Van Damme J, Geboes K. The T-lymphocyte chemoattractant Mig is Higly expressed in vernal keratoconjunctivitis. Am. J. Ophthalmol., 2003. 136: 853–860.PubMedCrossRefGoogle Scholar
  96. 96.
    Fujitsu Y, Fukuda K, Kimura K, Seki K, Kumagai N, Nishida T. Protection of human conjunctival fibroblasts from No indiced apoptosis by interleukin-4 or interleukin-13. Invest. Ophthalmol. Vis. Sci., 2005. 46: 797–802.PubMedCrossRefGoogle Scholar
  97. 97.
    Leonardi A, Borghesan F, DePaoli M, Plebani M, Secchi AG. Tear and serum soluble leukocyte activation markers in conjunctival allergic diseases. Am. J. Ophthalmol., 2000. 129: 151–158.PubMedCrossRefGoogle Scholar
  98. 98.
    Trocme SD, Aldave AJ. The eye and the eosinophil. Surv. Ophthalmol., 1994. 39: 241–252.PubMedCrossRefGoogle Scholar
  99. 99.
    Leonardi A, Fregona IA, Plebani M, Secchi AG, Calder VL. Th1- and Th2-type cytokines in chronic ocular allergy. Graefes Arch. Clin. Exp. Ophthalmol., 2006. 244(10): 1240–1245.PubMedCrossRefGoogle Scholar
  100. 100.
    Stern ME, Siemasko KF, Niederkorn JY. The Th1/Th2 paradigm in ocular allergy. Curr. Opin. Allergy Clin. Immunol., 2005. 5(5): 446–450.PubMedGoogle Scholar
  101. 101.
    Matsura N, Uchio E, Nakazawa M, Yago T, Matsumoto S, Ohno S, Minami M. Predominance of infiltrating IL-4producing T cells in conjunctiva of patients with allergic conjunctival disease. Curr. Eye Res., 2004. 29: 235–243.CrossRefGoogle Scholar
  102. 102.
    Abbas A, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996. 383: 787–793.PubMedCrossRefGoogle Scholar
  103. 103.
    Coffman R, Seymour BW, Lebman DA, Hiraki DD, Christiansen JA, Shrader B, Cherwinski HM, Savelkoul HF, Finkelman FD, Bond MW. The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol. Rev., 1988. 102 5–28.PubMedCrossRefGoogle Scholar
  104. 104.
    Larche' M, Robinson DS, Kay AB. The role of T lymphocytes in the pathogenesis of asthma. J. Allergy Clin. Immunol., 2003. 111: 450–463.CrossRefGoogle Scholar
  105. 105.
    Zhan H, Towler HM, Calder VL. The immunomodulatory role of human conjunctival epithelial cells. Invest. Ophthalmol. Vis. Sci., 2003. 44: 3906–3910.PubMedCrossRefGoogle Scholar
  106. 106.
    Parr M, Parr EL. Interferon-gamma up-regulates intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 and recruits lymphocytes into the vagina of immune mice challenged with herpes simplex virus-2. Immunology, 2000. 99: 540–545.PubMedCrossRefGoogle Scholar
  107. 107.
    Parr M, Parr EL. Immunity to vaginal herpes simplex virus-2 infection in B-cell knockout mice. Immunology, 2000. 101(1): 126–131.PubMedCrossRefGoogle Scholar
  108. 108.
    Leonardi A, Curnow SJ, Zhan H, Calder VL. Multiple cytokines in human tear specimens in seasonal and chronic allergic eye disease and in conjunctival fibroblast cultures. Clin. Exp. Allergy, 2006. 36(6): 777–784.PubMedCrossRefGoogle Scholar
  109. 109.
    Trocme SD, Hallberg CK, Gill KS, Gleich GJ, Tyring SK, Brysk MM. Effects of eosinophil granule proteins on human corneal epithelial cell viability and morphology. Invest. Ophthalmol. Vis. Sci., 1997. 38(3): 593–599.PubMedGoogle Scholar
  110. 110.
    Teran LM, Mochizuki M, Bartels J, Valencia EL, Nakajima T, Hirai K, Schroeder JM. Th1- and Th2-type cytokines regulate the expression and production of eotaxin and RANTES by human lung fibroblasts. Am. J. Respir. Cell Mol. Biol., 1999. 20: 777–786.PubMedGoogle Scholar
  111. 111.
    Smith RS, Smith TJ, Blieden TM, Phipps RP. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. Am. J. Pathol., 1997. 151: 317–322.PubMedGoogle Scholar
  112. 112.
