Insights into Local Orbital Immunity: Evidence for the Involvement of the Th17 Cell Pathway in Thyroid-Associated Ophthalmopathy.

Insights into Local Orbital Immunity: Evidence for the Involvement of the Th17 Cell Pathway in Thyroid-Associated Ophthalmopathy.

J Clin Endocrinol Metab. 2018 Dec 03;:

Authors: Fang S, Huang Y, Wang N, Zhang S, Zhong S, Li Y, Sun J, Liu X, Wang Y, Gu P, Li B, Zhou H, Fan X

Abstract
Context: Unique features of local immunity in thyroid-associated ophthalmopathy (TAO) may affect disease progression.
Objective: To investigate the association between the orbital immune microenvironment and TAO development.
Design/Setting/Participants: TAO and control orbital connective tissues were collected.
Main Outcome Measures: Single-cell sequencing examined orbital lymphocytic infiltrates. Multi-color flow cytometry explored the phenotypes of different cell subsets and in vitro models for cell functional studies. Co-culture experiment and western blotting assay were used to determine underlying mechanism of the enhanced T helper (Th)17 cell pathway.
Results: The TAO orbital microenvironment was composed of natural killer cells, dendritic cells, macrophages, T cells, plasma cells, and CD34+ orbital fibroblasts (OFs), but few B cells. Increases in CD3+CD8- interleukin (IL)-17A-producing and RAR-related orphan receptor (ROR)γt-expressing T cells and in CD3+CD8- IL-13-producing and GATA3-expressing T cells suggested Th17 cell and Th2 cell responses in TAO orbits. Increased interferon (IFN)-γ-producing and RORγt+Tbet+ T cells indicated a Th1-like phenotype of orbital-infiltrating Th17 cells. Higher IL-23R and IL-1R expression and lower IL-21R expression were also observed on Th17 cells in TAO orbits. Multivariate analyses revealed that the Th17 pathway [IL-17A (p=0.001), IFN-γ (p=0.009), RORγt (p=0.003), IL-23R (p=0.033), IL-21R (p=0.019)] and Th2 pathway [IL-13 (p=0.015), GATA3 (p=0.012)] were associated with TAO. IL-17A, IL-23R, and IL-1R correlated with clinical activity score and visual acuity. CD34+ OFs exhibited distinct cell surface marker expression and promoted IL-23R and IL-1R expression on T cells to facilitate the Th17-cell phenotype through prostaglandin E2-EP2/EP4-cAMP signaling.
Conclusion: Our study addressed the importance of retroorbital immunity and suggests possible means of disrupting TAO pathogenesis.

PMID: 30517642 [PubMed - as supplied by publisher]

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