Dry Eyes? It May be Immune Infiltration in Aging Lacrimal Glands

In a new editorial, researchers from Baylor College of Medicine artfully discuss the immune system’s role in dry eye disease. 

The lacrimal gland, found in the upper outer part of the eye’s hollow area, is an important gland that makes tears to protect the eye from infections. It’s split into two parts: one near the inside of the eyelid that can be seen when the eyelid is flipped, and another part with ducts lower in the eye that connects to its counterpart. In their fully functioning status, these ducts release fluid onto the surface of the eye. As humans age (especially women), the lacrimal gland gradually becomes infiltrated by aberrant immune cells and can ultimately lead to an uncomfortable condition known as dry eye disease.

“Burning and redness in the eyes, grittiness and blurry vision make life miserable and currently, eye drops with a variety of lubricant components and in the most severe cases, immunosuppressors, are the only therapies approved for this disease.”

In a well-written new editorial paper, researchers Claudia M. Trujillo-Vargas and Cintia S. de Paiva from the Department of Ophthalmology at Baylor College of Medicine artfully discuss their recent studies which shed light on the immune system’s role in dry eye disease. On August 11, 2023, their editorial was published in Aging’s Volume 15, Issue 15, entitled, “Our search of immune invaders in the aged lacrimal gland.”

Editorial Summary

The authors write that their research group has been dedicated to investigating the changes that occur in the lacrimal gland due to aging and focus on immunopathological alterations. Due to limited human samples, their studies have centered on understanding the infiltration of lymphocytes, specifically B and T cells, in aged mice’s lacrimal glands. This infiltration has been linked to increased dysfunction of the ocular surface. 

“In the search of mechanisms that can counteract the effects of the overwhelming immune infiltration, we started characterizing one of the main players of immune tolerance, the thymic-derived T regulatory cells (Tregs).”

The researchers and their team have a particular interest in thymic-derived T regulatory cells (Tregs), which play a key role in immune tolerance. Paradoxically, in the aged glands, these Tregs, while exhibiting markers for their suppressive function, display heightened differentiation, infiltrate the tissue, produce inflammatory cytokines, and demonstrate impaired suppressive capabilities. When transferred to immunodeficient recipients, these dysfunctional Tregs replicate lacrimal gland pathology. 

Aged lacrimal glands contain highly differentiated CD4+ T cells of the Th1 and Th17 phenotypes, which exhibit exhaustion and immunopathological features. This environment hampers Tregs’ ability to suppress immune responses. There’s also an increase in naïve CD4+ T cells and IgD+ B cells, suggesting a unique environment for the recruitment of inexperienced immune cells in the gland.

Ectopic lymphoid structures, resembling those found in aged tissues, are observed in the lacrimal gland, potentially contributing to immune dysregulation. Despite the concept of immune cells being unwelcome invaders, the lacrimal gland relies on immune cell influx for surveillance purposes, as it is highly vascularized. Nonetheless, with age, immune cell infiltration intensifies, accompanied by fibrosis, duct issues and gland atrophy. Interestingly, antigen-presenting cells diminish, adding to the peculiar immune environment.

In their running analogy to the movie “Men in Black,” the researchers explain that they are seeking effective therapies, akin to the “noisy crickets,” to combat this pathological immune infiltration. They’re investigating differentially expressed genes in the aged gland, focusing on Tregs expressing Il1r2, CD81 and Tbx21, and B cells showing increased CD79a/b expression. The researchers are also exploring the gut microbiota’s role in ocular barrier disruption and dry eye disease in mice. This could lead to more cost-effective microbial treatments for dry eye disease in humans. However, the effectiveness of these therapies in impeding lymphocyte infiltration in aged lacrimal glands remains uncertain.

Conclusions & Future Directions

In conclusion, their editorial provides valuable insights into the role of the lacrimal gland in the immune system and how it could be used to develop new treatments for dry eyes and other age-related eye diseases. The authors’ research has shown that aged lacrimal glands are infiltrated not only by highly differentiated B but also T cells. This landscape is associated with increased ocular surface dysfunction. The authors suggest that this information could be used to develop new therapies for age-related eye diseases.

Considering the rising pollution and screen dependence in the past decade, the researchers predict an increase in severely damaged lacrimal glands in the elderly. This environment could foster the development of ectopic lymphoid structures, potentially leading to a higher prevalence of dry eye disease. As such, interventions will be required to mitigate the immune damage to the lacrimal gland. Ultimately, protecting the lacrimal glands from the consequences of immune dysregulation is a critical goal.

“Unquestionably, more than ‘fancy sunglasses’ would be needed to hinder the ‘carbonizing’ immune damage in the gland. Thus, Yes! We certainly need to protect our lacrimal glands from the scum of our own immune universe!”

Click here to read the full editorial published in Aging.

Aging is an open-access, traditional, peer-reviewed journal that has published high-impact papers in all fields of aging research since 2009. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

The Impact of Age, Sex, CMV, and Smoking on Circulating Immune Cells

In a new study, researchers investigated associations between circulating immune cells and age, sex, CMV infection, and smoking.