    Kumagai N, Fukuda K, Fujitsu Y, Yamamoto K, Nishida T. Role of structural cells of the cornea and conjunctiva in the pathogenesis of vernal keratoconjunctivitis. Prog. Retin. Eye Res., 2006. 25(2): 165–187.PubMedCrossRefGoogle Scholar
  113. 113.
    Imai T, Baba M, Nishimura M, Kakizaki M, Takagi S, Yoshie O. The T cell-directed CC chemokine TARC is a highly specific biological ligand for CC chemokine receptor 4. J. Biol. Chem., 1997. 272: 15036–15042.PubMedCrossRefGoogle Scholar
  114. 114.
    Imai T, Chantry D, Raport CJ, Wood CL, Nishimura M, Godiska R, Yoshie O, Gray PW. Macrophage-derived chemokine is a functional ligand for the CC chemokine receptor 4. J. Biol. Chem., 1998. 273: 1764–1768.PubMedCrossRefGoogle Scholar
  115. 115.
    Sallusto F, Lenig D, Mackay CR, Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med., 1998. 187: 875–883.PubMedCrossRefGoogle Scholar
  116. 116.
    Bonecchi R, Bianchi G, Bordignon PP, D'Ambrosio D, Lang R, Borsatti A, Sozzani S, Allavena P, Gray PA, Mantovani A, Sinigaglia F. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J. Exp. Med., 1998. 187: 129–134.PubMedCrossRefGoogle Scholar
  117. 117.
    Fini ME, Parks WC, Rinehart WB, Girard MT, Matsubara M, Cook JR, West-Mays JA, Sadow PM, Burgeson RE, Jeffrey JJ, Raizman MB, Krueger RR, Zieske JD. Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury. Am. J. Pathol., 1996. 149: 1287–1302.PubMedGoogle Scholar
  118. 118.
    Fukuda K, Chikama T, Nakamura M, Nishida T. Differential distribution of subchains of the basement membrane components type IV collagen and laminin among the amniotic membrane, cornea, and conjunctiva. Cornea, 1999. 18: 73–79.PubMedCrossRefGoogle Scholar
  119. 119.
    Ryan ME, Ramamurthy NS, Sorsa T, Golub LM. MMP-mediated events in diabetes. Ann. NY Acad. Sci., 1999. 878: 311–334.PubMedCrossRefGoogle Scholar
  120. 120.
    Leonardi A, Abatangelo G, Cortivo R, Secchi AG. Collagen types I and III in giant papillae of vernal keratoconjunctivitis. Br. J. Ophthalmol., 1995. 79: 482–485.PubMedCrossRefGoogle Scholar
  121. 121.
    Vaday GG, Franitza S, Schor H, Hecht I, Brill A, Cahalon L, Hershkoviz R, Lider O. Combinatorial signals by inflammatory cytokines and chemokines mediate leukocyte interactions with extracellular matrix. J. Leukoc. Biol., 2001. 69: 885–892.PubMedGoogle Scholar
  122. 122.
    Medzhitov R, Janeway C. Jr. Innate immune recognition: mechanisms and pathways. Immunol. Rev., 2000. 173: 89–97.PubMedCrossRefGoogle Scholar
  123. 123.
    Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature, 2004. 430(6996): 257–263.PubMedCrossRefGoogle Scholar
  124. 124.
    Micera A, Stampachiacchiere B, Aronni S, Dos Santos MS, Lambiase A. Toll-like receptors and the eye. Curr. Opin. Allergy Clin. Immunol., 2005. 5(5): 451–458.PubMedGoogle Scholar
  125. 125.
    Elson CO, Cong Y. Understanding immune-microbial homeostasis in intestine. Immunol. Res., 2002. 26(1–3): 87–94.PubMedCrossRefGoogle Scholar
  126. 126.
    Song PI, Abraham TA, Park Y, Zivony AS, Harten B, Edelhauser HF, Ward SL, Armstrong CA, Ansel JC. The expression of functional LPS receptor proteins CD14 and toll-like receptor 4 in human corneal cells. Invest. Ophthalmol. Vis. Sci., 2001. 42(12): 2867–2877.PubMedGoogle Scholar
  127. 127.
    Ueta M, Nochi T, Jang MH, Park EJ, Igarashi O, Hino A, Kawasaki S, Shikina T, Hiroi T, Kinoshita S, Kiyono K. Intracellularly expressed TLR2s and TLR4s contribution to an immunosilent environment at the ocular mucosal epithelium. J. Immunol., 2004. 173(5): 3337–3347.PubMedGoogle Scholar
  128. 128.
