Dry eye as a mucosal autoimmune disease

International Reviews of Immunology

Volumn 32, Issue 1, 2013, Pages 19-41

  Stern, Michael E ^a   Schaumburg, Chris S ^a   Pflugfelder, Stephen C ^b  

^a ALLERGAN INC   (United States)

^b CULLEN EYE INSTITUTE   (United States)

Author keywords

Autoimmunity; Dry eye; Inflammation; Lacrimal functional unit; Sj gren's syndrome; T cell

Indexed keywords

ARTIFICIAL TEAR; AUTOANTIBODY; AUTOANTIGEN; CELL ADHESION MOLECULE; CLODRONIC ACID; CORTICOSTEROID; CYCLOSPORIN; CYCLOSPORIN A; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 17; INTERLEUKIN 1BETA; INTERLEUKIN 23; INTERLEUKIN 6; LIFITEGRAST; MUCIN; MUSCARINIC RECEPTOR; OMEGA 3 FATTY ACID; STEROID; TETRACYCLINE DERIVATIVE; TOLL LIKE RECEPTOR; TUMOR NECROSIS FACTOR ALPHA;

ADAPTIVE IMMUNITY; ANTIGEN PRESENTING CELL; APOPTOSIS; AUTOIMMUNE DISEASE; AUTOIMMUNITY; B LYMPHOCYTE; CATARACT; CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; DISEASE SEVERITY; DRY EYE; EYE INFECTION; EYE INFLAMMATION; EYE IRRITATION; GAMMA DELTA T LYMPHOCYTE; GLAUCOMA; GOBLET CELL; HEREDITY; HUMAN; IMMUNOPATHOGENESIS; IMMUNOREGULATION; INNATE IMMUNITY; LACRIMAL FUNCTION UNIT; LACRIMAL GLAND; LACRIMAL GLAND FUNCTION; LACRIMATION; LENS IMPLANT; LYMPHOCYTIC INFILTRATION; MONOCYTE; NATURAL KILLER CELL; NONHUMAN; OCULAR SURFACE DISEASE; PRIORITY JOURNAL; QUALITY OF LIFE; REVIEW; SENSORY NEUROPATHY; SIDE EFFECT; SIGNAL TRANSDUCTION; SJOEGREN SYNDROME; T LYMPHOCYTE ACTIVATION; TEAR FILM; TH1 CELL; TH17 CELL;

ADAPTIVE IMMUNITY; ANIMALS; AUTOIMMUNE DISEASES; CD4-POSITIVE T-LYMPHOCYTES; DRY EYE SYNDROMES; HOMEOSTASIS; HUMANS; IMMUNITY, MUCOSAL; IMMUNOMODULATION; INFLAMMATION MEDIATORS; LACRIMAL APPARATUS; TEARS;

EID: 84873306832     PISSN: 08830185     EISSN: 15635244     Source Type: Journal    
DOI: 10.3109/08830185.2012.748052     Document Type: Review

References (178)

1. Beuerman RW,Maitchouk DY, Varnell RJ, Pedroza-Schmidt L. Interactions between lacrimal function and the ocular surface. Curr Opin Kyoto Cornea Club 1998;2:1-10.
2. Stern ME, Beuerman RW, Fox RI, et al.The pathology of dry eye: the interaction between the ocular surface and lacrimal glands. Cornea 1998 Nov;17(6):584-589. (Pubitemid 28511901)
3. Stern ME, Beuerman RW, Fox RI, et al. A unified theory of the role of the ocular surface in dry eye. Adv ExpMed Biol 1998;438:643-651. (Pubitemid 28303801)
4. McDermott AM, Perez V, Huang AJ, et al. Pathways of corneal and ocular surface inflammation: a perspective fromthe cullen symposium. Ocul Surf 2005 Oct;3(4 Suppl):S131-S138.
5. McCarty CA, Bansal AK, Livingston PM, et al.The epidemiology of dry eye inMelbourne, Australia. Ophthalmology 1998 Jun;105(6):1114-1119. (Pubitemid 28268339)
6. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol 2000 Sep;118(9):1264-1268.
7. Moss SE, Klein R, Klein BE. Incidence of dry eye in an older population. Arch Ophthalmol 2004 Mar;122(3):369-373. (Pubitemid 38314200)
8. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003 Aug;136(2):318-326. (Pubitemid 36904081)
9. Shimmura S, Shimazaki J, TsubotaK. Results of a population-based questionnaire on the symptoms and lifestyles associated with dry eye. Cornea 1999 Jul;18(4):408-411. (Pubitemid 29294062)
10. Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates fromthe Physicians' Health Studies. Arch Ophthalmol 2009 Jun;127(6):763-768.
11. Uchino M, Schaumberg DA, Dogru M, et al. Prevalence of dry eye disease among Japanese visual display terminal users. Ophthalmology 2008 Nov;115(11):1982-1988.
12. Miljanovic B, Trivedi KA, Dana MR, et al. Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. AmJ Clin Nutr 2005 Oct;82(4):887-893. (Pubitemid 43779705)
13. Altinors DD, Akca S, Akova YA, et al. Smoking associatedwith damage to the lipid layer of the ocular surface. Am J Ophthalmol 2006 Jun;141(6):1016- 1021.
