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The Conjunctiva-Associated Lymphoid Tissue in Chronic Ocular Surface Diseases

Published online by Cambridge University Press:  08 May 2017

Rodolfo Mastropasqua ,
Luca Agnifili ,
Vincenzo Fasanella ,
Mario Nubile ,
Agbeanda A. Gnama ,
Gennaro Falconio ,
Paolo Perri ,
Silvio Di Staso  and
Cesare Mariotti
Rodolfo Mastropasqua
Affiliation:
Moorfields Eye Hospital, London EC1V 2PD, UK
Luca Agnifili*
Affiliation:
Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d’Annunzio of Chieti-Pescara, Chieti 66100, Italy
Vincenzo Fasanella
Affiliation:
Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d’Annunzio of Chieti-Pescara, Chieti 66100, Italy
Mario Nubile
Affiliation:
Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d’Annunzio of Chieti-Pescara, Chieti 66100, Italy
Agbeanda A. Gnama
Affiliation:
Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d’Annunzio of Chieti-Pescara, Chieti 66100, Italy
Gennaro Falconio
Affiliation:
Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d’Annunzio of Chieti-Pescara, Chieti 66100, Italy
Paolo Perri
Affiliation:
Department of Biomedical and Surgical Sciences, Division of Ophthalmology, University of Ferrara, Ferrara 44100, Italy
Silvio Di Staso
Affiliation:
Department of Surgical Science, Ophthalmic Clinic, University of L’Aquila, L’Aquila 67100, Italy
Cesare Mariotti
Affiliation:
Eye Clinic, Polytechnic University of Marche, Ancona 60020, Italy
*
*Corresponding author. l.agnifili@unich.it
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Abstract

Ocular surface diseases (OSDs) represent a widely investigated field of research given their growing incidence and the negative impact on quality of life. During OSDs, cytokines generated by damaged epithelia trigger and deregulate the lymphoid cells composing the eye-associated lymphoid tissues, inducing an immune-mediated chronic inflammation that amplifies and propagates the disease during time. The conjunctiva-associated lymphoid tissue (CALT), given its particular position that permits immune cells covering the cornea, might play a crucial role in the development of OSDs. Despite the recognized inflammatory role of mucosa-associated lymphoid tissues in other stations taking contact with the external environment (gut or bronchus), CALT did not gain the deserved consideration. In the last years, the diffusion of the in vivo confocal microscopy (IVCM) stimulated the interest to CALT, especially in dry eye, ocular allergy, and glaucoma. Though the initial stimuli were different, IVCM documented similar changes, represented by increased lymphoid cells within the diffuse layer, follicles and interfollicular spaces. These findings, which need to be validated by immunohistology, support the CALT stimulation during OSDs. However, while an involvement of the CALT in OSDs is hypothesizable, the exact role of this structure in their pathogenesis remains unclear and warrants further investigations.

Keywords

conjunctiva-associated lymphoid tissuein vivo confocal microscopyocular surface diseaseglaucoma therapy dry eye diseaseocular allergy
Type
Review Article
Information
Microscopy and Microanalysis , Volume 23 , Issue 4 , August 2017 , pp. 697 - 707
Copyright
© Microscopy Society of America 2017 

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Footnotes

†

