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Age-related Autoimmune Changes in Lacrimal Glands

  • Rodrigo G. de Souza (University of Sao Paulo) ;
  • Cintia S. de Paiva (University of Sao Paulo) ;
  • Milton R. Alves (University of Sao Paulo)
  • Received : 2018.12.07
  • Accepted : 2019.02.11
  • Published : 2019.02.28
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Abstract

Aging is a complex process associated with dysregulation of the immune system and low levels of inflammation, often associated with the onset of many pathologies. The lacrimal gland (LG) plays a vital role in the maintenance of ocular physiology and changes related to aging directly affect eye diseases. The dysregulation of the immune system in aging leads to quantitative and qualitative changes in antibodies and cytokines. While there is a gradual decline of the immune system, there is an increase in autoimmunity, with a reciprocal pathway between low levels of inflammation and aging mechanisms. Elderly C57BL/6J mice spontaneously show LGs infiltration that is characterized by Th1 but not Th17 cells. The aging of the LG is related to functional alterations, reduced innervation and decreased secretory activities. Lymphocytic infiltration, destruction, and atrophy of glandular parenchyma, ductal dilatation, and secretion of inflammatory mediators modify the volume and composition of tears. Oxidative stress, the capacity to metabolize and eliminate toxic substances decreased in aging, is also associated with the reduction of LG functionality and the pathogenesis of autoimmune diseases. Although further studies are required for a better understanding of autoimmunity and aging of the LG, we described anatomic and immunology aspects that have been described so far.

Keywords

Acknowledgement

This work was supported by the NIH EY026893 (C.S.D.P.), NIH EY-002520 (core grant for Vision Research Department of Ophthalmology), NIH NCI P30CA125123 (Pathology & Histology Core), Research to Prevent Blindness (Department of Ophthalmology), The Oshman Foundation, William Stamps Farish Fund, The Hamill Foundation, The Sid Richardson Foundation. We thank Leiqi Zhang for expert management of the aged C57BL/6J colony and Ralph Nichols for the preparation of electron microscopy specimens.

References

  1. Aunan JR, Watson MM, Hagland HR, Soreide K. Molecular and biological hallmarks of ageing. Br J Surg 2016;103:e29-e46. https://doi.org/10.1002/bjs.10053
  2. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244-254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x
  3. Rink L, Cakman I, Kirchner H. Altered cytokine production in the elderly. Mech Ageing Dev 1998;102:199-209. https://doi.org/10.1016/S0047-6374(97)00153-X
  4. Bruunsgaard H, Andersen-Ranberg K, Hjelmborg J, Pedersen BK, Jeune B. Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med 2003;115:278-283. https://doi.org/10.1016/S0002-9343(03)00329-2
  5. Nusser A, Nuber N, Wirz OF, Rolink H, Andersson J, Rolink A. The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4+ T-cell compartment. Eur J Immunol 2014;44:2893-2902. https://doi.org/10.1002/eji.201344408
  6. Ghia P, Melchers F, Rolink AG. Age-dependent changes in B lymphocyte development in man and mouse. Exp Gerontol 2000;35:159-165. https://doi.org/10.1016/S0531-5565(99)00095-9