14. Uchiyama E, Aronowicz JD, Butovich IA, McCulley JP. Increased evaporative rates in laboratory testing conditions simulating airplane cabin relative humidity: an important factor for dry eye syndrome. Eye Contact Lens 2007 Jul;33(4):174-176. (Pubitemid 47106558)
15. Parra A, Madrid R, Echevarria D, et al. Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. NatMed 2010 Dec;16(12):1396-1399.
16. Dvorscak L, Marfurt CF. Age-related changes in rat corneal epithelial nerve density. Invest Ophthalmol Vis Sci 2008Mar;49(3):910-916.
17. Schiffman RM, Walt JG, Jacobsen G, et al. Utility assessment among patients with dry eye disease. Ophthalmology 2003 Jul;110(7):1412-1419. (Pubitemid 36842481)
18. Benitez-del-Castillo JM, del Rio T, Iradier T, et al. Decrease in tear secretion and corneal sensitivity after laser in situ keratomileusis. Cornea 2001 Jan;20(1):30-32. (Pubitemid 32038151)
19. Tuisku IS, Konttinen YT, Konttinen LM, Tervo TM. Alterations in corneal sensitivity and nervemorphology in patients with primary Sjogren's syndrome. Exp Eye Res 2008 Jun;86:879-885.
20. Erdelyi B, Kraak R, Zhivov A, et al. In vivo confocal laser scanning microscopy of the cornea in dry eye. Graefes Arch Clin Exp Ophthalmol 2007 Jan;245(1):39-44. (Pubitemid 46766728)
21. Hosal BM, Ornek N, Zilelioglu G, Elhan AH. Morphology of corneal nerves and corneal sensation in dry eye: a preliminary study. Eye (Lond) 2005 Dec;19(12):1276-1279. (Pubitemid 43148501)
22. Tuominen IS, Konttinen YT, Vesaluoma MH, et al. Corneal innervation and morphology in primary Sjogren's syndrome. Invest Ophthalmol Vis Sci 2003 Jun;44(6):2545-2549. (Pubitemid 36618413)
23. Villani E, Galimberti D, Viola F, et al. The cornea in Sjogren's syndrome: an in vivo confocal study. Invest Ophthalmol Vis Sci 2007May;48(5):2017-2022. (Pubitemid 351261269)
24. Zhang M, Chen J, Luo L, et al. Altered corneal nerves in aqueous tear deficiency viewed by in vivo confocalmicroscopy. Cornea 2005 Oct;24(7):818-824. (Pubitemid 41400421)
25. Lambiase A,Micera A, Sacchetti M, et al. Alterations of tear neuromediators in dry eye disease. Arch Ophthalmol 2011 Aug;129(8):981-986.
26. Varnell RJ, Freeman JY, Maitchouk D, et al. Detection of substance P in human tears by laser desorptionmass spectrometry and immunoassay. Curr Eye Res 1997;28:960-963. (Pubitemid 27410082)
27. Lam H, Bleiden L, de Paiva CS, et al. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol 2009 Feb;147:198-205.
28. Bansal AS, Abdul-Karim B, Malik RA, et al. IgM ganglioside GM1 antibodies in patients with autoimmune disease or neuropathy, and controls. J Clin Pathol 1994 Apr;47(4):300-302. (Pubitemid 24171694)
29. Giordano N, Lucani B, Amendola A, et al. IgG and IgM antiganglioside M1 antibodies in primary Sjogren's syndromewith andwithout peripheral neuropathy. Clin Rheumatol 2003 Sep;22(3): 256-258. (Pubitemid 37258527)
30. Kunert KS, Tisdale AS, Stern ME, et al. Analysis of topical cyclosporine treatment of patientswith dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol 2000 Nov;118(11):1489-1496.
31. Knop E, Knop N. Lacrimal drainage-associated lymphoid tissue (LDALT): a part of the humanmucosal immune system. Invest Ophthalmol Vis Sci 2001Mar;42(3):566-574. (Pubitemid 32206893)
32. Knop N, Knop E. Conjunctiva-associated lymphoid tissue in the human eye. InvestOphthalmol Vis Sci 2000May;41(6):1270-1279. (Pubitemid 30261847)
33. Steven P, Rupp J, Huttmann G, et al. Experimental induction and three-dimensional twophoton imaging of conjunctiva-associated lymphoid tissue. Invest Ophthalmol Vis Sci 2008 Apr;49(4):1512-1517.
34. Steven P, Gebert A. Conjunctiva-associated lymphoid tissue - current knowledge, animal models and experimental prospects. Ophthalmic Res 2009;42(1):2-8.
35. Knop E, Knop N. The role of eye-associated lymphoid tissue in corneal immune protection. J Anat 2005Mar;206(3):271-285. (Pubitemid 40424847)
36. Dong Q, Brulc JM, Iovieno A, et al. Diversity of bacteria at healthy human conjunctiva. Invest Ophthalmol Vis Sci 2011 Jul 20;52(8):5408-5413.
