Alterations in corneal biomechanics underlie early stages of autoimmune-mediated dry eye disease

Abstract

Autoimmune-mediated dry eye disease is a pathological feature of multiple disorders including Sjögren's syndrome, lupus and rheumatoid arthritis that has a life-long, detrimental impact on vision and overall quality of life. Although late stage disease outcomes such as epithelial barrier dysfunction, reduced corneal innervation and chronic inflammation have been well characterized in both human patients and mouse models, there is little to no understanding of early pathological processes. Moreover, the mechanisms underlying the loss of cornea homeostasis and disease progression are unknown. Here, we utilize the autoimmune regulatory (Aire)-deficient mouse model of autoimmune-mediated dry eye disease in combination with genome wide transcriptomics, high-resolution imaging and atomic force microscopy to reveal a potential ECMbiomechanical-based mechanism driving cellular and morphological changes at early disease onset. Early disease in the Aire-deficient mouse model is associated with a mild reduction in tear production and moderate immune cell infiltration, allowing for interrogation of cellular, molecular and biomechanical changes largely independent of chronic inflammation. Using these tools, we demonstrate for the first time that the emergence of autoimmune-mediated dry eye disease is associated with an alteration in the biomechanical properties of the cornea. We reveal a dramatic disruption of the synthesis and organization of the extracellular matrix as well as degradation of the epithelial basement membrane during early disease. Notably, we provide evidence that the nerve supply to the cornea is severely reduced at early disease stages and that this is independent of basement membrane destruction or significant immune cell infiltration. Furthermore, diseased corneas display spatial heterogeneity in mechanical, structural and compositional changes, with the limbal compartment often exhibiting the opposite response compared to the central cornea. Despite these differences, however, epithelial hyperplasia is apparent in both compartments, possibly driven by increased activation of IL-1R1 and YAP signaling pathways. Thus, we reveal novel perturbations in corneal biomechanics, matrix organization and cell behavior during the early phase of dry eye that may underlie disease development and progression, presenting new potential targets for therapeutic intervention.

Alteration of corneal biomechanical properties in patients with dry eye disease

“…syndrome and ocular graft versus host disease had more compliant corneas compared with healthy corneas [27][28][29]. Long Q et al evaluated corneal biomechanics in dry eye patients without systemic autoimmune diseases using Corvis ST and found that the time to reach the highest concavity of cornea (HC-time) was significantly reduced in patients with DED compared with normal [30].…”

A synthetic tear protein resolves dry eye through promoting corneal nerve regeneration.

“…Aire knockout (KO) female mice develop classic signs of dry eye disease over a 2-week time period. This begins with small lymphocytic infiltrates in the lacrimal glands and mildly reduced tear secretion, corneal innervation, and barrier function at 5 weeks (wks), consistent with mild aqueous-deficient dry eye, that progresses to extensive CD4+ T cell-mediated exocrinopathy, severe tear reduction, and corneal pathologies at the epithelial, stromal and nerve-associated levels by 7 wks ( 8–10 ).…”

“…As basal tear production is dependent on sensory innervation of the cornea, and dry eye leads to diminished corneal innervation in humans ( 20, 21 ) and mice ( 8, 22 ), we next determined whether the maintenance of reflex tearing in response to lacripep was due to restoration of the nerve supply. Sensory nerves derived from the ophthalmic lobe of the trigeminal ganglion primarily enter the corneal stroma at the limbal region and extend along the basement membrane, with axon fibers branching upward through the multi-layered epithelium to establish nerve-epithelial interactions.…”

“…Although lacritin has been shown to promote basal tearing in a healthy rabbit model ( 5 ), whether lacripep is also capable of increasing basal tear production and can do so during dry eye disease progression is unknown. To test this, we evaluated basal tearing by utilizing the Aire mouse model of aqueous deficient dry eye ( 8 ). Aire knockout (KO) female mice develop classic signs of dry eye disease over a 2-week time period.…”

A simple cornea model for the tribological performance assessment of the lubricating eye drops

“…In addition to COF comparisons of the samples, the developed model is also sensitive to relatively small changes in Young’s modulus. This observation is very important for the discussion focusing on DES (Efraim et al , 2020) or intraocular pressure changes that lead to changes in corneal stiffness (Liu and He, 2009). In this study, C-NAC-BED revealed the lowest COF in both configurations with different Young’s modi.…”