  7. Haynes RJ, Tighe PJ, Dua HS. Antimicrobial defensin peptides of the human ocular surface. Br J Ophthalmol 1999;83:737-741. https://doi.org/10.1136/bjo.83.6.737
  8. Zhou L, Huang LQ, Beuerman RW, Grigg ME, Li SF, Chew FT, Ang L, Stern ME, Tan D. Proteomic analysis of human tears: defensin expression after ocular surface surgery. J Proteome Res 2004;3:410-416. https://doi.org/10.1021/pr034065n
  9. Rocha EM, Alves M, Rios JD, Dartt DA. The aging lacrimal gland: changes in structure and function. Ocul Surf 2008;6:162-174. https://doi.org/10.1016/S1542-0124(12)70177-5
  10. Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies. Arch Ophthalmol 2009;127:763-768. https://doi.org/10.1001/archophthalmol.2009.103
  11. Schein OD, Munoz B, Tielsch JM, Bandeen-Roche K, West S. Prevalence of dry eye among the elderly. Am J Ophthalmol 1997;124:723-728. https://doi.org/10.1016/S0002-9394(14)71688-5
  12. Micera A, Di Zazzo A, Esposito G, Longo R, Foulsham W, Sacco R, Sgrulletta R, Bonini S. Age-related changes to human tear composition. Invest Ophthalmol Vis Sci 2018;59:2024-2031. https://doi.org/10.1167/iovs.17-23358
  13. Patel R, Zhu M, Robertson DM. Shifting the IGF-axis: an age-related decline in human tear IGF-1 correlates with clinical signs of dry eye. Growth Horm IGF Res 2018;40:69-73. https://doi.org/10.1016/j.ghir.2018.02.001
  14. Nien CJ, Paugh JR, Massei S, Wahlert AJ, Kao WW, Jester JV. Age-related changes in the meibomian gland. Exp Eye Res 2009;89:1021-1027. https://doi.org/10.1016/j.exer.2009.08.013
  15. McElhaney JE, Effros RB. Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 2009;21:418-424. https://doi.org/10.1016/j.coi.2009.05.023
  16. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev 2005;205:158-169. https://doi.org/10.1111/j.0105-2896.2005.00256.x
  17. Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C. Immunosenescence and inflamm-aging as two sides of the same coin: Friends or foes? Front Immunol 2018;8:1960.
  18. Blomberg BB, Frasca D. Age effects on mouse and human B cells. Immunol Res 2013;57:354-360. https://doi.org/10.1007/s12026-013-8440-9
  19. Frasca D, Blomberg BB. Effects of aging on B cell function. Curr Opin Immunol 2009;21:425-430. https://doi.org/10.1016/j.coi.2009.06.001
  20. Pinti M, Appay V, Campisi J, Frasca D, Fulop T, Sauce D, Larbi A, Weinberger B, Cossarizza A. Aging of the immune system: focus on inflammation and vaccination. Eur J Immunol 2016;46:2286-2301. https://doi.org/10.1002/eji.201546178
  21. Fulop T, Larbi A, Douziech N, Levesque I, Varin A, Herbein G. Cytokine receptor signalling and aging. Mech Ageing Dev 2006;127:526-537. https://doi.org/10.1016/j.mad.2006.01.025
  22. Turner JE, Brum PC. Does regular exercise counter t cell immunosenescence reducing the risk of developing cancer and promoting successful treatment of malignancies? Oxid Med Cell Longev 2017;2017:4234765.
  23. Matejuk A, Hopke C, Vandenbark AA, Hurn PD, Offner H. Middle-age male mice have increased severity of experimental autoimmune encephalomyelitis and are unresponsive to testosterone therapy. J Immunol 2005;174:2387-2395. https://doi.org/10.4049/jimmunol.174.4.2387
  24. Harpaz I, Bhattacharya U, Elyahu Y, Strominger I, Monsonego A. Old mice accumulate activated effector CD4 T cells refractory to regulatory T cell-induced immunosuppression. Front Immunol 2017;8:283.