37. Zhang X, Chen W, de Paiva CS, et al. Desiccating stress induces CD4+ T-cell-mediated Sjogren's syndrome-like corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway by interferon-gamma. AmJ Pathol 2011 Oct 17;9(4):1807-1814.
38. Pflugfelder SC, de Paiva CS, Villarreal AL, Stern ME. Effects of sequential artificial tear and cyclosporine emulsion therapy on conjunctival goblet cell density and transforming growth factorbeta2 production. Cornea 2008 Jan;27:64-69.
39. Zhang X, Chen W, de Paiva CS, et al. Interferon-gamma exacerbates dry eye-induced apoptosis in conjunctiva through dual apoptotic pathways. Invest Ophthalmol Vis Sci 2011 Aug 9;52(9):6279-6285.
40. Gupta A, Monroy D, Ji Z, et al. Transforming growth factor beta-1 and beta-2 in human tear fluid. Curr Eye Res 1996;15:605-614. (Pubitemid 26276535)
41. Haynes RJ, Tighe PJ, Dua HS. Antimicrobial defensin peptides of the human ocular surface. Br J Ophthalmol 1999 Jun;83:737-741. (Pubitemid 29261667)
42. Sobrin L, Liu Z, Monroy DC, et al. Regulation of MMP-9 activity in human tear fluid and corneal epithelial culture supernatant. Invest Ophthalmol Vis Sci 2000 Jun;41(7):1703-1709. (Pubitemid 30354340)
43. Govindarajan B, Gipson IK.Membrane-tetheredmucins havemultiple functions on the ocular surface. Exp Eye Res 2010 Jun;90(6):655-663.
44. Spurr-Michaud S, Argueso P, Gipson I. Assay of mucins in human tear fluid. Exp Eye Res 2007 May;84(5):939-950. (Pubitemid 46590136)
45. Nava A, Barton K,Monroy DC, Pflugfelder SC.Theeffects of age, gender, and fluid dynamics on the concentration of tear film epidermal growth factor. Cornea 1997 Jul;16(4):430-438. (Pubitemid 27282182)
46. Yamada M, Ogata M, Kawai M, et al. Substance P in human tears. Cornea 2003 Oct;22(7 Suppl):S48-S54. (Pubitemid 37169604)
47. Jensen OL, Gluud BS, Birgens HS.The concentration of lactoferrin in tears of normals and of diabetics. Acta Ophthalmol (Copenh) 1986 Feb;64(1):83-87. (Pubitemid 16129812)
48. Vinding T, Eriksen JS, Nielsen NV. The concentration of lysozyme and secretory IgA in tears from healthy persons with and without contact lens use. Acta Ophthalmol (Copenh) 1987 Feb;65(1):23-26. (Pubitemid 17030566)
49. Zhou L, Huang LQ, Beuerman RW, et al. Proteomic analysis of human tears: defensin expression after ocular surface surgery. J Proteome Res 2004May;3(3):410-416. (Pubitemid 39207344)
50. Sathe S, Sakata M, Beaton AR, Sack RA. Identification, origins and the diurnal role of the principal serine protease inhibitors in human tear fluid. Curr Eye Res 1998 Apr;17(4):348-362. (Pubitemid 28176902)
51. Fleming A, Allison V.D. Observations on a bacteriolytic substance ("lysozyme") found in secretions and tissues. Br J Exp Pathol 1922;3:252-260.
52. Carreno E, Enriquez-de-Salamanca A, Teson M, et al. Cytokine and chemokine levels in tears from healthy subjects. Acta Ophthalmol 2010 Nov;88(7):e250-e258.
53. Markoulli M, Papas E, Cole N, Holden BA. The diurnal variation ofmatrix metalloproteinase-9 and its associated factors in human tears. Invest Ophthalmol Vis Sci 2012Mar 21;53(3):1479-1484.
54. Lass JH, Walter EI, Burris TE, et al. Expression of two molecular forms of the complement decay-accelerating factor in the eye and lacrimal gland. Invest Ophthalmol Vis Sci 1990 Jun;31(6):1136-1148. (Pubitemid 20197638)
55. Cocuzzi E, Szczotka LB, BrodbeckWG, et al. Tears contain the complement regulator CD59 as well as decay-accelerating factor (DAF). Clin Exp Immunol 2001 Feb;123(2):188-195. (Pubitemid 32174768)
56. Shen L, Barabino S, Taylor AW, Dana MR. Effect of the ocular microenvironment in regulating corneal dendritic cellmaturation. Arch Ophthalmol 2007 Jul;125(7):908-915. (Pubitemid 47076427)
57. Kennedy MC, RosenbaumJT, Brown J, et al. Novel production of interleukin-1 receptor antagonist peptides in normal human cornea. J Clin Invest. 1995 Jan;95:82-88.
58. Solomon A, Dursun D, Liu Z, et al. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci 2001 Sep;42(10):2283-2292. (Pubitemid 32848857)
59. Schaumburg CS, Siemasko KF, de Paiva CS, et al. Ocular surface antigen presenting cells are necessary for autoreactive T cell-mediated experimental autoimmune lacrimal keratoconjunctivitis. J Immunol 2011;187(7):3653-3662.