R. M. and L. A. equally contributed to this work and share primary authorship.

References

Agnifili, L., Fasanella, V., Costagliola, C., Ciabattoni, C., Mastropasqua, R., Frezzotti, P. & Mastropasqua, L. (2013). In vivo confocal microscopy of meibomian glands in glaucoma. Br J Ophthalmol 97, 343–349.Google Scholar
Agnifili, L., Mastropasqua, R., Fasanella, V., Di Staso, S., Mastropasqua, A., Brescia, L. & Mastropasqua, L. (2014). In vivo confocal microscopy of conjunctiva-associated lymphoid tissue in healthy humans. Invest Ophthalmol Vis Sci 55(8), 5254–5262.Google Scholar
Agnifili, L., Pieragostino, D., Mastropasqua, A., Fasanella, V., Brescia, L., Tosi, G.M., Sacchetta, P. & Mastropasqua, L. (2015). Molecular biomarkers in primary open-angle glaucoma: From noninvasive to invasive. Prog Brain Res 221, 1–32.CrossRefGoogle ScholarPubMed
Arnaoutakis, K. & Oo, T.H. (2009). Bronchus-associated lymphoid tissue lymphomas. South Med J 102, 1229–1233.CrossRefGoogle ScholarPubMed
Barabino, S., Chen, Y., Chauhan, S. & Dana, R. (2012). Ocular surface immunity: Homeostatic mechanisms and their disruption in dry eye disease. Prog Retin Eye Res 31, 271–285.Google Scholar
Barabino, S., Labetoulle, M., Rolando, M. & Messmer, E.M. (2016). Understanding symptoms and quality of life in patients with dry eye syndrome. Ocul Surf 14, 365–376.Google Scholar
Baudouin, C. (2008). Detrimental effect of preservatives in eyedrops: Implications for the treatment of glaucoma. Acta Ophthalmol 86, 716–726.Google Scholar
Baudouin, C., Labbé, A., Liang, H., Pauly, A. & Brignole-Baudouin, F. (2010). Preservatives in eyedrops: The good, the bad and the ugly. Prog Retin Eye Res 29, 312–334.Google Scholar
Baudouin, C., Liang, H., Hamard, P., Riancho, L., Creuzot-Garcher, C., Warnet, J.M. & Brignole-Baudouin, F. (2008). The ocular surface of glaucoma patients treated over the long term expresses inflammatory markers related to both T-helper 1 and T-helper 2 pathways. Ophthalmology 115, 109–115.CrossRefGoogle Scholar
Broadway, D.C., Grierson, I., O’Brien, C. & Hitchings, R.A. (1994). Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol 112, 1446–1454.CrossRefGoogle ScholarPubMed
Bron, A.J., Tomlinson, A., Foulks, G.N., Pepose, J.S., Baudouin, C., Geerling, G., Nichols, K.K. & Lemp, M.A. (2014). Rethinking dry eye disease: A perspective on clinical implications. Ocul Surf 12, S1–S31.CrossRefGoogle ScholarPubMed
Cain, C. & Phillips, T.E. (2008). Developmental changes in conjunctiva-associated lymphoid tissue of the rabbit. Invest Ophthalmol Vis Sci 49, 644–649.CrossRefGoogle ScholarPubMed
Chen, Y., Chauhan, S.K., Saban, D.R., Sadrai, Z., Okanobo, A. & Dana, R. (2011). Interferon-gamma-secreting NK cells promote induction of dry eye disease. J Leukoc Biol 89, 965–972.Google Scholar
Cornes, J.S. (1965a). Number, size and distribution of Peyer’s patches in the human small intestine: Part I The development of Peyer’s patches. Gut 6, 225–229.Google Scholar
Cornes, J.S. (1965b). Number, size and distribution of Peyer’s patches in the human small intestine: Part II The effect of age on Peyer’s patches. Gut 6, 230–233.Google Scholar
De Paiva, C.S., Villarreal, A.L., Corrales, R.M., Rahman, H.T., Chang, V.Y., Farley, W.J., Stern, M.E., Niederkorn, J.Y., Li, D. & Pflugfelder, S.C. (2007). Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma. Invest Ophthalmol Vis Sci 48, 2553–2560.Google Scholar
Dua, H.S., Jindal, V.K., Gomes, J.A., Amoaku, W.A., Donoso, L.A., Laibson, P.R. & Mahlebrg, K. (1996). The effect of topical cyclosporin on conjunctiva-associated lymphoid tissue (CALT). Eye (Lond) 10, 433–438.CrossRefGoogle ScholarPubMed
