Age-related Autoimmune Changes in Lacrimal Glands

Rodrigo G. de Souza; Cintia S. de Paiva; Milton R. Alves

doi:10.4110/in.2018.19.e3

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Souza, Paiva, and Alves: Age-related Autoimmune Changes in Lacrimal Glands

Review Article

Immune Netw 2019;19(1):e3.

Published online: 4 February 2019

DOI: https://doi.org/10.4110/in.2018.19.e3

Age-related Autoimmune Changes in Lacrimal Glands

Rodrigo G. de Souza^1,², Cintia S. de Paiva^1,^2,^*, Milton R. Alves¹

¹University of Sao Paulo, Sao Paulo, Brazil

²Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA

^*Correspondence to Cintia S. de Paiva Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin Street, NC 505G, Houston, TX 77030, United States. E-mail: cintiadp@bcm.edu

Received 7 December 2018 Revised 10 February 2019 Accepted 11 February 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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: Aging, Dry eye, Lacrimal gland

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Figure 1.

Aging is accompanied by a systemic increase in Igs. Sera from 8-week-old (8W) and 15-month-old (15M) female C57BL/6J mice were collected by cardiac puncture upon euthanasia and Igs were measured using Luminex assay (Mann-Whitney U test).

Figure 2.

Pathological changes to the aged lacrimal gland (LG). (A) Macro images of 8-week (8W) and 24 months old (24M) female LG of C57BL/6 mice. Arrow heads indicate cysts. (B) Representative images of lacrimal gland sections stained with H&E. Areas of lymphocytic infiltration are demarcated in the 24M section. (C) Right and left LG wet weight/body ratio (n=19/group). One-way ANOVA followed by Sidak's multiple comparison test. * Asterisks indicate enlarged ducts.

Figure 3.

Transmission electron microscopic examination of lacrimal gland acinar of young (8W) and aged (24M) C57BL/6J female mice. Frequent marked structural changes in mitochondria (see insets) in aged mice were observed, including swelling and loss of cristae and disorganization. Increased number of mucous-containing granules were also observed (bar=04 µm). 8W, 8 weeks of age; 24M, 24 months of age.

Figure 4.

Lipofuscin and lipofuscin-like structures are increased in female aged C57BL/6J lacrimal gland. Paraffin-embedded lacrimal gland histologic sections were fixed in formalin and routinely processed in paraffin and stained with H&E. The same area was photographed with a color camera or with a fluorescent camera with the indicated filters. Autofluorescence in ducts is visible with the 488 and 594 filters, while distinct structures are autofluorescent with the 594 and CY5 filters. (bar=25 µm). 8W, 8 weeks of age; 24M, 24 months of age.

Table 1.

Tear parameters in young and aged female C57B/6J mice

Parameter/age	8W	24M	p value
Tear volume^* (µL) (n=8)	0.07±0.01	0.15±0.07	0.0005
Body weight (g) (n=8)	20.0±1.12	40.3±6.70	0.01
Tear volume/body weight^* (µL/g) (n=8)	0.0034±0.0007	0.0037±0.0010	0.65
Tear IgA^† (pg/ml, n=4–8)	1,237±1,279	9,731±4,099	0.0006
Tear IgM^† (pg/mL, n=4–8)	3.3±3.0	2,580±2,300	0.007
IgA/IgM ratio^† (n=4–8)	325.8±250.8	4.53±2.7	0.03

8W, 8 weeks of age; 24M, 24 months of age.* One sample equals mean the combined measurements from right and left eye from one mouse;

^† one sample equals tear washings pooled from the right and left eyes from ten mice (20 eyes = 1 sample; the 8W group had 8 samples while the aged had 4).

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