Age-related Autoimmune Changes in Lacrimal Glands

다국어 초록 (Multilingual 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.

참고문헌 (Reference)

1 Seehafer SS, "You say lipofuscin, we say ceroid: defining autofluorescent storage material" 27 : 576-588, 2006

2 Parfitt GJ, "Transcriptome analysis of aging mouse meibomian glands" 22 : 518-527, 2016

3 Saccà SC, "The eye, oxidative damage and polyunsaturated fatty acids" 10 : 668-, 2018

4 Nava A, "The effects of age, gender, and fluid dynamics on the concentration of tear film epidermal growth factor" 16 : 430-438, 1997

5 Marco B, "The effect of aging on nerve morphology and substance p expression in mouse and human corneas" 59 : 5329-5335, 2018

6 Nusser A, "The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4+ T-cell compartment" 44 : 2893-2902, 2014

7 Rocha EM, "The aging lacrimal gland: changes in structure and function" 6 : 162-174, 2008

8 Nobrega A, "The age-associated increase in autoreactive immunoglobulins reflects a quantitative increase in specificities detectable at lower concentrations in young mice" 44 : 437-443, 1996

9 Lam H, "Tear cytokine profiles in dysfunctional tear syndrome" 147 : 198-205, 2009

10 Bron AJ, "TFOS DEWS II pathophysiology report" 15 : 438-510, 2017

11 Marko CK, "Spdef null mice lack conjunctival goblet cells and provide a model of dry eye" 183 : 35-48, 2013

12 Patel R, "Shifting the IGF-axis: an age-related decline in human tear IGF-1 correlates with clinical signs of dry eye" 40 : 69-73, 2018

13 Voskuhl R, "Sex differences in autoimmune diseases" 2 : 1-, 2011

14 Zhu ML, "Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator" 7 : 11350-, 2016

15 Ferrucci L, "Serum IL-6 level and the development of disability in older persons" 47 : 639-646, 1999

16 Damato BE, "Senile atrophy of the human lacrimal gland: the contribution of chronic inflammatory disease" 68 : 674-680, 1984

17 Stepp MA, "Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice" 169 : 91-98, 2018

18 Mariani E, "RANTES and MIP-1alpha production by T lymphocytes, monocytes and NK cells from nonagenarian subjects" 37 : 219-226, 2002

19 Zhou L, "Proteomic analysis of human tears: defensin expression after ocular surface surgery" 3 : 410-416, 2004

20 Voulgarelis M, "Prognosis and outcome of non-Hodgkin lymphoma in primary Sjögren syndrome" 91 : 1-9, 2012

21 Schaumberg DA, "Prevalence of dry eye disease among US men: estimates from the Physicians' Health Studies" 127 : 763-768, 2009

22 Schein OD, "Prevalence of dry eye among the elderly" 124 : 723-728, 1997

23 Bruunsgaard H, "Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people" 132 : 24-31, 2003

24 Hall JC, "Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases" 109 : 17609-17614, 2012

25 Pitcher JD 3rd, "Pharmacological cholinergic blockade stimulates inflammatory cytokine production and lymphocytic infiltration in the mouse lacrimal gland" 52 : 3221-3227, 2011

26 Deng R, "Oxidative stress markers induced by hyperosmolarity in primary human corneal epithelial cells" 10 : e0126561-, 2015

27 Pinazo-Durán MD, "Oxidative stress and its downstream signaling in aging eyes" 9 : 637-652, 2014

28 Harpaz I, "Old mice accumulate activated effector CD4 T cells refractory to regulatory T cell-induced immunosuppression" 8 : 283-, 2017

29 McClellan AJ, "Ocular surface disease and dacryoadenitis in aging C57BL/6 mice" 184 : 631-643, 2014

30 Nooh HZ, "Neuroprotective effects of food restriction on autonomic innervation of the lacrimal gland in the rat" 213 : 8-18, 2017

31 Nagele EP, "Natural IgG autoantibodies are abundant and ubiquitous in human sera, and their number is influenced by age, gender, and disease" 8 : e60726-, 2013

32 Mircheff AK, "Mucosal immunity and self-tolerance in the ocular surface system" 3 : 182-192, 2005

33 Chung HY, "Molecular inflammation as an underlying mechanism of the aging process and age-related diseases" 90 : 830-840, 2011

