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 K_2P-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.

Keywords: K2P channel; Piezo2 channelopathy; TASK1 channel; autoimmune disease; dry eye disease; rheumatoid arthritis.

Figure 1

In vivo confocal microscopic images of corneal subepithelial nerves in a healthy eye (A) and in the eye of a patient with rheumatoid arthritis and dry eye (B). Note the lower density and reduced thickness of the subepithelial nerve plexi (arrow) in RA compared to in normal eyes. The number of branches (arrowhead) is minimal in RA. Langerhans cells with elongated dendrites are also demonstrated (empty arrow).

Figure 2

Correlation of CNFD Average and Schirmer’s-test results.

Figure 3

Correlation of CNFL Average and Schirmer’s-test results.

Figure 4

Correlation of CNFD Highest and Schirmer’s-test results.

Figure 5

Correlation of CNFA Highest and CRP values.