60. Bardenstein DS, Dietz Y, Lass JH, Medof ME. Localization of the complement membrane attack complex inhibitor (CD59) in human conjunctiva and lacrimal gland. Curr Eye Res 1994 Dec;13(12):851-855.
61. SternME, Schaumburg CS, Siemasko KF, et al. Autoantibodies contribute to theimmunopathogenesis of experimental dry eye disease. Invest Ophthalmol Vis Sci 2012 Apr 24;53(4):2062-2075.
62. Hori J,Wang M,MiyashitaM, et al. B7-H1-induced apoptosis as amechanism of immune privilege of corneal allografts. J Immunol 2006 Nov 1;177:5928-5935. (Pubitemid 44628806)
63. Hori J. Role of B7-H1 in immune privilege of the eye. J NipponMed Sch 2008 Feb;75:56-57. (Pubitemid 351303863)
64. Shen L, Jin Y, Freeman GJ, et al. The function of donor versus recipient programmed death-ligand 1 in corneal allograft survival. J Immunol 2007 Sep 15;179:3672-3679.
65. El AJ, Goyal S, Zhang Q, et al. Regulation of T-cell chemotaxis by programmed deathligand 1 (PD-L1) in dry eye-associated corneal inflammation. Invest Ophthalmol Vis Sci 2010 Jul;51(7):3418-3423.
66. SternME, Gao J, Siemasko KF, et al.The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res 2004Mar;78(3):409-416. (Pubitemid 38183319)
67. Thakur A,Willcox MD, Stapleton F. The proinflammatory cytokines and arachidonic acid metabolites in human overnight tears: homeostaticmechanisms. J Clin Immunol 1998 Jan;18(1):61-70. (Pubitemid 28079074)
68. Poussier P,Ning T,Banerjee D, Julius M.Aunique subset of self-specific intraintestinal T cellsmaintains gut integrity. J ExpMed 2002 Jun 3;195(11):1491-1497. (Pubitemid 34602826)
69. Sacks EH, Wieczorek R, Jakobiec FA, Knowles DM. Lymphocytic subpopulations in the normal human conjunctiva. A monoclonal antibody study. Ophthalmology 1986 Oct;93(10):1276-1283. (Pubitemid 16008990)
70. Niederkorn JY, Stern ME, Pflugfelder SC, et al. Desiccating stress induces T cell-mediated Sjogren's syndrome-like lacrimal keratoconjunctivitis. J Immunol 2006 Apr 1;176(7):3950-3957. (Pubitemid 44264372)
71. Siemasko KF, Gao J, Calder VL, et al. In vitro expanded CD4+CD25+Foxp3+ regulatory T cells maintain a normal phenotype and suppress immune-mediated ocular surface inflammation. Invest Ophthalmol Vis Sci 2008 Jul 24;49(12):5434-5440.
72. Gilbard JP, Farris RL, Santamaria J. Osmolarity of tear microvolumes in keratoconjunctivitis sicca. Arch Ophthalmol 1978 Apr;96(4):677-681. (Pubitemid 8301697)
73. Tomlinson A, Khanal S, Ramaesh K, et al. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci 2006 Oct;47(10):4309-4315. (Pubitemid 46579353)
74. King-Smith PE, Nichols JJ, Nichols KK, Fink BA, Braun RJ. Contributions of evaporation and other mechanisms to tear film thinning and break-up. Optom Vis Sci 2008 Aug;85(8):623-630.
75. Stewart P, Chen Z, Farley W, et al. Effect of experimental dry eye on tear sodium concentration in the mouse. Eye Contact Lens 2005 Jul;31(4):175-178. (Pubitemid 43197021)
76. Corrales RM, Stern ME, de Paiva CS, et al. Desiccating stress stimulates expression ofmatrix metalloproteinases by the corneal epithelium. Invest Ophthalmol Vis Sci 2006 Aug;47(8):3293-3302. (Pubitemid 351639689)
77. Li DQ, Chen Z, Song XJ, et al. Stimulation of matrix metalloproteinases by hyperosmolarity via a JNK pathway in human corneal epithelial cells. Invest Ophthalmol Vis Sci 2004 Dec;45(12): 4302-4311. (Pubitemid 39564654)
78. Luo L, Li DQ, Corrales RM, Pflugfelder SC. Hyperosmolar saline is a proinflammatory stress on the mouse ocular surface. Eye & Contact Lens 2005;31(5):186-193. (Pubitemid 43197004)
79. Luo L, LiDQ, Pflugfelder SC.Hyperosmolarity-induced apoptosis in human corneal epithelial cells is mediated by cytochrome c and MAPK pathways. Cornea 2007May;26:452-460. (Pubitemid 46684387)
80. Luo L, Li DQ, Doshi A, FarleyW, et al. Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest Ophthalmol Vis Sci 2004 Dec;45(12):4293-4301. (Pubitemid 39564653)
81. Li DQ, Luo L, Chen Z, et al. JNK and ERK MAP kinases mediate induction of IL-1beta, TNFalpha and IL-8 following hyperosmolar stress in human limbal epithelial cells. Exp Eye Res 2006 Apr;82:588-596. (Pubitemid 43122089)
82. Yamagami S, Dana MR, Tsuru T. Draining lymph nodes play an essential role in alloimmunity generated in response to high-risk corneal transplantation. Cornea 2002May;21(4):405-409. (Pubitemid 34450478)
83. Johnson GL, Nakamura K.Thec-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim Biophys Acta 2007 Aug;1773(8):1341-1348. (Pubitemid 47125977)
84. Redfern RL, McDermott AM. Toll-like receptors in ocular surface disease. Exp Eye Res 2010 Jun;90(6):679-687.
85. Zheng X, Bian F, Ma P, et al. Induction of Th17 differentiation by corneal epithelial-derived cytokines. J Cell Physiol 2010 Jan;222(1):95-102.