34 Aunan JR, "Molecular and biological hallmarks of ageing" 103 : e29-e46, 2016

35 Matejuk A, "Middle-age male mice have increased severity of experimental autoimmune encephalomyelitis and are unresponsive to testosterone therapy" 174 : 2387-2395, 2005

36 Benlloch-Navarro S, "Lipid peroxidation is increased in tears from the elderly" 115 : 199-205, 2013

37 Bluestone R, "Lacrimal immunoglobulins and complement quantified by counter-immunoelectrophoresis" 59 : 279-281, 1975

38 Mangano EN, "Interferon-γ plays a role in paraquat-induced neurodegeneration involving oxidative and proinflammatory pathways" 33 : 1411-1426, 2012

39 Daniels PJ, "Interferon-mediated block in cell cycle and altered integrin expression in a differentiated salivary gland cell line (HSG) cultured on Matrigel" 20 : 1101-1109, 2000

40 Volpe EA, "Interferon-gamma deficiency protects against aging-related goblet cell loss" 7 : 64605-64614, 2016

41 García-Posadas L, "Interaction of IFN-γ with cholinergic agonists to modulate rat and human goblet cell function" 9 : 206-217, 2016

42 Sullivan DA, "Influence of gender, sex steroid hormones, and the hypothalamic-pituitary axis on the structure and function of the lacrimal gland" 438 : 11-42, 1998

43 Franceschi C, "Inflamm-aging. An evolutionary perspective on immunosenescence" 908 : 244-254, 2000

44 McElhaney JE, "Immunosenescence: what does it mean to health outcomes in older adults?" 21 : 418-424, 2009

45 Grubeck-Loebenstein B, "Immunosenescence and vaccine failure in the elderly" 21 : 201-209, 2009

46 ulop T, "Immunosenescence and inflamm-aging as two sides of the same coin: Friends or foes" 8 : 1960-, 2018

47 Giefing-Kröll C, "How sex and age affect immune responses, susceptibility to infections, and response to vaccination" 14 : 309-321, 2015

48 Sullivan DA, "Hormonal influence on the secretory immune system of the eye: endocrine impact on the lacrimal gland accumulation and secretion of IgA and IgG" 34 : 253-262, 1989

49 Obata H, "Histopathologic study of human lacrimal gland. Statistical analysis with special reference to aging" 102 : 678-686, 1995

50 Tsaknaridis L, "Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity" 74 : 296-308, 2003

51 Baudouin C, "Flow cytometric analysis of the inflammatory marker HLA DR in dry eye syndrome: results from 12 months of randomized treatment with topical cyclosporin A" 506 : 761-769, 2002

52 Brignole F, "Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes" 41 : 1356-1363, 2000

53 Pisella PJ, "Flow cytometric analysis of conjunctival epithelium in ocular rosacea and keratoconjunctivitis sicca" 107 : 1841-1849, 2000

54 Furman D, "Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states" 23 : 174-184, 2017

55 Choi W, "Expression of lipid peroxidation markers in the tear film and ocular surface of patients with non-sjogren syndrome: potential biomarkers for dry eye disease" 41 : 1143-1149, 2016

56 Draper CE, "Evidence to suggest morphological and physiological alterations of lacrimal gland acini with ageing" 68 : 265-276, 1999

57 Bruunsgaard H, "Elevated levels of tumor necrosis factor alpha and mortality in centenarians" 115 : 278-283, 2003

58 Frasca D, "Effects of aging on B cell function" 21 : 425-430, 2009

59 Miller RA, "Early activation defects in T lymphocytes from aged mice" 160 : 79-90, 1997

60 Xiao B, "Dynamic ocular surface and lacrimal gland changes induced in experimental murine dry eye" 10 : e0115333-, 2015

61 De Paiva CS, "Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma" 48 : 2553-2560, 2007

62 Schein OD, "Dry eye and dry mouth in the elderly: a population-based assessment" 159 : 1359-1363, 1999

63 Turner JE, "Does regular exercise counter t cell immunosenescence reducing the risk of developing cancer and promoting successful treatment of malignancies?" 2017 : 4234765-, 2017