  25. van der Geest KS, Abdulahad WH, Tete SM, Lorencetti PG, Horst G, Bos NA, Kroesen BJ, Brouwer E, Boots AM. Aging disturbs the balance between effector and regulatory CD4+ T cells. Exp Gerontol 2014;60:190-196. https://doi.org/10.1016/j.exger.2014.11.005
  26. Tsaknaridis L, Spencer L, Culbertson N, Hicks K, LaTocha D, Chou YK, Whitham RH, Bakke A, Jones RE, Offner H, et al. Functional assay for human CD4+ CD25+ Treg cells reveals an age-dependent loss of suppressive activity. J Neurosci Res 2003;74:296-308. https://doi.org/10.1002/jnr.10766
  27. Coursey TG, Bian F, Zaheer M, Pflugfelder SC, Volpe EA, de Paiva CS. Age-related spontaneous lacrimal keratoconjunctivitis is accompanied by dysfunctional T regulatory cells. Mucosal Immunol 2017;10:743-756. https://doi.org/10.1038/mi.2016.83
  28. McClellan AJ, Volpe EA, Zhang X, Darlington GJ, Li DQ, Pflugfelder SC, de Paiva CS. Ocular surface disease and dacryoadenitis in aging C57BL/6 mice. Am J Pathol 2014;184:631-643. https://doi.org/10.1016/j.ajpath.2013.11.019
  29. Chauhan SK, El Annan J, Ecoiffier T, Goyal S, Zhang Q, Saban DR, Dana R. Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression. J Immunol 2009;182:1247-1252. https://doi.org/10.4049/jimmunol.182.3.1247
  30. Miller RA, Garcia G, Kirk CJ, Witkowski JM. Early activation defects in T lymphocytes from aged mice. Immunol Rev 1997;160:79-90. https://doi.org/10.1111/j.1600-065X.1997.tb01029.x
  31. Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol 2004;5:133-139. https://doi.org/10.1038/ni1033
  32. Kolar GR, Mehta D, Wilson PC, Capra JD. Diversity of the Ig repertoire is maintained with age in spite of reduced germinal centre cells in human tonsil lymphoid tissue. Scand J Immunol 2006;64:314-324. https://doi.org/10.1111/j.1365-3083.2006.01817.x
  33. Banerjee M, Mehr R, Belelovsky A, Spencer J, Dunn-Walters DK. Age- and tissue-specific differences in human germinal center B cell selection revealed by analysis of IgVH gene hypermutation and lineage trees. Eur J Immunol 2002;32:1947-1957. https://doi.org/10.1002/1521-4141(200207)32:7<1947::AID-IMMU1947>3.0.CO;2-1
  34. Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R, Kondeatis E, Nilsson BO, Wikby A, Kipling D, Dunn-Walters DK. B-cell diversity decreases in old age and is correlated with poor health status. Aging Cell 2009;8:18-25. https://doi.org/10.1111/j.1474-9726.2008.00443.x
  35. Grubeck-Loebenstein B, Della Bella S, Iorio AM, Michel JP, Pawelec G, Solana R. Immunosenescence and vaccine failure in the elderly. Aging Clin Exp Res 2009;21:201-209. https://doi.org/10.1007/BF03324904
  36. Nobrega A, Haury M, Gueret R, Coutinho A, Weksler ME. The age-associated increase in autoreactive immunoglobulins reflects a quantitative increase in specificities detectable at lower concentrations in young mice. Scand J Immunol 1996;44:437-443. https://doi.org/10.1046/j.1365-3083.1996.d01-335.x
  37. Mariani E, Pulsatelli L, Neri S, Dolzani P, Meneghetti A, Silvestri T, Ravaglia G, Forti P, Cattini L, Facchini A. RANTES and MIP-1alpha production by T lymphocytes, monocytes and NK cells from nonagenarian subjects. Exp Gerontol 2002;37:219-226. https://doi.org/10.1016/S0531-5565(01)00187-5
  38. Ferrucci L, Harris TB, Guralnik JM, Tracy RP, Corti MC, Cohen HJ, Penninx B, Pahor M, Wallace R, Havlik RJ. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc 1999;47:639-646. https://doi.org/10.1111/j.1532-5415.1999.tb01583.x
  39. Bruunsgaard H, Ladelund S, Pedersen AN, Schroll M, Jorgensen T, Pedersen BK. Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people. Clin Exp Immunol 2003;132:24-31. https://doi.org/10.1046/j.1365-2249.2003.02137.x
  40. Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, Knop E, Markoulli M, Ogawa Y, Perez V, et al. TFOS DEWS II pathophysiology report. Ocul Surf 2017;15:438-510. https://doi.org/10.1016/j.jtos.2017.05.011
  41. Shiboski SC, Shiboski CH, Criswell L, Baer A, Challacombe S, Lanfranchi H, Schiodt M, Umehara H, Vivino F, Zhao Y, et al. American College of Rheumatology classification criteria for Sjogren's syndrome: a data-driven, expert consensus approach in the Sjogren's International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475-487. https://doi.org/10.1002/acr.21591
  42. Stern ME, Gao J, Schwalb TA, Ngo M, Tieu DD, Chan CC, Reis BL, Whitcup SM, Thompson D, Smith JA. Conjunctival T-cell subpopulations in Sjogren's and non-Sjogren's patients with dry eye. Invest Ophthalmol Vis Sci 2002;43:2609-2614.