86. Lee HS, Hattori T, Park EY, et al. Expression of toll-like receptor (TLR) 4 contributes to corneal inflammation in experimental dry eye disease. Invest Ophthalmol Vis Sci 2012 Aug 17;53(9):5632-5640.
87. Theofilopoulos AN, Kono DH, Beutler B, Baccala R. Intracellular nucleic acid sensors and autoimmunity. J Interferon Cytokine Res 2011 Dec;31(12):867-886.
88. Theofilopoulos AN, Gonzalez-Quintial R, Lawson BR, et al. Sensors of the innate immune system: their link to rheumatic diseases. Nat Rev Rheumatol 2010Mar;6(3):146-156.
89. Yeh S, Song XJ, Farley W, et al. Apoptosis of ocular surface cells in experimentally induced dry eye. Invest Ophthalmol Vis Sci 2003 Jan;44(1):124-129. (Pubitemid 36134264)
90. Gao J, Gelber-Schwalb TA, Addeo JV, SternME. Apoptosis in the lacrimal gland and conjunctiva of dry eye dogs. Adv ExpMed Biol 1998;438:453-460. (Pubitemid 28303773)
91. Reinoso R, Calonge M, Castellanos E, et al. Differential cell proliferation, apoptosis, and immune response in healthy and evaporative-type dry eye conjunctival epithelia. Invest Ophthalmol Vis Sci 2011 Jul 1;52(7):4819-4828.
92. Bave U,Nordmark G, Lovgren T, et al. Activation of the type I interferon system in primary Sjogren's syndrome: a possible etiopathogenicmechanism. Arthritis Rheum 2005 Apr;52(4):1185-1195. (Pubitemid 40530126)
93. Gottenberg JE, Cagnard N, Lucchesi C, et al. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjogren's syndrome. Proc Natl Acad Sci USA 2006 Feb 21;103(8):2770-2775.
94. Higuchi A, Kawakita T, Tsubota K. IL-6 induction in desiccated corneal epithelium in vitro and in vivo.Mol Vis 2011;17:2400-2406.
95. Narayanan S, Corrales RM, Farley W, et al. Interleukin-1 receptor-1-deficient mice show attenuated production of ocular surface inflammatory cytokines in experimental dry eye. Cornea 2008 Aug;27(7):811-817.
96. Pisella PJ, Brignole F, Debbasch C, et al. Flow cytometric analysis of conjunctival epithelium in ocular rosacea and keratoconjunctivitis sicca. Ophthalmology 2000 Oct;107(10):1841-1849.
97. Gao J, Morgan G, Tieu D, et al. ICAM-1 expression predisposes ocular tissues to immune-based inflammation in dry eye patients and Sjogrens syndrome-like MRL/lpr mice. Exp Eye Res 2004 Apr;78(4):823-835. (Pubitemid 38252959)
98. Yoon KC, de Paiva CS, Qi H, et al. Expression of th-1 chemokines and chemokine receptors on the ocular surface of C57BL/6 mice: effects of desiccating stress. Invest Ophthalmol Vis Sci 2007 Jun;48(6):2561-2569. (Pubitemid 351261206)
99. Yoon KC, Park CS, You IC, et al. Expression of CXCL9, CXCL10, and CXCL11, and CXCR3 in the tear film and ocular surface of patients with dry eye syndrome. Invest Ophthalmol Vis Sci 2009 Oct 22.
100. Choi W, Li Z, Oh HJ, et al. Expression of CCR5 and its ligands CCL3, -4, and -5 in the tear film and ocular surface of patients with dry eye disease. Curr Eye Res 2012 Jan;37(1):12-17.
101. Enriquez-de-Salamanca A, Castellanos E, Stern ME, et al. Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease.Mol Vis 2010May19;16:862-873.
102. Hamrah P, Liu Y, Zhang Q, Dana MR. Alterations in corneal stromal dendritic cell phenotype and distribution in inflammation. Arch Ophthalmol 2003 Aug;121:1132-1140. (Pubitemid 36962167)
103. Rashid S, Jin Y, Ecoiffier T, et al. Topical omega-3 and omega-6 fatty acids for treatment of dry eye. Arch Ophthalmol 2008 Feb;126(2):219-225. (Pubitemid 351240851)
104. Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell subpopulations in Sjogren's and non- Sjogren's patients with dry eye. Invest Ophthalmol Vis Sci 2002 Aug;43(8):2609-2614. (Pubitemid 34809449)
105. Chen Y, Chauhan SK, Saban DR, et al. Interferon-{gamma}-secreting NK cells promote induction of dry eye disease. J Leukoc Biol 2011Mar 14;89(6):965-972.
