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Yihe Chen, Nai-Wen Fan, Joy Li, Sharad Mittal, Elsayed Elbasiony, Sunil Chauhan; Chronic autoimmune uveitis is characterized by memory Th17 response. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3666.
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Chronic autoimmune uveitis (CAU) is often a treatment-resistant disease, and the underlying pathogenesis remains poorly understood. In this study, we established a mouse model of CAU and characterized the underlying immune response.
CAU was induced in wild-type C57BL/6 mice by immunization with 150 µg interphotoreceptor retinoid-binding protein (IRBP) peptide 161–180 plus 300 µg IRBP 1–20 emulsified in 0.2ml Complete Freund's Adjuvant (CFA). Mice also received 0.2μg Bordetella pertussis toxin. Mice receiving CFA alone served as the control. Digital fundus images were taken weekly using a Micron III system, and disease severity was scored on a scale of 0 - 4. At week 12, mice were further evaluated for retinal degeneration and function using the optical coherence tomography (OCT) and electroretinography (ERG). Upon completion of clinical evaluation, mice were sacrificed and eyes were collected for histopathological examination. In addition, T cell response in retina and peripheral lymphoid tissues were analyzed by flow cytometry.
The immunized animals showed a slowly onset (by week 3, score of 0.14±0.10), progressive (until week 7, score of 1.3±0.2), and chronic (remaining at a plateau through the end of observation at week 12, score of 1.5±0.2) uveitis, without spontaneous resolution. At week 12, mice with CAU exhibited blurred optic disc margins, enlarged juxtapapillary areas, perivascular cuffing, and retinal scars by fundoscopy, as well as decreased retinal thickness (174.5±0.7 vs. 180.7±0.7µm, p < 0.001) by OCT, and significantly reduced amplitudes of dark-adapted a-wave (10% drop) and b-wave (12% drop), and light-adapted b-wave (20% drop) by ERG. The histology showed prominent choroiditis with wide-range destruction of photoreceptor and outer nuclear layers in retina. Flow cytometry analysis showed significantly increased IL-17+IFN-γ- Th17 (but not Th1 or Th17/1) cells in the retina (6.2±0.4% vs. 0.4±0.2%, p=0.002), cervical lymph nodes (LN) (1.0±0.1% vs. 0.4±0.1%, p=0.01), inguinal LN (0.81±0.05% vs. 0.47±0.04%, p=0.003), and spleen (0.42±0.05% vs. 0.22±0.04%, p=0.04), but not in peripheral blood or bone marrow. These Th17 cells were exclusively CD44hi memory cell.
Our data has demonstrated a predominant memory Th17 response in chronic autoimmune uveitis, suggesting a critical role of Th17-mediated immunological memory in sustaining the chronic intraocular inflammation.
This is a 2020 ARVO Annual Meeting abstract.
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