  43. Pflugfelder SC, De Paiva CS, Moore QL, Volpe EA, Li DQ, Gumus K, Zaheer ML, Corrales RM. Aqueous tear deficiency increases conjunctival interferon-γ (IFN-γ) expression and goblet cell loss. Invest Ophthalmol Vis Sci 2015;56:7545-7550. https://doi.org/10.1167/iovs.15-17627
  44. Pisella PJ, Brignole F, Debbasch C, Lozato PA, Creuzot-Garcher C, Bara J, Saiag P, Warnet JM, Baudouin C. Flow cytometric analysis of conjunctival epithelium in ocular rosacea and keratoconjunctivitis sicca. Ophthalmology 2000;107:1841-1849. https://doi.org/10.1016/S0161-6420(00)00347-X
  45. Brignole F, Pisella PJ, Goldschild M, De Saint Jean M, Goguel A, Baudouin C. Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes. Invest Ophthalmol Vis Sci 2000;41:1356-1363.
  46. Baudouin C, Brignole F, Pisella PJ, De Jean MS, Goguel A. Flow cytometric analysis of the inflammatory marker HLA DR in dry eye syndrome: results from 12 months of randomized treatment with topical cyclosporin A. Adv Exp Med Biol 2002;506:761-769. https://doi.org/10.1007/978-1-4615-0717-8_107
  47. Mircheff AK, Wang Y, Jean MS, Ding C, Trousdale MD, Hamm-Alvarez SF, Schechter JE. Mucosal immunity and self-tolerance in the ocular surface system. Ocul Surf 2005;3:182-192. https://doi.org/10.1016/S1542-0124(12)70204-5
  48. Giefing-Kroll C, Berger P, Lepperdinger G, Grubeck-Loebenstein B. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell 2015;14:309-321. https://doi.org/10.1111/acel.12326
  49. Schein OD, Hochberg MC, Munoz B, Tielsch JM, Bandeen-Roche K, Provost T, Anhalt GJ, West S. Dry eye and dry mouth in the elderly: a population-based assessment. Arch Intern Med 1999;159:1359-1363. https://doi.org/10.1001/archinte.159.12.1359
  50. Zhu ML, Bakhru P, Conley B, Nelson JS, Free M, Martin A, Starmer J, Wilson EM, Su MA. Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator. Nat Commun 2016;7:11350.
  51. Sullivan DA, Wickham LA, Rocha EM, Kelleher RS, da Silveira LA, Toda I. Influence of gender, sex steroid hormones, and the hypothalamic-pituitary axis on the structure and function of the lacrimal gland. Adv Exp Med Biol 1998;438:11-42. https://doi.org/10.1007/978-1-4615-5359-5_2
  52. Voskuhl R. Sex differences in autoimmune diseases. Biol Sex Differ 2011;2:1.
  53. Nagele EP, Han M, Acharya NK, DeMarshall C, Kosciuk MC, Nagele RG. Natural IgG autoantibodies are abundant and ubiquitous in human sera, and their number is influenced by age, gender, and disease. PLoS One 2013;8:e60726.