106. Zhang X, Volpe EA, Gandhi NB, et al. NK cells promoteTh-17 mediated corneal barrier disruption in dry eye. PLoS One 2012;7(5):e36822.
107. LiDQ, Lokeshwar BL, Solomon A, et al. Regulation ofMMP-9 production by human corneal epithelial cells. Exp Eye Res 2001 Oct;73(4):449-459. (Pubitemid 33078221)
108. Chotikavanich S, de Paiva CS, Li dQ, et al. Production and activity of matrix metalloproteinase- 9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci 2009 Jul;50(7):3203-3209.
109. Okanobo A, Chauhan SK, Dastjerdi MH, et al. Efficacy of topical blockade of interleukin-1 in experimental dry eye disease. Am J Ophthalmol 2012 Jul;154(1):63-71.
110. Kim HS, Shang T, Chen Z, et al. TGF-beta1 stimulates production of gelatinase (MMP-9), collagenases (MMP-1, -13) and stromelysins (MMP-3, -10, -11) by human corneal epithelial cells. Exp Eye Res 2004 Aug;79(2):263-274. (Pubitemid 39119415)
111. Kim HS, Luo L, Pflugfelder SC, Li DQ. Doxycycline inhibits TGF-{beta}1-induced MMP-9 via Smad and MAPK pathways in human corneal epithelial cells. Invest Ophthalmol Vis Sci 2005 Mar;46(3):840-848. (Pubitemid 41321019)
112. Zheng X, de Paiva CS, Rao K, et al. Evaluation of the transforming growth factor-beta activity in normal and dry eye human tears by CCL-185 cell bioassay. Cornea 2010 Sep;29(9):1048-1054.
113. Barabino S,Montaldo E, Solignani F, et al. Immune response in the conjunctival epithelium of patients with dry eye. Exp Eye Res 2010 Oct;91(4):524-529.
114. Chan JH, Amankwah R, Robins RA, et al. Kinetics of immune cell migration at the human ocular surface. Br J Ophthalmol 2008 Jul;92:970-975. (Pubitemid 351969681)
115. Jameson JM, Sharp LL, Witherden DA, Havran WL. Regulation of skin cell homeostasis by gamma delta T cells. Front Biosci 2004 Sep 1;9:2640-2651.
116. Sutton CE, Lalor SJ, Sweeney CM, et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 2009 Aug 21;31(2):331-341.
117. Roark CL, French JD, Taylor MA, et al. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing gamma delta T cells. J Immunol 2007 Oct 15;179(8):5576-5583.
118. Cui Y, ShaoH, Lan C, et al.Major role of gamma delta T cells in the generation of IL-17+uveitogenic T cells. J Immunol 2009 Jul 1;183(1):560-567.
119. Bialasiewicz AA, Schaudig U, Ma JX, et al. Alpha/beta- and gamma/delta-T-cell-receptor-positive lymphocytes in healthy and inflamed human conjunctiva. Graefes Arch Clin Exp Ophthalmol 1996 Jul;234(7):467-471. (Pubitemid 26202583)
120. Soukiasian SH, Rice B, Foster CS, Lee SJ. The T cell receptor in normal and inflamed human conjunctiva. Invest Ophthalmol Vis Sci 1992 Feb;33(2):453-459.
121. Uhlig HH,McKenzie BS,Hue S, et al. Differential activity of IL-12 and IL-23 inmucosal and systemic innate immune pathology. Immunity 2006 Aug;25(2):309-318.
122. Chen Y, Chauhan SK, Saban DR, et al. Interferon-gamma-secreting NK cells promote induction of dry eye disease. J Leukoc Biol 2011 Jun;89(6):965-972.
123. de Paiva CS, Villarreal AL, Corrales RM, et al. IFN- g promotes goblet cell loss in response to desiccating ocular stress. Invest Ophthalmol Vis Sci 2006;47:E-Abstract 5579.
124. de Paiva CS, Villarreal AL, Corrales RM, et al. Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-{gamma}. Invest Ophthalmol Vis Sci 2007 Jun;48(6):2553-2560. (Pubitemid 351261205)
125. Albertsmeyer AC, Kakkassery V, Spurr-Michaud S, et al. Effect of pro-inflammatory mediators on membrane-associatedmucins expressed by human ocular surface epithelial cells. Exp Eye Res 2010 Mar;90(3):444-451.
126. de Paiva CS, Chotikavanich S, Pangelinan SB, et al. IL-17 disrupts corneal barrier following desiccating stress.Mucosal Immunol 2009May;2(3):243-253.
127. de PaivaCS, Raince JK,McClellan AJ, et al.Homeostatic control of conjunctivalmucosal goblet cells by NKT-derived IL-13.Mucosal Immunol 2011 Jul;4(4):397-408.
128. Goyal S, Chauhan SK, Zhang Q, Dana R. Amelioration ofmurine dry eye disease by topical antagonist to chemokine receptor 2. Arch Ophthalmol 2009 Jul;127(7):882-887.
