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

Abstract

Our objective in this study was to analyze the aberrant neural regeneration activity in the cornea by means of in vivo confocal microscopy in systemic lupus erythematosus patients with concurrent dry eye disease. We examined 29 systemic lupus erythematosus patients and 29 age-matched healthy control subjects. Corneal nerve fiber density (CNFD, the number of fibers/mm2) and peripheral Langerhans cell morphology were lower (p < 0.05) in systemic lupus erythematosus patients compared to the control group. Interestingly, corneal nerve branch density, corneal nerve fiber length, corneal nerve fiber total branch density, and corneal nerve fiber area showed a negative correlation with disease duration. A negative correlation was also demonstrated between average corneal nerve fiber density and central Langerhans cell density. This is in line with our hypothesis that corneal somatosensory terminal Piezo2 channelopathy-induced impaired Piezo2–Piezo1 crosstalk not only disrupts regeneration and keeps transcription activated, but could lead to Piezo1 downregulation and cell activation on Langerhans cells when we consider a chronic path. Hence, Piezo2 containing mechanosensory corneal nerves and dendritic Langerhans cells could also be regarded as central players in shaping the ocular surface neuroimmune homeostasis through the Piezo system. Moreover, lost autoimmune neuroinflammation compensation, lost phagocytic self-eating capacity, and lost transcription regulation, not to mention autoantibodies against vascular heparin sulfate proteoglycans and phospholipids, could all contribute to the progressive fashion of dry eye disease in systemic lupus erythematosus.

Unveiling Ocular Manifestations in Systemic Lupus Erythematosus

“…T-helper type 17 lymphocyte (Th-17), which is typified by the production of interleukin-17 (IL-17), a powerful pro-inflammatory mediator, has been specifically identified as the leading cause of chronic ocular surface inflammation and consequent epithelial metaplasia resulting in the loss of goblet cells, the mucin-aqueous adherence complex and subsequent dry eye disease [99][100][101]. A neural origin of excessive cytokine expression by leukocytes due to a failure of the sensory afferent mechanotransduction of mechanosensitive ion channel (Piezo1 and Piezo2) has been proposed as the initial cause of events that could result in the activation of the innate and adaptative immune system, which eventually ends in the dysregulation of autoantigen production and consequent dry eyes disease [3].…”

“…Mild retinopathy can be asymptomatic and incidental, severe vascular occlusive retinopathy is characterized by vision impairment, distortions, and visual field abnormalities. Retinal neovascularization, retinal detachment, microaneurysms, artery constriction, lesions at arteriovenous junctions, retinal edema, retinal exudation, and multifocal serous retinal detachment or pigment epithelial detachment are common retinopathies presented in SLE [3].…”

“…Systemic lupus erythematosus (SLE) is a chronic autoimmune systemic disorder of the connective tissue that does not affect only one certain organ but has a diversified effect all over the body [1,2]. The etiology of SLE is may be idiopathic, genetic, hormonal, or environmental [3]. Choudhary et al have suggested that SLE is nine times more common in females as compared to males [4].…”

“…In its early stages, both hereditary and acquired immune systems are implicated, leading to the activation of T and B cells. The result is an overproduction of proinflammatory cytokines [3]. The diagnosis of SLE is difficult and requires a series of tests and findings which can be systemic or ocular.…”

“…Common symptoms include ophthalmoplegia, reduced vision, ocular proptosis, eyelid lesions, and orbital inflammation [1,8]. Elevated levels of creatine kinase, aldolase, CRP, procalcitonin, and myoglobins are reported from laboratory test results [1][2][3][4][5][6][7][8][9].…”