Desiccating Stress Induces T Cell-Mediated Sjögren’s Syndrome-Like Lacrimal Keratoconjunctivitis

Abstract

Chronic dry eye syndrome affects over 10 million people in the United States; it is associated with inflammation of the lacrimal gland (LG) and in some cases involves T cell infiltration of the conjunctiva. We demonstrate that environmental desiccating stress (DS) elicits T cell-mediated inflammation of the cornea, conjunctiva, and LG, but not other organs in mice. The lacrimal keratoconjunctivitis (LKC) was mediated by CD4+ T cells, which, when adoptively transferred to T cell-deficient nude mice, produced inflammation in the LG, cornea, and conjunctiva, but not in any other organ. Adoptively transferred CD4+ T cells produced LKC even though recipients were not exposed to DS. LKC was exacerbated in euthymic mice depleted of CD4+CD25+forkhead/winged helix transcription factor+ regulatory T cells. The results suggest that DS exposes shared epitopes in the cornea, conjunctiva, and LG that induce pathogenic CD4+ T cells that produce LKC, which under normal circumstances is restrained by CD4+CD25+forkhead/winged helix transcription factor+ regulatory T cells.

Desiccating environmental stress exacerbates autoimmune lacrimal keratoconjunctivitis in non-obese diabetic mice

“…We have previously reported that desiccating stress-induced lacrimal keratoconjunctivitis was mediated by CD4+ T cells and was mitigated by CD4+CD25+ natural regulatory T cells [9]. In this study, an increase in CD4+ T cells and CCR5+ cells was accompanied by a decrease in CD8+ T cells in the ocular surface epithelium and lacrimal gland, resulting in an increased CD4/CD8 ratio.…”

“…The effects of desiccating stress on salivary gland immunopathology in the NOD strain were not investigated in this study. Our group had previously reported that desiccating stress promoted development of auto reactive CD4+ T cells in BALB/c mice that were capable of producing lacrimal keratoconjunctivitis, but not salivary gland inflammation when adoptively transferred to nude mouse recipients [9].…”

“…Fourweek-old male mice served as young controls (4W). Sixteen-week-old male mice were untreated (16W) or subjected to desiccating stress by exposure to an air draft with a fan, without (F) or with (FS) subcutaneous injection of 0.5 mg/0.2 mL of the muscarinic receptor blocker, scopolamine hydrobromide (Sigma-Aldrich, St. Louis, MO) in alternating hindquarters four times a day (8 am, 11 am, 2 pm and 5 pm), as previously reported [9,18]. Mice were euthanized after 5 or 10 days (D) of treatment.…”

“…Sjögren's syndrome causes severe dysfunction of the lacrimal functional unit. Desiccating ocular surface stress has been found to induce autoreactive T cells that when adoptively transferred to naïve immunodeficient hosts cause Sjögren's syndrome-like inflammation in the lacrimal gland, cornea, and conjunctiva, but not in other organs, suggesting the existence of shared epitopes among the components of the lacrimal functional unit [9].…”

Anti-inflammatory effects of hinokitiol on human corneal epithelial cells: an in vitro study

“…10 In turn, inflammation may cause dysfunction or disappearance of the cells responsible for tear secretion or retention. 11 Hinokitiol is a natural component isolated from Chamaecyparis taiwanensis that exhibits antibacterial, antifungal, antiviral, antitumor, and insecticidal activities, with insignificant cytotoxicity. [12][13][14][15] Recent studies reported that Hinokitiol displayed a significant antiinflammatory activity in a series of cells through different mechanisms.…”