129. Steinman RM,Hemmi H.Dendritic cells: translating innate to adaptive immunity. Curr TopMicrobiol Immunol 2006;311:17-58. (Pubitemid 47413194)
130. Ueno H, Klechevsky E, Morita R, et al. Dendritic cell subsets in health and disease. Immunol Rev 2007 Oct;219:118-142. (Pubitemid 47393528)
131. Dursun D,Wang M,Monroy D, et al. A mousemodel of keratoconjunctivitis sicca. Invest Ophthalmol Vis Sci 2002Mar;43(3):632-638.
132. Hamrah P, Liu Y, Zhang Q, Dana MR.The corneal stroma is endowed with a significant number of resident dendritic cells. Invest Ophthalmol Vis Sci 2003 Feb;44:581-589. (Pubitemid 36159702)
133. Jin Y, Shen L, Chong EM, et al.Thechemokine receptor CCR7mediates corneal antigen-presenting cell trafficking.Mol Vis 2007;13:626-634. (Pubitemid 46710813)
134. Dana R. Corneal antigen presentation: molecular regulation and functional implications. Ocul Surf 2005 Oct;3(4 Suppl):S169-S172.
135. Goyal S, Chauhan SK, El AJ, et al. Evidence of corneal lymphangiogenesis in dry eye disease: a potential link to adaptive immunity? Arch Ophthalmol 2010 Jul;128(7):819-824.
136. van RN, Hendrikx E. Liposomes for specific depletion of macrophages from organs and tissues. MethodsMol Biol 2010;605:189-203.
137. Pflugfelder SC, de Paiva CS, LiDQ, Stern ME. Epithelial-immune cell interaction in dry eye. Cornea 2008 Sep;27 (Suppl 1):S9-S11.
138. Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol 2002 Mar;120(3):330-337. (Pubitemid 34250055)
139. Ecoiffier T, El AJ, Rashid S, et al. Modulation of integrin alpha4beta1 (VLA-4) in dry eye disease. Arch Ophthalmol 2008 Dec;126(12):1695-1699.
140. Chauhan SK, El AJ, Ecoiffier T, et al. Autoimmunity in dry eye is due to resistance ofTh17 to Treg suppression. J Immunol 2009 Feb 1;182(3):1247-1252.
141. Reinoso R, Calonge M, Castellanos E, et al. Differential cell proliferation, apoptosis, and immune response in healthy and evaporative-type dry eye conjunctival epithelia. Invest Ophthalmol Vis Sci 2011 Jul 1;52(7):4819-4828.
142. El AJ, Chauhan SK, Ecoiffier T, et al. Characterization of effector T cells in dry eye disease. Invest Ophthalmol Vis Sci 2009 Aug;50(8):3802-3807.
143. Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity 2009 May;30(5):646-655.
144. Corrales RM, Villarreal A, Farley W, et al. Strain-related cytokine profiles on themurine ocular surface in response to desiccating stress. Cornea 2007 Jun;26(5):579-584. (Pubitemid 47164717)
145. Enriquez-de-Salamanca A, Calder V, Gao J, Galatowicz G, et al. Cytokine responses by conjunctival epithelial cells: an in vitro model of ocular inflammation. Cytokine 2008 Oct;44(1):160-167.
146. MassingaleML, Li X, VallabhajosyulaM, et al. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea 2009 Oct;28(9):1023-1027.
147. Pflugfelder SC, Farley W, Luo L, et al. Matrix metalloproteinase-9 knockout confers resistance to corneal epithelial barrier disruption in experimental dry eye. AmJ Pathol 2005 Jan;166(1):61-71. (Pubitemid 40051660)
148. Katsifis GE, Rekka S, Moutsopoulos NM, et al. Systemic and local interleukin-17 and linked cytokines associated with Sjogren's syndrome immunopathogenesis. Am J Pathol 2009 Sep;175(3):1167-1177.
149. Hirota K, Yoshitomi H, Hashimoto M, et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J Exp Med 2007 Nov 26;204(12):2803-2812. (Pubitemid 350179551)
150. Humphreys-BeherMG, Brinkley L, PurushothamKR, et al. Characterization of antinuclear autoantibodies present in the serum from nonobese diabetic (NOD) mice. Clin Immunol Immunopathol 1993 Sep;68(3):350-356. (Pubitemid 23284095)
151. Yamamoto H, Sims NE, Macauley SP, et al. Alterations in the secretory response of non-obese diabetic (NOD) mice to muscarinic receptor stimulation. Clin Immunol Immunopathol 1996 Mar;78(3):245-255. (Pubitemid 26127987)
152. Kovacs L, Marczinovits I, Gyorgy A, et al. Clinical associations of autoantibodies to human muscarinic acetylcholine receptor 3(213-228) in primary Sjogren's syndrome. Rheumatology (Oxford) 2005 Aug;44(8):1021-1025. (Pubitemid 41487176)
153. Bacman S, Berra A, Sterin-Borda L, Borda E.Muscarinic acetylcholine receptor antibodies as a new marker of dry eye Sjogren syndrome. Invest Ophthalmol Vis Sci 2001 Feb;42(2):321-327. (Pubitemid 32121458)
154. Bacman S, Sterin-Borda L, Camusso JJ, et al. Circulating antibodies against rat parotid gland M3 muscarinic receptors in primary Sjogren's syndrome. Clin Exp Immunol 1996 Jun;104(3): 454-459.
