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Meibomian gland dysfunction (MGD) is a leading cause of dry eye disease and one of the most common ophthalmic conditions encountered in eye clinics worldwide. These holocrine glands are situated in the eyelid, where they produce specialized lipids, or meibum, needed to lubricate the eye surface and slow tear film evaporation - functions which are critical to preserving high-resolution vision. MGD results in tear instability, rapid tear evaporation, changes in local microflora, and dry eye disease, amongst other pathological entities. While studies identifying the mechanisms of MGD have generally focused on gland obstruction, we now know that age is a major risk factor for MGD that is associated with abnormal cell differentiation and renewal. It is also now appreciated that immune-inflammatory disorders, such as certain autoimmune diseases and atopy, may trigger MGD, as demonstrated through a T cell-driven neutrophil response. Here, we independently discuss the underlying roles of gland and immune related factors in MGD, as well as the integration of these two distinct mechanisms into a unified perspective that may aid future studies. From this unique standpoint, we propose a revised model in which glandular dysfunction and immunopathogenic pathways are not primary versus secondary contributors in MGD, but are fluid, interactive, and dynamic, which we likened to the Yin and Yang of MGD., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The etiology of meibomian gland dysfunction (MGD) is incompletely understood, despite being a common ophthalmic condition and an area of unmet medical need. It is characterized by an insufficiency in glandular provision of specialized lipids (meibum) to the tear film and is a major cause of dry eye. Work in the allergic eye disease (AED) mouse model has revealed an immunopathogenic role in MGD causation, now raising interest in the applicability of immunomodulatory therapies. As such, we herein ask whether inhibition of lymphocyte function associated antigen (LFA)-1/intracellular adhesion molecules (ICAM)-1 signaling via topical lifitegrast administration has a therapeutic effect on MGD in AED mice., Methods: Mice were induced with AED by i.p. injection of ovalbumin (OVA) mixed with alum and pertussis toxin, followed 2 weeks later by once daily topical OVA challenges for 7 days. Mice were treated topically with 5% lifitegrast ophthalmic solution or vehicle (PBS) 30 min prior to challenge. We developed a clinical ranking method to assess MGD severity, and also scored clinical allergy. Conjunctivae and draining lymph nodes were collected for flow cytometry., Results: Topical lifitegrast significantly inhibited clinical MGD severity, which was associated with diminished pathogenic T H 17 cell and neutrophil numbers in the conjunctiva. No significant change in conjunctival T H 2 cells or eosinophils, and only marginal differences in ocular allergy were observed., Conclusions: In AED mice, lifitegrast inhibited MGD severity marked by a reduction in select immune populations in the conjunctiva. Our findings warrant future examination of lifitegrast in the treatment of patients with forms of MGD., (Copyright © 2021. Published by Elsevier Inc.)

Although sensory reinnervation occurs after injury in the peripheral nervous system, poor reinnervation in the elderly and those with diabetes often leads to pathology. Here we quantify sub-basal axon density in the central and peripheral mouse cornea over time after three different types of injury. The mouse cornea is highly innervated with a dense array of sub-basal nerves that form a spiral called the vortex at the corneal center or apex; these nerves are readily detected within flat mounted corneas. After anesthesia, corneal epithelial cells were removed using either a dulled blade or a rotating burr within an area demarcated centrally with a 1.5 mm trephine. A third wound type, superficial trephination, involved demarcating the area with the 1.5 mm trephine but not removing cells. By 7 days after superficial trephination, sub-basal axon density returns to control levels; by 28 days the vortex reforms. Although axon density is similar to control 14 days after dulled blade and rotating burr wounding, defects in axon morphology at the corneal apex remain. After 14 days, axons retract from the center leaving the sub-basal axon density reduced by 37.2 and 36.8% at 28 days after dulled blade and rotating burr wounding, respectively, compared with control. Assessment of inflammation using flow cytometry shows that persistent inflammation is not a factor in the incomplete reinnervation. Expression of mRNAs encoding 22 regeneration-associated genes involved in axon targeting assessed by QPCR reveals that netrin-1 and ephrin signaling are altered after wounding. Subpopulations of corneal epithelial basal cells at the corneal apex stop expressing ki67 as early as 7 days after injury and by 14 and 28 days after wounding, many of these basal cells undergo apoptosis and die. Although sub-basal axons are restored to their normal density and morphology after superficial trephination, sub-basal axon recovery is partial after debridement wounds. The increase in corneal epithelial basal cell apoptosis at the apex observed at 14 days after corneal debridement may destabilize newly reinnervated sub-basal axons and lead to their retraction toward the periphery.

Dendritic cells (DCs) are highly potent stimulators of the immune system, and their contribution as such to the pathogenesis of corneal and ocular surface inflammatory disease has been well established. These vigorous antigen-presenting cells are reliant upon their effective migration from peripheral tissues (e.g., those of the ocular surface) to the lymphoid organs, where immune responses are triggered and can then cause disease. The chemokine receptor CCR7 expressed on DCs has emerged as the master mediator of this highly complex migratory process, and thus it is important in causing corneal and ocular surface inflammation. Furthermore, CCR7 has received considerable attention as a potential therapeutic target, as topically instilled antagonists of this receptor are quite effective therapeutically in a mouse model of ocular allergy. These findings and more are reviewed in the current article. In addition, the understanding regarding CCR7 function in mice and humans, and the biology of DCs that populate the ocular surface are also detailed herein. The involvement of DCs and their expression of CCR7 in corneal and ocular surface diseases such as in ocular allergy, dry eye disease, immune rejection and more, are also reviewed here., (Copyright © 2014 Elsevier Inc. All rights reserved.)