El Annan, J., Chauhan, S.K., Ecoiffier, T., Zhang, Q., Saban, D.R. & Dana, R. (2009). Characterization of effector T cells in dry eye disease. Invest Ophthalmol Vis Sci 50, 3802–3807.Google Scholar
Fasanella, V., Agnifili, L., Mastropasqua, R., Brescia, L., Di Staso, S. & Ciancaglini, M. (2016). In vivo laser scanning confocal microscopy of human meibomian glands in aging and ocular surface diseases. Biomed Res Int 2016, 7432131.Google Scholar
Fix, A.S. & Arp, L.H. (1989). Conjunctiva-associated lymphoid tissue (CALT) in normal and Bordetella avium-infected turkeys. Vet Pathol 26, 222–230.Google Scholar
Gerberick, G.F., Cruse, L.W., Ryan, C.A., Hulette, B.C., Chaney, J.G., Skinner, R.A., Dearman, R.J. & Kimber, I. (2002). Use of a B cell marker (B220) to discriminate between allergens and irritants in the local lymph node assay. Toxicol Sci 68, 420–428.Google Scholar
Haynes, R.J., Tighe, P.J., Scott, R.A. & Singh Dua, H. (1999). Human conjunctiva contains high endothelial venules that express lymphocyte homing receptors. Exp Eye Res 69, 397–403.Google Scholar
Hein, W.R. (1999). Organization of mucosal lymphoid tissue. In Defense of Mucosal Surfaces: Pathogenesis, Immunity and Vaccines, Kraehenbuhl J.R. & Neutra M.R. (Eds.), pp. 1–15. Berlin: Springer Verlag.Google Scholar
Hiller, A.S., Tschernig, T., Kleemann, W.J. & Pabst, R. (1998). Bronchus-associated lymphoid tissue (BALT) and larynx-associated lymphoid tissue (LALT) are found at different frequencies in children, adolescents and adults. Scand J Immunol 47, 159–162.Google Scholar
Kessing, S.V. (1968). Mucous gland system of the conjunctiva. A quantitative normal anatomical study. Acta Ophthalmol (Copenh) 95, 91+.Google Scholar
Knop, E. & Knop, N. (2000). Conjunctiva-associated lymphoid tissue in the human eye. Invest Ophthalmol Vis Sci 41, 1270–1279.Google Scholar
Knop, E. & Knop, N. (2001). Lacrimal drainage-associated lymphoid tissue (LDALT): A part of the human mucosal immune system. Invest Ophthalmol Vis Sci 42, 566–574.Google Scholar
Knop, E. & Knop, N. (2002). A functional unit for ocular surface immune defense formed by the lacrimal gland, conjunctiva and lacrimal drainage system. Adv Exp Med Biol 506, 835–844.CrossRefGoogle ScholarPubMed
Knop, E., Knop, N. & Pleyer, U. (2004). Clinical aspects of MALT. In Uveitis and Immunological Disorders, Pleyer U. & Mondino B. (Eds.), pp. 67–89. Berlin: Springer Verlag.Google Scholar
Knop, E. & Knop, N. (2005a). Influence of the eye-associated lymphoid tissue (EALT) on inflammatory ocular surface disease. Ocul Surf 3, 180–187.Google Scholar
Knop, E. & Knop, N. (2005b). The role of eye-associated lymphoid tissue in corneal immune protection. J Anat 206, 271–285.Google Scholar
Knop, N. & Knop, E. (2010). Regulation of the inflammatory component in chronic dry eye disease by the eye-associated lymphoid tissue (EALT). Dev Ophthalmol 45, 23–39.Google Scholar
Knop, E. & Knop, N. (2003). Eye-associated lymphoid tissue (EALT) is continuously spread throughout the ocular surface from the lacrimal gland to the lacrimal drainage system. Ophthalmologe 100, 929–942.Google Scholar
Kodati, S., Chauhan, S.K., Chen, Y., Dohlman, T.H., Karimian, P., Saban, D. & Dana, R. (2014). CCR7 is critical for the induction and maintenance of Th17 immunity in dry eye disease. Invest Ophthalmol Vis Sci 55, 5871–5877.Google Scholar
Kumar, S. (2009). Vernal keratoconjunctivitis: A major review. Acta Ophthalmol 87, 133–147.Google Scholar
