Th17 cells mediate inflammation in a novel model of spontaneous experimental autoimmune lacrimal keratoconjunctivitis with neural damage

Publication date: Available online 27 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Kyoung Yul Seo, Kazuya Kitamura, Soo Jung Han, Brian Kelsall
BackgroundDry eye disease (DED) affects one third of population worldwide. In prior studies, experimental autoimmune lacrimal keratoconjunctivitis (EALK) induced by desiccating stress in mice has been used as a model of DED. This model is complicated by a requirement for exogenous epithelial cell injury and the administration of anticholinergic agents that have broad immunological effects.ObjectiveWe sought to develop a novel mouse model of EALK, and to demonstrate the responsible immunological pathogenic mechanisms.MethodsCD4+CD45RB^high naïve T cells with and without CD4+CD45RB^loCD25+ regulatory T cells were adoptively transferred to C57BL/10 RAG2^-/- mice. The eyes, draining lymph nodes, lacrimal glands and surrounding tissues of mice that spontaneously developed keratoconjuctivitis were evaluated for histopathological changes, cellular infiltration, and cytokine production in tissues and by isolated cells. Furthermore, the integrity of corneal nerves was evaluated by whole tissue immunofluorescence imaging. Gene-deficient naïve T cells or RAG2-hosts were evaluated to assess the roles of IFN-γ, IL-17A and IL-23 in disease pathogenesis. Finally, cytokine levels were determined in the tears of patients with DED.ResultsEALK spontaneously developed in C57BL/10 RAG2^-/- mice following adoptive of CD4+CD45RB^high naïve T cells characterized by the infiltration of CD4⁺ T cells, macrophages, and neutrophils. In addition to lacrimal keratoconjunctivitis, mice also developed damage to the corneal nerve, which connects components of lacrimal functional unit (LFU). Pathogenic T cell differentiation was dependent on IL-23p40 and controlled by co-transferred CD4+CD45RB^loCD25⁺ regulatory T cells (Tregs). Th17 rather than Th1 CD4+ cells were primarily responsible for EALK even though both IL-17 and IFN-γ were increased in inflammatory tissues likely due to their ability to drive the expression of CXC chemokines within the cornea, and the subsequent influx of myeloid cells. Consistent with the findings of this model, the tears of patients with DED had increased levels of inflammatory cytokines including IL-17A and TNFα.ConclusionWe describe a novel model of spontaneous EALK that supports a role for Th17 cells in disease pathogenesis, and that will contribute to our understanding of autoimmune lacrimal keratoconjunctivitis in many human eye diseases, including DED.

Graphical abstract

Teaser

Demonstrated is a novel spontaneous mouse model of experimental autoimmune lacrimal keratoconjunctivitis that results from Th17 cell activation, and will be important for understanding the contribution of environmental or microbial antigens to disease pathogenesis.


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