The Impact of Age, Sex, CMV, and Smoking on Circulating Immune Cells

As we age, our immune system undergoes changes that influence our susceptibility to various diseases. Certain factors, such as smoking, viruses, age, and sex can have differential impacts on our various circulating immune cells. How changes to these immune cells contribute to cardiovascular disease and other age-related diseases is not yet fully understood. More research is needed to fully understand the underlying mechanisms and implications. 

“Understanding the composition of circulating immune cells with aging and the underlying biologic mechanisms driving aging may provide molecular targets to slow the aging process and reduce age-related disease.”

In a new study, researchers Yuan Fang, Margaret F. Doyle, Jiachen Chen, Jesse Mez, Claudia L. Satizabal, Michael L. Alosco, Wei Qiao Qiu, Kathryn L. Lunetta, and Joanne M. Murabito from Boston University, Boston Medical Center, University of Vermont, and University of Texas Health Science Center aimed to characterize the circulating innate and adaptive immune system by profiling immune cell phenotypes from a community-based cohort. Their research paper was published in Aging’s Volume 15, Issue 10, on April 27, 2023, entitled, “Circulating immune cell phenotypes are associated with age, sex, CMV, and smoking status in the Framingham Heart Study offspring participants.”

“We hypothesize that we will identify immune cell phenotype and ARIP [age-related immune phenotype] measure associations with CMV serostatus, age, and sex, as well as associations with cardiovascular risk factors.”

The Study and Participant Characteristics

The Framingham Heart Study (FHS) is a community-based prospective cohort study that began in 1948. It initially recruited 5,209 primarily white American adults of European ancestry as the Original cohort. In 1971, the Offspring cohort was established, consisting of the children of the Original cohort and their spouses. The Offspring participants have been examined every 4-8 years since enrollment. 

For this study, 1,332 Offspring participants who attended exam seven (1998 to 2001) and had two or more vials of stored peripheral blood mononuclear cells (PBMCs) were identified. From this group, a study sample of 996 dementia-free individuals, aged 40 years and older, was selected. This cohort had a mean age of 62 years, with 52% representing males. All participants provided written informed consent, and the FHS exams were approved by the Institutional Review Board at Boston University Medical Center.

The research team used cryopreserved cell samples from the study participants to conduct comprehensive analyses of 116 circulating immune cell phenotypes, including subtypes of CD4 and CD8 T cells, B cells, NK cells, and monocytes. These subsets were further categorized based on specific surface markers to provide a detailed characterization of the immune cell populations.

The Results

Significant associations between circulating immune cell phenotypes and age, sex, a common virus, and smoking were revealed in this study. With advancing age, researchers saw a decline in the overall number of immune cells, as well as alterations in the distribution of different immune cell subsets. Notably, older individuals exhibited a higher proportion of memory T cells and a lower proportion of naive T cells, suggesting a shift towards a more experienced immune profile. Furthermore, females exhibited a higher abundance of immune cells compared to males, which may contribute to their generally stronger immune responses.

Cytomegalovirus (CMV), a common herpesvirus, can have a profound impact on the immune system. The study found that CMV seropositivity was associated with distinct alterations in immune cell phenotypes. CMV-positive individuals displayed higher numbers of late-stage differentiated effector memory T cells, which are indicative of previous exposure to CMV. This observation suggests that CMV infection contributes to the age-related changes in immune cell populations.

Smoking has long been recognized as a detrimental habit that affects overall health, including the immune system. This study uncovered compelling evidence linking smoking status to immune cell phenotypes. Smokers exhibited a higher proportion of pro-inflammatory immune cells, such as activated T cells and pro-inflammatory monocytes, while non-smokers had a higher proportion of regulatory T cells that help maintain immune balance. These findings emphasize the detrimental impact of smoking on immune cell profiles and further underscore the importance of smoking cessation.

“Importantly, we did not identify significant immune cell associations with other risk factors, such as body mass index, prevalent cardiovascular disease, hypertension or diabetes.”


“Our observations confirm and extend known associations of immune cell subtypes with CMV and age that show a shift from a naïve phenotype towards an exhausted phenotype. We report sex differences, with males exhibiting a more exhausted, cytotoxic landscape than females. We identified associations between CD8 exhausted cells and B cell subsets, but not overall B cells, with smoking status.” 

This research provides valuable insights into the relationship between circulating immune cell phenotypes and age, sex, CMV infection, and smoking status. In conclusion, the team did not find significant associations between these immune cells and cardiovascular risk factors. They did find some weak associations with cardiovascular disease, diabetes and hypertension. The findings contribute to our understanding of age-related changes in the immune system and highlight the impact of lifestyle factors on immune health. By unraveling the complex interplay between these variables, this study paves the way for future research on interventions and strategies to support healthy immune aging.

“While further studies in larger, more diverse sample[s] and more than one time point with immunophenotypic data are needed, this work will provide a valuable resource for future studies of the association of immune cell phenotypes and incident age-related disease.”

Click here to read the full research paper published by Aging.

Aging is an open-access, peer-reviewed journal that has been publishing high-impact papers in all fields of aging research since 2009. These papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.

Click here to subscribe to Aging publication updates.

For media inquiries, please contact [email protected].

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