Age-associated antigen-presenting cell alterations promote dry-eye inducing Th1 cells

Abstract

Aging is a significant risk factor for dry eye. Here we used a murine aged mode to investigate the effects of aging on antigen presenting cells (APCs) and generation of pathogenic T helper (Th)1. Our results showed that APCs from aged mice accumulate at the conjunctiva, have higher levels of co-activation marker CD86 and lower aldehyde dehydrogenase activity. Using topical ovalbumin peptide as a surrogate antigen, we observed an increased number of antigen-loaded APCs in the draining cervical lymph nodes in the aged group and loss of tight junction protein occludin in the conjunctiva. Aged cervical lymph nodes APCs showed a greater generation of Th1 cells than young APCs in antigen-presentation assays in vitro . Aged lacrimal glands and draining nodes showed an accumulation of IFN-γ producing CD4 + T cells, while Th17 cells were present only in aged draining nodes. There was also an age-related increase in CD4 + CXCR3 + IFN-γ + cells in the conjunctiva, nodes and lacrimal glands while CD4 + CCR6 + IL-17A + cells increased in the draining nodes of aged mice. Adoptive transfer of aged CD4 + CXCR3 + donor cells into young, naive immunodeficient recipients caused greater goblet cell loss than young CD4 + CXCR3 + cells. Our results demonstrate that age-associated changes in APCs are critical for the pathogenesis of age-related dry eye.

Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model

“…Given that the survival of immune cells may be affected differentially by the surrounding environment where the resident tissue cells provide survival factors, the shifting of IL-17 + cell or IFN γ + cell changes from 1 year of age to 2 years of age is presumably affected by the (1) pathogenic increase of autoimmunity, (2) age-dependent cellular senescence, or (3) different survival rates based on where they reside. The changes in effector T cells were accompanied by increased populations of activated antigen-presenting cells in the DLNs, suggesting that an increased presence of the antigen is crucial to age-related dry eye, as previously reported [4]. High levels of IFN-γ in the conjunctiva are known to impact the loss of goblet cells [5,12].…”

“…This finding may present different age-related changes of IL-17 + or IFNγ + cells, depending on the location. A previous report also showed that the percentage of IFNγ + cells increased across all tissues (conjunctiva, LG, and lymph nodes) at 24 months, while, on the contrary, the percentage of IL-17 + cells decreased in the LG and conjunctiva, unlike in the lymph nodes, at 24 months [4]. A healthy human study has demonstrated that age deeply impacts the contraction of CD4 + IL-17 + cell populations in peripheral blood, while the population of CD4 + IFNγ + cells are relatively maintained, regardless of age [13].…”

“…The aging-dependent changes in the ocular surface with DED are related to biological changes in the lacrimal glands (LGs) and meibomian glands (MGs). Although the pathogenesis of aging-associated DED has not yet been fully understood, recent studies have shown that autoimmune changes or oxidative stress in the LGs and acinar cell atrophies in the MGs occur with aging [4][5][6][7][8].…”

Disease-Specific Expression of Conjunctiva Associated Lymphoid Tissue (CALT) in Mouse Models of Dry Eye Disease and Ocular Allergy

“…To avoid excessive inflammation and tissue damage, immune tolerance mechanisms are crucial. Goblet cell-associated passage of antigens through the conjunctiva and controlled processing plays a crucial role in the induction of the local immune tolerance, but is disturbed in dry eye disease and age-related ocular surface inflammation [ 33 , 34 ]. Previously we demonstrated that particles and bacteria are also directly transported into CALT [ 10 , 11 ].…”

Parity Attenuates Intraepithelial Corneal Sensory Nerve Loss in Female Mice

“…However, it has become evident that both innate and adaptive immunity immune responses are involved [ 51 ]. Animal models have shown active participation of CD4+ T cells [ 52 , 53 ]. Although both sexes are affected, dry eye affects more women than men, and its prevalence increases sharply in women in the 5th decade [ 10 , 11 , 13 , 54 , 55 , 56 ] Because of its strong association in women and perimenopause, the influences of sex hormones have been postulated as playing roles in either promoting or ameliorating dry eye disease [ 57 , 58 , 59 ].…”