155. Borda E, Camusso JJ, Perez LC, et al. Circulating antibodies against neonatal cardiac muscarinic acetylcholine receptor in patients with Sjogren's syndrome. Mol Cell Biochem 1996 Oct;163-164:335-341.
156. Nguyen KH, Brayer J, Cha S, et al. Evidence for antimuscarinic acetylcholine receptor antibodymediated secretory dysfunction in nod mice. Arthritis Rheum 2000 Oct;43(10):2297-2306.
157. Robinson CP, Brayer J, Yamachika S, et al. Transfer of human serumIgG to nonobese diabetic Igmu null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjogren's syndrome. Proc Natl Acad Sci U S A 1998 Jun 23;95(13):7538-7543.
158. Rose CM, Qian L, Hakim L, et al. Accumulation of catalytically active proteases in lacrimal gland acinar cell endosomes during chronic ex vivo muscarinic receptor stimulation. Scand J Immunol 2005 Jan;61(1):36-50. (Pubitemid 40188346)
159. Jiang G, Ke Y, Sun D, et al. A new model of experimental autoimmune keratoconjunctivitis sicca (KCS) induced in Lewis rat by the autoantigen Klk1b22. Invest Ophthalmol Vis Sci 2009 May;50(5):2245-2254.
160. Takada K, TakiguchiM, Konno A, InabaM. Autoimmunity against a tissue kallikrein in IQI/JicMice: amodel for Sjogren's syndrome. J Biol Chem 2005 Feb 4;280:3982-3988. (Pubitemid 40223867)
161. Chan OT, Hannum LG, Haberman AM, et al. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med 1999 May 17;189(10):1639-1648.
162. Rodriguez-Pinto D. B cells as antigen presenting cells. Cell Immunol 2005 Dec;238(2):67-75.
163. SerrezeDV, Fleming SA, ChapmanHD, et al. B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Immunol 1998 Oct 15;161(8):3912-3918. (Pubitemid 28468965)
164. O'Neill SK, Shlomchik MJ, Glant TT, et al. Antigen-specific B cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis. J Immunol 2005 Mar 15;174(6):3781-3788. (Pubitemid 40354091)
165. Lund FE. Cytokine-producing B lymphocytes-key regulators ofimmunity. CurrOpin Immunol 2008 Jun;20(3):332-338.
166. Manz RA, Arce S, Cassese G, et al. Humoral immunity and long-lived plasma cells. Curr Opin Immunol 2002 Aug;14(4):517-521. (Pubitemid 34671256)
167. Daha NA, Banda NK, Roos A, et al. Complement activation by (auto-) antibodies. Mol Immunol 2011 Aug;48(14):1656-1665.
168. Van den Berg CW, Aerts PC, Van DH. In vivo anti-complementary activities of the cobra venom factors from Naja naja and Naja haje. J ImmunolMethods 1991 Feb 15;136(2):287-294.
169. Cochrane CG,Muller-Eberhard HJ, Aikin BS. Depletion of plasma complement in vivo by a protein of cobra venom: its effect on various immunologic reactions. J Immunol 1970 Jul;105(1):55-69.
170. Vogel CW, Fritzinger DC, Hew BE, et al. Recombinant cobra venom factor. Mol Immunol 2004 Jun;41(2-3):191-199. (Pubitemid 38668629)
171. Management and therapy of dry eye disease: report of theManagement andTherapy Subcommittee of the International Dry EyeWorkShop (2007). Ocul Surf 2007 Apr;5(2):163-178.
172. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology 2000 Apr;107(4):631-639. (Pubitemid 30191329)
173. Turner K, Pflugfelder SC, Ji Z, et al. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion. Cornea 2000 Jul;19(4):492-496. (Pubitemid 30460887)
174. Baudouin C, Brignole F, Pisella PJ, et al. Flow cytometric analysis of the inflammatorymarker HLA DR in dry eye syndrome: results from 12 months of randomized treatment with topical cyclosporin A. Adv ExpMed Biol 2002;506(Pt B):761-769. (Pubitemid 36308260)
175. Semba CP, Torkildsen GL, Lonsdale JD, et al. A phase 2 randomized, double-masked, placebocontrolled study of a novel integrin antagonist (SAR 1118) for the treatment of dry eye. Am J Ophthalmol 2012 Jun;153(6):1050-1060.
176. Nava A, Barton K,Monroy DC, Pflugfelder SC.Theeffects of age, gender, and fluid dynamics on the concentration of tear film epidermal growth factor. Cornea 1997 Jul;16(4):430-438. (Pubitemid 27282182)
177. Ambati BK,NozakiM, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1.Nature 2006 Oct 26;443(7114):993-997. (Pubitemid 44646176)
178. Cursiefen C, Chen L, Saint-Geniez M, et al. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc Natl Acad Sci U S A 2006 Jul 25;103(30):11405-11410. (Pubitemid 44156530)