64 Kolar GR, "Diversity of the Ig repertoire is maintained with age in spite of reduced germinal centre cells in human tonsil lymphoid tissue" 64 : 314-324, 2006

65 Fulop T, "Cytokine receptor signalling and aging" 127 : 526-537, 2006

66 Stern ME, "Conjunctival T-cell subpopulations in Sjögren's and non-Sjögren's patients with dry eye" 43 : 2609-2614, 2002

67 Vallejo AN, "CD28 extinction in human T cells: altered functions and the program of T-cell senescence" 205 : 158-169, 2005

68 Gibson KL, "B-cell diversity decreases in old age and is correlated with poor health status" 8 : 18-25, 2009

69 Chauhan SK, "Autoimmunity in dry eye is due to resistance of Th17 to Treg suppression" 182 : 1247-1252, 2009

70 Rattan SI, "Autofluorescence as an index of ageing in human fibroblasts in culture" 2 : 561-567, 1982

71 Tzioufas AG, "Autoantibodies in Sjögren's syndrome: clinical presentation and regulatory mechanisms" 41 : e451-e460, 2012

72 Bacman S, "Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjögren's syndrome" 39 : 151-156, 1998

73 Pflugfelder SC, "Aqueous tear deficiency increases conjunctival interferon-γ (IFN-γ) expression and goblet cell loss" 56 : 7545-7550, 2015

74 Haynes RJ, "Antimicrobial defensin peptides of the human ocular surface" 83 : 737-741, 1999

75 Shiboski SC, "American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort" 64 : 475-487, 2012

76 Rink L, "Altered cytokine production in the elderly" 102 : 199-209, 1998

77 Pinti M, "Aging of the immune system: focus on inflammation and vaccination" 46 : 2286-2301, 2016

78 van der Geest KS, "Aging disturbs the balance between effector and regulatory CD4+ T cells" 60 : 190-196, 2014

79 Coursey TG, "Age-related spontaneous lacrimal keratoconjunctivitis is accompanied by dysfunctional T regulatory cells" 10 : 743-756, 2017

80 You IC, "Age-related conjunctival disease in the C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren syndrome develops independent of lacrimal dysfunction" 56 : 2224-2233, 2015

81 Micera A, "Age-related changes to human tear composition" 59 : 2024-2031, 2018

82 Nien CJ, "Age-related changes in the meibomian gland" 89 : 1021-1027, 2009

83 Draper CE, "Age-related changes in morphology and secretory responses of male rat lacrimal gland" 69 : 173-183, 1998

84 Linton PJ, "Age-related changes in lymphocyte development and function" 5 : 133-139, 2004

85 El-Fadaly AB, "Age-related alterations in the lacrimal gland of adult albino rat: a light and electron microscopic study" 196 : 336-351, 2014

86 Batista TM, "Age-dependent changes in rat lacrimal gland anti-oxidant and vesicular related protein expression profiles" 18 : 194-202, 2012

87 Ghia P, "Age-dependent changes in B lymphocyte development in man and mouse" 35 : 159-165, 2000

88 Ríos JD, "Age-dependent alterations in mouse exorbital lacrimal gland structure, innervation and secretory response" 80 : 477-491, 2005

89 Fang Bian, "Age-associated antigen-presenting cell alterations promote dry-eye inducing Th1 cells" Springer Science and Business Media LLC 12 (12): 897-908, 2019

90 Banerjee M, "Age- and tissue-specific differences in human germinal center B cell selection revealed by analysis of IgVH gene hypermutation and lineage trees" 32 : 1947-1957, 2002

91 Sullivan DA, "Age- and gender-related influence on the lacrimal gland and tears" 68 : 188-194, 1990

92 Marcozzi G, "Age- and gender-related differences in human lacrimal fluid peroxidase activity" 217 : 294-297, 2003

93 Blomberg BB, "Age effects on mouse and human B cells" 57 : 354-360, 2013

94 Zoukhri D, "A single injection of interleukin-1 induces reversible aqueous-tear deficiency, lacrimal gland inflammation, and acinar and ductal cell proliferation" 84 : 894-904, 2007

95 Uchino Y, "A new mouse model of dry eye disease: oxidative stress affects functional decline in the lacrimal gland" 31 (31): S63-S67, 2012