Bilateral Alterations in Corneal Nerves, Dendritic Cells, and Tear Cytokine Levels in Ocular Surface Disease

Abstract

This review summarizes recent literature regarding corneal imaging in human subjects using in vivo confocal microscopy and corneal immune cells, nerves, and tear cytokine levels in ocular surface diseases as well as corneal immune privilege. The significance of interactions between corneal immune cells and nerves in health, neurotrophic keratopathy, and infectious keratitis are discussed. Furthermore, bilateral alterations of immune cells and nerves in clinically unilateral corneal diseases and the link to changes of tear cytokines or neuropeptide levels in contralateral eyes are described. Recent studies reported increased density and morphologic changes of corneal dendritic cells in ocular surface disease that correlated with a decrease in sub-basal nerve corneal nerves, suggesting potential interactions between the immune and nervous systems in the cornea. Although the relevance of tear cytokines is poorly understood, tear cytokines might have an important role in the pathogenesis of ocular surface diseases. In humans and experimental animal models, alterations in immune cells, cytokines and immunomodulatory neuropeptide levels in contralateral eyes might mediate the incidence of bilateral infectious keratitis and loss of immune privilege of the cornea in bilateral corneal transplantation or neurotrophic keratopathy cases. The discovery of bilateral alterations of immune cells and nerves in ocular surface diseases is considered the missing link between the immune and nervous systems in the cornea, and demonstrates how studies of animal models and human patients aid our understanding of human corneal disease phenomena.

Acute Hyperalgesia and Delayed Dry Eye After Corneal Abrasion Injury

“…The mechanisms underlying these contralateral changes are unclear, especially given that there are other examples of unilateral corneal injury and disease states that affect both contralateral nerve density and sensation [21]. Possible mechanisms of bilateral changes induced by unilateral corneal injury include bilateral increases in dendritic cells which mediate immune responses and alterations in tear cytokines in the context of unilateral bacterial keratitis [56]. Others have suggested that contralateral hyperalgesia, or mirror pain, after nerve injury may be related to changes in the peripheral nervous system, central pathways and/or the activation of immunocompetent cells such as cytokines, macrophages, microglia and astrocytes [15; 49].…”

Effect of Uveitis on the Development of Keratopathy: A Population-Based Cohort Study

“…22 Moreover, the corneal endothelial cells were damaged with an altered central corneal thickness in patients with uveitis, [14][15][16]23 whereas inflammatory cell infiltration into the corneal stoma was also observed during the onset of anterior uveitis. 24 On the other hand, the same inflammatory mediators and immune cells increased with uveitis and keratopathies, 17,25,26 indicating that a general immune reaction and inflammatory response could cause both uveitis and several types of keratopathies. In clinical studies, systemic disorders featuring immune and inflammation impairment, such as rheumatoid arthritis and psoriasis, were associated with the occurrence of uveitis and keratopathies.…”

Reduced association between dendritic cells and corneal sub‐basal nerve fibers in patients with fibromyalgia syndrome

“…Integrity of the corneal sub‐basal nerve plexus is regulated by interactions between immune cells and nerve fiber endings . Their communication is crucial controlling the corneal immune status . A disruption of these fine‐tuned neuro‐immune interactions may alter corneal innervation.…”

“…21,22 Their communication is crucial controlling the corneal immune status. 23,24 A disruption of these fine-tuned neuro-immune interactions may alter corneal innervation. Hence, they are promising targets for pathophysiological mechanisms in small fiber pathology.…”