  54. Tzioufas AG, Tatouli IP, Moutsopoulos HM. Autoantibodies in Sjogren's syndrome: clinical presentation and regulatory mechanisms. Presse Med 2012;41:e451-e460. https://doi.org/10.1016/j.lpm.2012.05.022
  55. Voulgarelis M, Ziakas PD, Papageorgiou A, Baimpa E, Tzioufas AG, Moutsopoulos HM. Prognosis and outcome of non-Hodgkin lymphoma in primary Sjogren syndrome. Medicine (Baltimore) 2012;91:1-9. https://doi.org/10.1097/MD.0b013e31824125e4
  56. Volpe EA, Henriksson JT, Wang C, Barbosa FL, Zaheer M, Zhang X, Pflugfelder SC, de Paiva CS. Interferon-gamma deficiency protects against aging-related goblet cell loss. Oncotarget 2016;7:64605-64614. https://doi.org/10.18632/oncotarget.11872
  57. Parfitt GJ, Brown DJ, Jester JV. Transcriptome analysis of aging mouse meibomian glands. Mol Vis 2016;22:518-527.
  58. Obata H, Yamamoto S, Horiuchi H, Machinami R. Histopathologic study of human lacrimal gland. Statistical analysis with special reference to aging. Ophthalmology 1995;102:678-686. https://doi.org/10.1016/S0161-6420(95)30971-2
  59. Damato BE, Allan D, Murray SB, Lee WR. Senile atrophy of the human lacrimal gland: the contribution of chronic inflammatory disease. Br J Ophthalmol 1984;68:674-680. https://doi.org/10.1136/bjo.68.9.674
  60. Draper CE, Adeghate EA, Singh J, Pallot DJ. Evidence to suggest morphological and physiological alterations of lacrimal gland acini with ageing. Exp Eye Res 1999;68:265-276. https://doi.org/10.1006/exer.1998.0605
  61. El-Fadaly AB, El-Shaarawy EA, Rizk AA, Nasralla MM, Shuaib DM. Age-related alterations in the lacrimal gland of adult albino rat: a light and electron microscopic study. Ann Anat 2014;196:336-351. https://doi.org/10.1016/j.aanat.2014.06.005
  62. Rattan SI, Keeler KD, Buchanan JH, Holliday R. Autofluorescence as an index of ageing in human fibroblasts in culture. Biosci Rep 1982;2:561-567. https://doi.org/10.1007/BF01314216
  63. Seehafer SS, Pearce DA. You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiol Aging 2006;27:576-588. https://doi.org/10.1016/j.neurobiolaging.2005.12.006
  64. Rios JD, Horikawa Y, Chen LL, Kublin CL, Hodges RR, Dartt DA, Zoukhri D. Age-dependent alterations in mouse exorbital lacrimal gland structure, innervation and secretory response. Exp Eye Res 2005;80:477-491. https://doi.org/10.1016/j.exer.2004.10.012
  65. Zoukhri D, Macari E, Kublin CL. A single injection of interleukin-1 induces reversible aqueous-tear deficiency, lacrimal gland inflammation, and acinar and ductal cell proliferation. Exp Eye Res 2007;84:894-904. https://doi.org/10.1016/j.exer.2007.01.015
  66. Draper CE, Adeghate E, Lawrence PA, Pallot DJ, Garner A, Singh J. Age-related changes in morphology and secretory responses of male rat lacrimal gland. J Auton Nerv Syst 1998;69:173-183. https://doi.org/10.1016/S0165-1838(98)00026-5
  67. Marco B, Alessandro R, Philippe F, Fabio B, Paolo R, Giulio F. The effect of aging on nerve morphology and substance p expression in mouse and human corneas. Invest Ophthalmol Vis Sci 2018;59:5329-5335. https://doi.org/10.1167/iovs.18-24707
  68. Stepp MA, Pal-Ghosh S, Tadvalkar G, Williams A, Pflugfelder SC, de Paiva CS. Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice. Exp Eye Res 2018;169:91-98. https://doi.org/10.1016/j.exer.2018.01.024
  69. Bian F, Xiao Y, Barbosa FL, de Souza RG, Hernandez H, Yu Z, Pflugfelder SC, de Paiva CS. Age-associated antigen-presenting cell alterations promote dry-eye inducing Th1 cells. Mucosal Immunol 2019. doi: 10.1038/s41385-018-0127-z.