    Kumagai N, Fukuda K, Fujitsu Y, Lu Y, Chikamoto N, Nishida T. Lipopolysaccharide-induced expression of intercellular adhesion molecule-1 and chemokines in cultured human corneal fibroblasts. Invest. Ophthalmol. Vis. Sci., 2005. 46(1): 114–120.PubMedCrossRefGoogle Scholar
  129. 129.
    Bonini S, Micera A, Iovieno A, Lambiase A, Bonini S. Expression of Toll-like receptors in healthy and allergic conjunctiva. Ophthalmology, 2005. 112(9): 1528; discussion 1548–1549.CrossRefGoogle Scholar
  130. 130.
    Miyazaki D, Liu G, Clark L, Ono SJ. Prevention of acute allergic conjunctivitis and late-phase inflammation with immunostimulatory DNA sequences. Invest. Ophthalmol. Vis. Sci., 2000. 41(12): 3850–3855.PubMedGoogle Scholar
  131. 131.
    Lawton JA, Ghosh P. Novel therapeutic strategies based on toll-like receptor signaling. Curr. Opin. Chem. Biol., 2003. 7(4): 446–451.PubMedCrossRefGoogle Scholar
  132. 132.
    Bellou A, Schaub B, Ting L, Finn PW. Toll receptors modulate allergic responses:interaction with dendritic cells, T cells and mast cells. Curr. Opin. Allergy Clin. Immunol., 2003 3(6): 487–494.PubMedCrossRefGoogle Scholar
  133. 133.
    Abelson MB, Schaefer K, Wun PJ. Antihistamines and anthistamine\vasocostrictors combinations. In: Allergic Diseases of the Eye, ed. W.S. Co., Philadelphia, PA, 2001. pp. 206–214.Google Scholar
  134. 134.
    Yanni JM, Sharif NA, Gamache DA, Miller ST, Weimer LK, Spellman JM. A current appreciation of sites for pharmacological intervention in allergic conjunctivitis. Acta Ophthalmol., 1999. 77: 33–37.CrossRefGoogle Scholar
  135. 135.
    Leonardi A, DeFranchis G, DePaoli M, Fregona IA, Plebani M, Secchi AG, 2002. Curr. Eye Res., 2002. 25: 189–196.PubMedCrossRefGoogle Scholar
  136. 136.
    Bielory L, Lien KW, Bigelsen S. Efficacy and tolerability of newer anthistamines in the treatment of allergic conjunctivis. Drugs, 2005. 65: 215–228.PubMedCrossRefGoogle Scholar
  137. 137.
    Yanni JM, Miller ST, Gamache DA, Spellman JM, Xu S, Sherif NA. Comparative effects of topical ocular anti-allergy drugs on human conjunctival mast cells. Ann. Allergy Asthma Immunol., 1997. 79: 541–545.PubMedCrossRefGoogle Scholar
  138. 138.
    Cerqueti PM, Ricca V, Tosca MA, Buscaglia S, Ciprandi G. Lodoxamide treatment of allergic conjunctivitis. Int. Arch. Allergy Immunol., 1994. 105: 185–189.PubMedCrossRefGoogle Scholar
  139. 139.
    Gunduz K, Ucakhan O, Budan K, Eryilmaz T, Ozkan M. Efficacy of lodoxamide 0.1% versus N-Acetyl aspartyl glutamic acid 6% ophthalmic solutions in patients with Vernal Keratoconjunctivitis. Ophthalmic Res., 1996. 28: 80–87.PubMedCrossRefGoogle Scholar
  140. 140.
    Abelson MB, Berdy GJ, Mundrof T, Amadahl LD, Graves AL. Pemirolast study group. Pemirolast potassium 0.1% ophthalmic solution is an effective treatment for allergic conjunctivitis: a pooled analysis of two prospective, randomized, double-masked, placebocontroled, phase III studies. J. Ocul. Pharmacol. Ther., 2002. 18: 475–488.PubMedCrossRefGoogle Scholar
  141. 141.
    Denis D, Bloch-Michel E, Verin P, Sebastiani A, Tazartes M, Helleboid L, Di Giovanni A, Lecorvec M. Treatment of common ocular allergic disorders; a comparison of lodoxamide and NAAGA. Br. J. Ophthalmol., 1998. 82(10): 1135–1138.PubMedCrossRefGoogle Scholar
  142. 142.
    Abelson MB. A review of Olopatadine for the treatment of ocular allergy. Expert. Opin. Pharmacother., 2004. 5: 1979–1994.PubMedCrossRefGoogle Scholar
  143. 143.