Le, Q., Hong, J., Zhu, W., Sun, X. & Xu, J. (2011). In vivo laser scanning confocal microscopy of vernal keratoconjunctivitis. Clin Exp Ophthalmol 39, 53–60.Google Scholar
Lemp, M.A., Baudouin, C., Baum, J., Dogru, M., Foulks, G.N., Kinoshita, S., Laibson, P., McCulley, J., Murube, J., Pflugfelder, S.C., Rolando, M. & Toda, I. (2007). The definition and classification of dry eye disease: Report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop. Ocul Surf 5, 75–92.Google Scholar
Lemp, M.A., Crews, L.A., Bron, A.J., Foulks, G.N. & Sullivan, B.D. (2012). Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: A retrospective study. Cornea 31, 472–478.Google Scholar
Leske, M.C., Heijl, A., Hussein, M., Bengtsson, B., Hyman, L. & Komaroff, E., Early Manifest Glaucoma Trial Group (2003). Factors for glaucoma progression and the effect of treatment: The early manifest glaucoma trial. Arch Ophthalmol 121, 48–56.Google Scholar
Leung, E.W., Medeiros, F.A. & Weinreb, R.N. (2008). Prevalence of ocular surface disease in glaucoma patients. J Glaucoma 17, 350–355.Google Scholar
Li, D.Q., Lokeshwar, B.L., Solomon, A., Monroy, D., Ji, Z. & Pflugfelder, S.C. (2001). Regulation of MMP-9 production by human corneal epithelial cells. Exp Eye Res 73, 449–459.Google Scholar
Liang, H., Baudouin, C., Dupas, B. & Brignole-Baudouin, F. (2010). Live conjunctiva-associated lymphoid tissue analysis in rabbit under inflammatory stimuli using in vivo confocal microscopy. Invest Ophthalmol Vis Sci 51, 1008–1015.CrossRefGoogle ScholarPubMed
Liang, H., Baudouin, C., Faure, M.O., Lambert, G. & Brignole-Baudouin, F. (2009). Comparison of the ocular tolerability of a latanoprost cationic emulsion versus conventional formulations of prostaglandins: An in vivo toxicity assay. Mol Vis 15, 1690–1699.Google ScholarPubMed
Liang, H., Baudouin, C., Labbè, A., Riancho, L. & Brignole-Baudouin, F. (2012a). Conjunctiva-associated lymphoid tissue (CALT) reactions to antiglaucoma prostaglandins with or without BAK-preservative in rabbit acute toxicity study. PLoS One 7, e33913.Google Scholar
Liang, H., Baudouin, C., Pauly, A. & Brignole-Baudouin, F. (2008a). Conjunctival and corneal reactions in rabbits following short- and repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02% benzalkonium chloride. Br J Ophthalmol 92, 1275–1282.Google Scholar
Liang, H., Brignole-Baudouin, F., Pauly, A., Riancho, L. & Baudouin, C. (2011). Polyquad-preserved travoprost/timolol, benzalkonium chloride (BAK)-preserved travoprost/timolol, and latanoprost/timolol in fixed combinations: A rabbit ocular surface study. Adv Ther 28, 311–325.CrossRefGoogle ScholarPubMed
Liang, H., Brignole-Baudouin, F., Rabinovich-Guilatt, L, Mao, Z., Riancho, L., Faure, M.O., Warnet, J.M., Lambert, G. & Baudouin, C. (2008b). Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: An in vivo study in rabbits. Mol Vis 14, 204–216.Google Scholar
Liang, H., Brignole-Baudouin, F., Riancho, L. & Baudouin, C. (2012b). Reduced in vivo ocular surface toxicity with polyquad-preserved travoprost versus benzalkonium-preserved travoprost or latanoprost ophthalmic solutions. Ophthalmic Res 48, 89–101.Google Scholar
Lin, P.Y., Tsai, S.Y., Cheng, C.Y., Liu, J.H., Chou, P. & Hsu, W.M. (2003). Prevalence of dry eye among an elderly Chinese population in Taiwan: The Shihpai eye study. Ophthalmology 110, 1096–1101.CrossRefGoogle ScholarPubMed
Liu, H., Meagher, C.K., Moore, C.P. & Phillips, T.E. (2005). M cells in the follicle-associated epithelium of the rabbit conjunctiva preferentially bind and translocate latex beads. Invest Ophthalmol Vis Sci 46, 4217–4223.Google Scholar
