Evidence of Disruption in Neural Regeneration in Dry Eye Secondary to Rheumatoid Arthritis

Abstract

The purpose of our study was to analyze abnormal neural regeneration activity in the cornea through means of confocal microscopy in rheumatoid arthritis patients with concomitant dry eye disease. We examined 40 rheumatoid arthritis patients with variable severity and 44 volunteer age- and gender-matched healthy control subjects. We found that all examined parameters were significantly lower (p < 0.05) in rheumatoid arthritis patients as opposed to the control samples: namely, the number of fibers, the total length of the nerves, the number of branch points on the main fibers and the total nerve-fiber area. We examined further variables, such as age, sex and the duration of rheumatoid arthritis. Interestingly, we could not find a correlation between the above variables and abnormal neural structural changes in the cornea. We interpreted these findings via implementing our hypotheses. Correspondingly, one neuroimmunological link between dry eye and rheumatoid arthritis could be through the chronic Piezo2 channelopathy-induced K2P-TASK1 signaling axis. This could accelerate neuroimmune-induced sensitization on the spinal level in this autoimmune disease, with Langerhans-cell activation in the cornea and theorized downregulated Piezo1 channels in these cells. Even more importantly, suggested principal primary-damage-associated corneal keratocyte activation could be accompanied by upregulation of Piezo1. Both activation processes on the periphery would skew the plasticity of the Th17/Treg ratio, resulting in Th17/Treg imbalance in dry eye, secondary to rheumatoid arthritis. Hence, chronic somatosensory-terminal Piezo2 channelopathy-induced impaired Piezo2–Piezo1 crosstalk could result in a mixed picture of disrupted functional regeneration but upregulated morphological regeneration activity of these somatosensory axons in the cornea, providing the demonstrated abnormal neural corneal morphology.

Progressive Irreversible Proprioceptive Piezo2 Channelopathy-Induced Lost Forced Peripheral Oscillatory Synchronization to the Hippocampal Oscillator May Explain the Onset of Amyotrophic Lateral Sclerosis Pathomechanism

“…It was suggested earlier that the chronic Piezo2 channelopathy-induced impaired Piezo2–Piezo1 crosstalk will deplete certain proteoglycans on the chronic path [ 86 ]. Even more importantly syndecans are suspected in this mechanotransduction-associated depletory mechanism [ 17 ] in the aforementioned manner.…”

Neural Regeneration in Dry Eye Secondary to Systemic Lupus Erythematosus Is Also Disrupted like in Rheumatoid Arthritis, but in a Progressive Fashion

“…Piezo2 has a central role in sensory processes, and its theorized excessive mechanotransduction-derived non-contact microinjury could lead to a wide array of diseases, including even autoimmune conditions [ 12 , 13 ]. It has been postulated that the channelopathy of Piezo2 at somatosensory terminals contributing to proprioception may initially be responsible for the cascade of events that could lead to the activation of the innate [ 14 ] and adaptive immune system and eventually to uncontrolled production of autoantigens [ 15 ]. However, it is important to note that earlier, it was postulated that DED could also be induced as a result of peripheral Piezo1 channelopathy leading to neural Piezo2 channelopathy, hence constructing the base of the spectrum nature of DED [ 16 ].…”

“…However, chronic Piezo2 channelopathy not only keeps transcription activated and wound healing unfinished, but is also postulated to disrupt the crosstalk with Piezo1 of peripheral cells [ 16 ]. As a result, Piezo1 of keratinocytes could be upregulated [ 13 ], as could be the case with corneal keratinocytes as well [ 15 ]. On the contrary, Piezo1 of dendritic cells (DC) is downregulated [ 20 ], as could be the case in corneal dendritic Langerhans cells (LC) [ 15 ].…”

“…As a result, Piezo1 of keratinocytes could be upregulated [ 13 ], as could be the case with corneal keratinocytes as well [ 15 ]. On the contrary, Piezo1 of dendritic cells (DC) is downregulated [ 20 ], as could be the case in corneal dendritic Langerhans cells (LC) [ 15 ]. If genetic or environmental factors, like repetitive re-injury, even non-contact ones, interferes with the due closure of this process, then remodeling and regeneration could be altered and/or disrupted [ 19 ], as is observed in DED secondary to rheumatoid arthritis (RA) [ 15 ].…”

“…On the contrary, Piezo1 of dendritic cells (DC) is downregulated [ 20 ], as could be the case in corneal dendritic Langerhans cells (LC) [ 15 ]. If genetic or environmental factors, like repetitive re-injury, even non-contact ones, interferes with the due closure of this process, then remodeling and regeneration could be altered and/or disrupted [ 19 ], as is observed in DED secondary to rheumatoid arthritis (RA) [ 15 ]. Another proposed consequence of this lost Piezo2–Piezo1 crosstalk is the osmotic pressure changes on the ocular surface secondary to DED [ 16 , 21 ].…”