    Abelson MB, Ferzola NJ, McWirther CL Crampton HJ. Efficacy and safety of single- and multiple-dose ketotifen fumarate 0.025% ophthalmic solution in a pediatric population. Pediatr. Allergy Immunol., 2004. 15(6): 551–557.PubMedCrossRefGoogle Scholar
  144. 144.
    Crampton HJ. A comparison of the relative clinical efficacy of a single dose of ketotifen fumarate 0.025% ophthalmic solution versus placebo in inhibiting the signs and symptoms of allergic rhinoconjunctivitis as induced by the conjunctival allergen challenge model. Clin. Ther., 2002. 24(11): 1800–1808.PubMedCrossRefGoogle Scholar
  145. 145.
    Ciprandi G, Buscaglia S, Catrullo A, Pesce G, Fiorino M, Montagna P, Bagnasco M, canonica GW. Azelastine eye drops reduce and prevent conjunctival reaction and exert antiallergic activity. Clin. Exp. Allergy, 1997. 27: 182–191.PubMedCrossRefGoogle Scholar
  146. 146.
    Fraunfelder FW. Epinastine hydrochloride for atopic disease. Drugs Today, 2004. 40: 677–683.PubMedCrossRefGoogle Scholar
  147. 147.
    Deschenes J, Discepola M, Abelson MB. Comparative evaluation of olopatadine solution (0.1%) versus ketorolac ophthalmic solution (0.5%) using the provocative antigen challenge model. Acta Ophthalmol. Scand., 1999. 77: 47–52.Google Scholar
  148. 148.
    Tabbara KF, al-Kharashi SA. Efficacy of nedocromil 2% versus fluorometholone 0.1%: a randomised, double masked trial comparing the effects on severe vernal keratoconjunctivitis. Br. J. Ophthalmol., 1999. 83(2): 180–184.PubMedCrossRefGoogle Scholar
  149. 149.
    Lambiase A, Bonini S, Rasi G, Coassin M, Bruscolini A, Bonini S. Montelukast, a leukotriene receptor antagonist, in vernal keratoconjunctivitis associated with asthma. Arch. Ophthalmol., 2003. 121: 615–620.PubMedCrossRefGoogle Scholar
  150. 150.
    Kalpaxis JG, Thayer TO. Double-blind trial of pentigetide ophthalmic solution, 0.5%, compared with cromolyn sodium, 4%, ophthalmic solution for allergic conjunctivitis. Ann. Allergy 1991. 66: 393–398.PubMedGoogle Scholar
  151. 151.
    Babu KS, Arshad SH, Holgate ST. Omalizumab, a novel anti-IgE therapy in allergic disorders. Expert. Opin. Biol. Ther., 2001. 1: 1049–1058.PubMedCrossRefGoogle Scholar
  152. 152.
    Soler M. Omalizumab, a monoclonal antibody against IgEfor the treatment of allergic diseases. Int. J. Clin. Pract., 2001. 55(7): 480–483.PubMedGoogle Scholar
  153. 153.
    Ito F, Toyota N, Sakai H et al. FK506 and Cyclosporin A inhibit stem cell factor-dependent cell proliferation\survival, while inducing upregulation of c-kit expression in cells of mast cells line MC\9. Arch. Dermatol. Res., 1999. 291: 275–283.PubMedCrossRefGoogle Scholar
  154. 154.
    Ito F, Toyota F, Sakai H, Takahashi H, Izuka H. FK506 and cyclosporin A inhibit stem cell factor-dependent cell proliferation/survival, while inducing upregulation of c-kit expression in cells of the mast cell line MC/9. Arch. Dermatol. Res., 1999. 291(5): 275–283.PubMedCrossRefGoogle Scholar
  155. 155.
    Toyota N, Hashimoto Y, Matsuo S, Kitamura Y, Izuka H. Effects of FK506 and cyclosporin A on proliferation, histamine release and phenotype of murine mast cells. Arch. Dermatol. Res., 1996. 288(8): 474–480.PubMedCrossRefGoogle Scholar
  156. 156.
    Matsuda S, Koyasu S. Mechanism of action of cyclosporin. Immunopharmacology, 2000. 47: 119–125.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Stefano Bonini
    • 1
  • Roberto Sgrulletta
    • 1
  • Marco Coassin
    • 1
  • Sergio Bonini
    • 2
  1. 1.Coassin Department of OphthalmologyUniversity of Rome “ Campus Bio-Medico”RomeItaly
  2. 2.University of Naples and Institute of Neurobiology & Molecular MedicineNational Research Council (INMM-CNR) - RomeItaly

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