Liu, M., Gao, H., Wang, T., Wang, S., Li, S. & Shi, W. (2014). An essential role for dendritic cells in vernal keratoconjunctivitis: Analysis by laser scanning confocal microscopy. Clin Exp Allergy 44, 362–370.Google Scholar
Luo, L., Li, D.Q., Doshi, A., Farley, W., Corrales, R.M. & Pflugfelder, S.C. (2004). Experimental dry eye stimulates production of inflammatory cytokines and MMP-9 and activates MAPK signaling pathways on the ocular surface. Invest Ophthalmol Vis Sci 45, 4293–4301.Google Scholar
Martone, G., Frezzotti, P., Tosi, G.M., Traversi, C., Mittica, V., Malandrini, A., Pichierri, P., Balestrazzi, A., Motolese, P.A., Motolese, I. & Motolese, E. (2009). An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 147, 725–735.Google Scholar
Mashaghi, A., Hong, J., Chauhan, S.K. & Dana, R. (2017). Ageing and ocular surface immunity. Br J Ophthalmol 101, 1–5.Google Scholar
Mastropasqua, L., Agnifili, L., Fasanella, V., Curcio, C., Ciabattoni, C., Mastropasqua, R., Toto, L. & Ciancaglini, M. (2013a). Conjunctival goblet cells density and preservative-free tafluprost therapy for glaucoma: An in vivo confocal microscopy and impression cytology study. Acta Ophthalmol 91, e397–e405.Google Scholar
Mastropasqua, L., Agnifili, L., Mastropasqua, R. & Fasanella, V. (2013b). Conjunctival modifications induced by medical and surgical therapies in patients with glaucoma. Curr Opin Pharmacol 13, 56–64.Google Scholar
Mastropasqua, L., Agnifili, L., Mastropasqua, R., Fasanella, V., Nubile, M., Toto, L., Carpineto, P. & Ciancaglini, M. (2014). In vivo laser scanning confocal microscopy of the ocular surface in glaucoma. Microsc Microanal 20(3), 879–894.Google Scholar
Mastropasqua, R., Agnifili, L., Fasanella, V., Curcio, C., Lanzini, M., Fresina, M., Mastropasqua, L. & Marchini, G. (2015). Corneoscleral limbus in glaucoma patients: In vivo confocal microscopy and immunocytological study. Invest Ophthalmol Vis Sci 56, 2050–2058.Google Scholar
Mastropasqua, R., Agnifili, L., Fasanella, V., Lappa, A., Brescia, L., Lanzini, M., Oddone, F., Perri, P. & Mastropasqua, L. (2016). In vivo distribution of corneal epithelial dendritic cells in patients with glaucoma. Invest Ophthalmol Vis Sci 57, 5996–6002.Google Scholar
McGhee, J.R., Lamm, M.E. & Strober, W. (1999). Mucosal immune responses. An overview. In Handbook of Mucosal Immunology , Ogra P.L., Mestecky J., Lamm M.E., Strober, W., McGhee J.R. & Bienenstock J. (Eds.), pp. 485–506. San Diego, CA: Academic Press.Google Scholar
Miljanovic, B., Dana, R., Sullivan, D.A. & Schaumberg, D.A. (2007). Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol 143, 409–415.Google Scholar
Moss, S.E., Klein, R. & Klein, B.E. (2004). Incidence of dry eye in an older population. Arch Ophthalmol 122, 369–373.Google Scholar
Nagatake, T., Fukuyama, S., Kim, D.Y., Goda, K., Igarashi, O., Stao, S., Nochi, T., Sagara, H., Yokota, Y., Jetten, A.M., Kaisho, T., Akira, S., Mimuro, H., Sasakawa, C., Fukui, Y., Fujihashi, K., Akiyama, T., Inoue, J., Penninger, J.M., Kunisawa, J. & Kiyono, H. (2009). Id2-, RORgammat-, and LTbetaR-independent initiation of lymphoid organogenesis in ocular immunity. J Exp Med 206, 2351–2364.Google Scholar
Oh, S.Y., Kim, NY, Oh, D.H., Bang, S.M., Choi, Y.J., Lee, J.Y., Lee, K.W., Yoon, H.I., Yang, H.C., Paik, J.H., Lee, D.H. & Jung, H.C. (2015). Concurrent gastric and pulmonary mucosa-associated lymphoid tissue lymphomas with pre-existing intrinsic chronic inflammation: A case report and a review of the literature. Gut Liver 9, 424–429.Google Scholar
