Abstract
The ocular surface mucosa is constantly exposed to allergens and, therefore, highly susceptible for develo** 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.
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References
Phipatanakul W. Allergic rhinoconjunctivitis:epidemiology. Immunol. Allergy Clin. North Am., 2005. 25(2): 263–281.
Weeke ER. Epidemiology of hay fever and perennial allergic rhinitis. Monogr. Allergy, 1987. 21: 1–20.
Foster CS. The pathophysiology of ocular allergy: current thinking. Allergy, 1995. 50(21 Suppl): 6–9; discussion 34–38.
Ehlers WH, Donshik PC. Allergic ocular disorders: a spectrum of diseases. Clao J., 1992. 18(2): 117–124.
MC Gill JI, Church MK, Anderson DF, Bacon A. Allergic eye disease mechabism. Br. J. Ophthalmol., 1998. 82: 1203–1214.
Bielory L. Allergic and immunology disorders of the eye. Part II: ocular allergy. J. Allergy Clin. Immunol., 2000. 106: 1019–1032.
Foster C. The pathophysiology of ocular allergy: current thinking. Allergy, 1995. 50: 6–9.
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.
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.
Ono SJ. Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. J. Allergy Clin. Immunol., 2005. 115: 118–122.
Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and prospects for future treatment. J. Allergy Clin. Immunol., 2005. 115: 118–122.
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.
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.
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.
Bonini S, Coassin M, Aronni S, Lambiase A. Vernal keratoconjunctivitis. Eye, 2004. 18(4): 345–351.
Bonini S, Lambiase A, Schiavone M, Centofanti M, Palma LA, Bonini S. Estrogen and progesteron receptors in vernal Keratoconjunctivitis. Ophthalmology, 1995. 102: 1374–1279.
Bonini S. Atopic keratoconjunctivitis. Allergy, 2004. 59(78 Suppl): 71–73.
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.
Allansmith MR. Vernal conjunctivitis. In: The Eye and Immunology, ed. C.V.M. Company, St. Louis, 1982. pp. 118–124.
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.
Bonini S, Pierdomenico R, Bonini S. Levocabastine eye drops in vernal conjunctivitis. Eur. J. Ophthalmol., 1995. 5(4): 283–284.
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.
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.
Allansmith MR, Greiner JV, Baird RS. Number of inflammatory cells in normal conjunctiva. Am. J. Ophthalmol., 1978. 86: 250–259.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Cameron JA. Shield ulcers and plaques of the cornea in vernal keratoconjunctivitis. Ophthalmology, 1995. 102: 985–993.
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.
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.
Rothenberg M. Eosinophilia. N. Engl. J. Med., 1998. 338: 1592–1600.
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.
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.
Goetzl EJ. mediators of immediate hypersensitivityderived from arachidonic acid. N. Engl. J. Med., 1980. 303: 822–825.
Baggiolini M. Chemokines and leukocyte traffic. Nature, 1998. 392: 565–568.
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.
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.
Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu. Rev. Immunol., 1997. 15: 675–705.
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.
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.
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.
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.
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.
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.
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.
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.
Sallusto F, Mackay CR, Lanzavecchia A. Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 1997. 277: 2005–2007.
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.
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.
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.
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.
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.
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.
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.
Conroy DM, Williams TJ. Eotaxin and the attraction of eosinophils to the asthmatic lung. Respir. Res., 2001. 2(3): 150–156.
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.
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.
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.
Fukuda K, kumagai N, Fujitsu Y, Nishida T. Fibroblasts as local immune modulators in ocular allergic disease. Allergol. Int., 2006. 55(2): 121–129.
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.
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.
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.
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.
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.
Barton K, Monroy DC, Nava A, Pflugfelder SC. Inflammatory cytokines in the tears of patients with ocular rosacea. Ophthalmology, 1997. 104: 1868–1874.
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.
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.
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.
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.
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.
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.
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.
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.
Wynn TA. IL-13 effector functions. Annu. Rev. Immunol., 2003. 21: 425–456.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Trocme SD, Aldave AJ. The eye and the eosinophil. Surv. Ophthalmol., 1994. 39: 241–252.
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.
Stern ME, Siemasko KF, Niederkorn JY. The Th1/Th2 paradigm in ocular allergy. Curr. Opin. Allergy Clin. Immunol., 2005. 5(5): 446–450.
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.
Abbas A, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996. 383: 787–793.
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.
Larche' M, Robinson DS, Kay AB. The role of T lymphocytes in the pathogenesis of asthma. J. Allergy Clin. Immunol., 2003. 111: 450–463.
Zhan H, Towler HM, Calder VL. The immunomodulatory role of human conjunctival epithelial cells. Invest. Ophthalmol. Vis. Sci., 2003. 44: 3906–3910.
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.
Parr M, Parr EL. Immunity to vaginal herpes simplex virus-2 infection in B-cell knockout mice. Immunology, 2000. 101(1): 126–131.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Ryan ME, Ramamurthy NS, Sorsa T, Golub LM. MMP-mediated events in diabetes. Ann. NY Acad. Sci., 1999. 878: 311–334.
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.
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.
Medzhitov R, Janeway C. Jr. Innate immune recognition: mechanisms and pathways. Immunol. Rev., 2000. 173: 89–97.
Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature, 2004. 430(6996): 257–263.
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.
Elson CO, Cong Y. Understanding immune-microbial homeostasis in intestine. Immunol. Res., 2002. 26(1–3): 87–94.
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.
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.
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.
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.
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.
Lawton JA, Ghosh P. Novel therapeutic strategies based on toll-like receptor signaling. Curr. Opin. Chem. Biol., 2003. 7(4): 446–451.
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.
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.
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.
Leonardi A, DeFranchis G, DePaoli M, Fregona IA, Plebani M, Secchi AG, 2002. Curr. Eye Res., 2002. 25: 189–196.
Bielory L, Lien KW, Bigelsen S. Efficacy and tolerability of newer anthistamines in the treatment of allergic conjunctivis. Drugs, 2005. 65: 215–228.
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.
Cerqueti PM, Ricca V, Tosca MA, Buscaglia S, Ciprandi G. Lodoxamide treatment of allergic conjunctivitis. Int. Arch. Allergy Immunol., 1994. 105: 185–189.
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.
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.
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.
Abelson MB. A review of Olopatadine for the treatment of ocular allergy. Expert. Opin. Pharmacother., 2004. 5: 1979–1994.
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.
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.
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.
Fraunfelder FW. Epinastine hydrochloride for atopic disease. Drugs Today, 2004. 40: 677–683.
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.
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.
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.
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.
Babu KS, Arshad SH, Holgate ST. Omalizumab, a novel anti-IgE therapy in allergic disorders. Expert. Opin. Biol. Ther., 2001. 1: 1049–1058.
Soler M. Omalizumab, a monoclonal antibody against IgEfor the treatment of allergic diseases. Int. J. Clin. Pract., 2001. 55(7): 480–483.
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.
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.
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.
Matsuda S, Koyasu S. Mechanism of action of cyclosporin. Immunopharmacology, 2000. 47: 119–125.
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Bonini, S., Sgrulletta, R., Coassin, M., Bonini, S. (2009). Allergic Conjunctivitis: Update on Its Pathophysiology and Perspectives for Future Treatment. In: Pawankar, R., Holgate, S.T., Rosenwasser, L.J. (eds) Allergy Frontiers: Clinical Manifestations. Allergy Frontiers, vol 3. Springer, Tokyo. https://doi.org/10.1007/978-4-431-88317-3_2
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