  70. Daniels PJ, Gustafson SA, French D, Wang Y, DePond W, McArthur CP. Interferon-mediated block in cell cycle and altered integrin expression in a differentiated salivary gland cell line (HSG) cultured on Matrigel. J Interferon Cytokine Res 2000;20:1101-1109. https://doi.org/10.1089/107999000750053771
  71. Hall JC, Casciola-Rosen L, Berger AE, Kapsogeorgou EK, Cheadle C, Tzioufas AG, Baer AN, Rosen A. Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. Proc Natl Acad Sci U S A 2012;109:17609-17614. https://doi.org/10.1073/pnas.1209724109
  72. Garcia-Posadas L, Hodges RR, Li D, Shatos MA, Storr-Paulsen T, Diebold Y, Dartt DA. Interaction of IFN-γ with cholinergic agonists to modulate rat and human goblet cell function. Mucosal Immunol 2016;9:206-217. https://doi.org/10.1038/mi.2015.53
  73. De Paiva CS, Villarreal AL, Corrales RM, Rahman HT, Chang VY, Farley WJ, Stern ME, Niederkorn JY, Li DQ, Pflugfelder SC. Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma. Invest Ophthalmol Vis Sci 2007;48:2553-2560. https://doi.org/10.1167/iovs.07-0069
  74. Pitcher JD 3rd, De Paiva CS, Pelegrino FS, McClellan AJ, Raince JK, Pangelinan SB, Rahimy E, Farley WJ, Stern ME, Li DQ, et al. Pharmacological cholinergic blockade stimulates inflammatory cytokine production and lymphocytic infiltration in the mouse lacrimal gland. Invest Ophthalmol Vis Sci 2011;52:3221-3227. https://doi.org/10.1167/iovs.09-4212
  75. Xiao B, Wang Y, Reinach PS, Ren Y, Li J, Hua S, Lu H, Chen W. Dynamic ocular surface and lacrimal gland changes induced in experimental murine dry eye. PLoS One 2015;10:e0115333.
  76. Bacman S, Perez Leiros C, Sterin-Borda L, Hubscher O, Arana R, Borda E. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjogren's syndrome. Invest Ophthalmol Vis Sci 1998;39:151-156.
  77. Bluestone R, Easty DL, Goldberg LS, Jones BR, Pettit TH. Lacrimal immunoglobulins and complement quantified by counter-immunoelectrophoresis. Br J Ophthalmol 1975;59:279-281. https://doi.org/10.1136/bjo.59.5.279
  78. Sullivan DA, Hann LE. Hormonal influence on the secretory immune system of the eye: endocrine impact on the lacrimal gland accumulation and secretion of IgA and IgG. J Steroid Biochem 1989;34:253-262. https://doi.org/10.1016/0022-4731(89)90089-7
  79. You IC, Bian F, Volpe EA, de Paiva CS, Pflugfelder SC. Age-related conjunctival disease in the C57BL/6. NOD-Aec1Aec2 mouse model of Sjogren syndrome develops independent of lacrimal dysfunction. Invest Ophthalmol Vis Sci 2015;56:2224-2233. https://doi.org/10.1167/iovs.14-15668
  80. Sullivan DA, Hann LE, Yee L, Allansmith MR. Age- and gender-related influence on the lacrimal gland and tears. Acta Ophthalmol (Copenh) 1990;68:188-194. https://doi.org/10.1111/j.1755-3768.1990.tb01902.x
  81. Marko CK, Menon BB, Chen G, Whitsett JA, Clevers H, Gipson IK. Spdef null mice lack conjunctival goblet cells and provide a model of dry eye. Am J Pathol 2013;183:35-48.  https://doi.org/10.1016/j.ajpath.2013.03.017
  82. Marcozzi G, Liberati V, Madia F, Centofanti M, de Feo G. Age- and gender-related differences in human lacrimal fluid peroxidase activity. Ophthalmologica 2003;217:294-297. https://doi.org/10.1159/000070638
  83. Nava A, Barton K, Monroy DC, Pflugfelder SC. The effects of age, gender, and fluid dynamics on the concentration of tear film epidermal growth factor. Cornea 1997;16:430-438. https://doi.org/10.1097/00003226-199707000-00010
  84. Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol 2009;147:198-205. https://doi.org/10.1016/j.ajo.2008.08.032
  85. Batista TM, Tomiyoshi LM, Dias AC, Roma LP, Modulo CM, Malki LT, Filho EB, Deminice R, Jordao AA Jr, Cunha DA, et al. Age-dependent changes in rat lacrimal gland anti-oxidant and vesicular related protein expression profiles. Mol Vis 2012;18:194-202.