Osterlind, G. (1944). An investigation into the presence of lymphatic tissue in the human conjunctiva, and its biological and clinical importance. Acta Ophthalmol 23, 1–79.Google Scholar
Paulsen, F.P., Schaudig, U. & Thale, A.B. (2003). Drainage of tears: Impact on the ocular surface and lacrimal system. Ocul Surf 1, 180–191.Google Scholar
Pauly, A., Labbè, A., Baudouin, C., Liang, H., Warnet, J.M. & Brignole-Baudouin, F. (2008). In vivo confocal microscopic grading system for standardized corneal evaluation: Application to toxic-induced damage in rat. Curr Eye Res 33, 826–838.Google Scholar
Pflugfelder, S.C., Jones, D., Ji, Z., Afonso, A. & Monroy, D. (1999). Altered cytokine balance in the tear fluid and conjunctiva of patients with Sjogren’s syndrome keratoconjunctivitis sicca. Curr Eye Res 19, 201–211.Google Scholar
Pieragostino, D., Agnifili, L., Fasanella, V., D’Aguanno, S., Mastropasqua, R., Di Ilio, C., Sacchetta, P., Urbani, A. & Del Boccio, P. (2013). Shotgun proteomics reveals specific modulated protein patterns in tears of patients with primary open angle glaucoma naïve to therapy. Mol Biosyst 9, 1108–1116.Google Scholar
Pieragostino, D., Bucci, S., Agnifili, L., Fasanella, V., D’Aguanno, S., Mastropasqua, A., Ciancaglini, M., Mastropasqua, L., Di Ilio, C., Sacchetta, P., Urbani, A. & Del Boccio, P. (2012). Differential protein expression in tears of patients with primary open angle and pseudoexfoliative glaucoma. Mol Biosyst 8, 1017–1028.Google Scholar
Pisella, P.J., Pouliquen, P. & Baudouin, C. (2002). Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 86, 418–423.CrossRefGoogle ScholarPubMed
Quigley, H.A. & Broman, A.T. (2006). The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90, 262–267.CrossRefGoogle ScholarPubMed
Schaumberg, D.A., Nichols, J.J., Papas, E.B., Tong, L., Uchino, M. & Nichols, K.K. (2011). The international workshop on meibomian gland dysfunction: Report of the subcommittee on the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci 52, 1994–2005.Google Scholar
Schmucker, D.L., Owen, R.L., Outenreath, R. & Thoreux, K. (2003). Basis for the age-related decline in intestinal mucosal immunity. Clin Dev Immunol 10, 167–172.Google Scholar
Sherwood, M.B., Grierson, I., Millar, L. & Hitchings, R.A. (1989). Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon’s capsule in glaucomatous patients. Ophthalmology 96, 327–335.Google Scholar
Siebelmann, S., Gehlsen, U., Hüttmann, G., Knop, N., Bolke, T., Gebert, A., Stern, M.E., Niederkorn, J.Y. & Steven, P. (2013). Development, alteration and real time dynamics of conjunctiva-associated lymphoid tissue. PLoS One 8, e82355.Google Scholar
Sminia, T., Janse, E.M. & Plesch, B.E. (1983). Ontogeny of Peyer’s patches of the rat. Anat Rec 207, 309–316.Google Scholar
Smith, J.A., Albeitz, J., Begley, C., Caffery, B., Nichols, K., Schaumberg, D. & Schein, O. (2007). The epidemiology of dry eye disease: Report of the Epidemiology Subcommittee of the International Dry Eye WorkShop. Ocul Surf 5, 93–107.Google Scholar
Stern, M.E., Gao, J., Schwalb, T.A., Ngo, M., Tieu, D.D., Chan, C., Reis, B.L., Whitcup, S.M., Thompson, D. & Smith, J.A. (2002). Conjunctival T-cell subpopulations in Sjogren’s and non-Sjogren’s patients with dry eye. Invest Ophthalmol Vis Sci 43, 2609–2614.Google Scholar
Stern, M.E., Siemasko, K.F., Gao, J., Calonge, M., Niederkorn, J.Y. & Pflugfelder, S.C. (2005). Evaluation of ocular surface inflammation in the presence of dry eye and allergic conjunctival disease. Ocul Surf 3, S161–S164.Google Scholar