  86. Benlloch-Navarro S, Franco I, Sanchez-Vallejo V, Silvestre D, Romero FJ, Miranda M. Lipid peroxidation is increased in tears from the elderly. Exp Eye Res 2013;115:199-205. https://doi.org/10.1016/j.exer.2013.07.011
  87. Chung HY, Lee EK, Choi YJ, Kim JM, Kim DH, Zou Y, Kim CH, Lee J, Kim HS, Kim ND, et al. Molecular inflammation as an underlying mechanism of the aging process and age-related diseases. J Dent Res 2011;90:830-840. https://doi.org/10.1177/0022034510387794
  88. Furman D, Chang J, Lartigue L, Bolen CR, Haddad F, Gaudilliere B, Ganio EA, Fragiadakis GK, Spitzer MH, Douchet I, et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat Med 2017;23:174-184. https://doi.org/10.1038/nm.4267
  89. Mangano EN, Litteljohn D, So R, Nelson E, Peters S, Bethune C, Bobyn J, Hayley S. Interferon-γ plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways. Neurobiol Aging 2012;33:1411-1426. https://doi.org/10.1016/j.neurobiolaging.2011.02.016
  90. Pinazo-Duran MD, Gallego-Pinazo R, Garcia-Medina JJ, Zanon-Moreno V, Nucci C, Dolz-Marco R, Martinez-Castillo S, Galbis-Estrada C, Marco-Ramirez C, Lopez-Galvez MI, et al. Oxidative stress and its downstream signaling in aging eyes. Clin Interv Aging 2014;9:637-652. https://doi.org/10.2147/CIA.S52662
  91. Choi W, Lian C, Ying L, Kim GE, You IC, Park SH, Yoon KC. Expression of lipid peroxidation markers in the tear film and ocular surface of patients with non-sjogren syndrome: potential biomarkers for dry eye disease. Curr Eye Res 2016;41:1143-1149. https://doi.org/10.3109/02713683.2015.1098707
  92. Deng R, Hua X, Li J, Chi W, Zhang Z, Lu F, Zhang L, Pflugfelder SC, Li DQ. Oxidative stress markers induced by hyperosmolarity in primary human corneal epithelial cells. PLoS One 2015;10:e0126561.
  93. Uchino Y, Kawakita T, Ishii T, Ishii N, Tsubota K. A new mouse model of dry eye disease: oxidative stress affects functional decline in the lacrimal gland. Cornea 2012;31 Suppl 1:S63-S67. https://doi.org/10.1097/ICO.0b013e31826a5de1
  94. Nooh HZ, El-Saify GH, Eldien NM. Neuroprotective effects of food restriction on autonomic innervation of the lacrimal gland in the rat. Ann Anat 2017;213:8-18. https://doi.org/10.1016/j.aanat.2017.05.001
  95. Sacca SC, Cutolo CA, Ferrari D, Corazza P, Traverso CE. The eye, oxidative damage and polyunsaturated fatty acids. Nutrients 2018;10:668.