Steven, P. & Gebert, A. (2009). Conjunctiva-associated lymphoid tissue – current knowledge, animal models and experimental prospects, should be cited and discussed. Ophthalmic Res 42, 2–8.Google Scholar
Steven, P., Rupp, J., Hüttmann, G., Knop, N., Lensing, C., Laqua, H. & Gebert, A. (2008). Experimental induction and three-dimensional two-photon imaging of conjunctiva-associated lymphoid tissue. Invest Ophthalmol Vis Sci 49, 1512–1517.Google Scholar
Stevenson, W., Chauhan, S.K. & Dana, R. (2012). Dry eye disease: An immune-mediated ocular surface disorder. Arch Ophthalmol 130, 90–100.Google Scholar
Uchino, M., Nishiwaki, Y., Michikawa, T., Shirakawa, K., Kuwahara, E., Yamada, M., Dogru, M., Schaumberg, D.A., Kawakita, T., Takebayashi, T. & Tsubota, K. (2011). Prevalence and risk factors of dry eye disease in Japan: Koumi study. Ophthalmology 118, 2361–2367.Google Scholar
Ueta, M. & Kinoshita, S. (2012). Ocular surface inflammation is regulated by innate immunity. Prog Retin Eye Res 31, 551–575.Google Scholar
Villani, E., Baudouin, C., Efron, N., Hamrah, P., Kojima, T., Patel, S.V., Pflugfelder, S.C., Zhivov, A. & Dogru, M. (2013a). In vivo confocal microscopy of the ocular surface: From bench to bedside. Curr Eye Res 39, 213–231.Google Scholar
Villani, E., Beretta, S., De Capitani, M., Galimberti, D., Viola, F. & Ratiglia, R. (2011). In vivo confocal microscopy of meibomian glands in Sjögren’s syndrome. Invest Ophthalmol Vis Sci 52, 933–939.Google Scholar
Villani, E., Galimberti, D., Viola, F., Mapelli, C. & Ratiglia, R. (2007). The cornea in Sjogren’s syndrome: An in vivo confocal study. Invest Ophthalmol Vis Sci 48, 2017–2022.Google Scholar
Villani, E., Magnani, F., Viola, F., Santaniello, A., Scorza, R., Nucci, P. & Ratiglia, R. (2013b). In vivo confocal evaluation of the ocular surface morpho-functional unit in dry eye. Optom Vis Sci 90, 576–586.Google Scholar
Villani, E., Mantelli, F. & Nucci, P. (2013c). In-vivo confocal microscopy of the ocular surface: Ocular allergy and dry eye. Curr Opin Allergy Clin Immunol 13, 569–576.Google Scholar
Wakamatsu, T.H., Okada, N., Kojima, T., Matsumoto, Y., Ibrahim, O.M.A., Dogru, M., Adan, E.S., Fugakawa, K., Katakami, C., Tsubota, K., Shimazaki, J. & Fujishima, H. (2009). Evaluation of conjunctival inflammatory status by confocal scanning laser microscopy and conjunctival brush cytology in patients with atopic keratoconjunctivitis (AKC). Mol Vis 15, 1611–1619.Google Scholar
Wan, K.H., Chen, L.J., Rong, S.S., Pang, C.P. & Young, A.L. (2013). Topical cyclosporine in the treatment of allergic conjunctivitis: A meta-analysis. Ophthalmology 120, 2197–2203.CrossRefGoogle ScholarPubMed
Williams, D.E., Nguyen, K.D., Shapourifar-Tehrani, S., Kitada, S. & Lee, D.A. (1992). Effects of timolol, betaxolol, and levobunolol on human Tenon’s fibroblasts in tissue culture. Invest Ophthalmol Vis Sci 33, 2233–2241.Google Scholar
Willis, C.M., Stephens, C.J. & Wilkinson, J.D. (1990). Differential effects of structurally unrelated chemical irritants on the density and morphology of epidermal CD1+ cells. J Invest Dermatol 95, 711–716.Google Scholar
Zhang, Y., Chen, H. & Wu, X. (2012). Prevalence and risk factors associated with dry eye syndrome among senior high school students in a county of Shandong province, China. Ophthalmic Epidemiol 19, 226–230.CrossRefGoogle Scholar
Zhivov, A., Stachs, O., Kraak, R., Stave, J. & Guthoff, R.F. (2006). In vivo confocal microscopy of the ocular surface. Ocul Surf 4, 81–93.Google Scholar