Section of Immunobiology, Department of Ophthalmology, University Hospital, LMU Munich, Mathildenstr. 8, 80336 Munich, Germany.
Section of Immunobiology, Department of Ophthalmology, University Hospital, LMU Munich, Mathildenstr. 8, 80336 Munich, Germany.
Prog Retin Eye Res. 2018 Jul;65:107-126. doi: 10.1016/j.preteyeres.2018.02.003. Epub 2018 Feb 27.
Autoimmune diseases usually follow a relapsing-remitting or a chronic progressive course. To understand the underlying immunopathogenesis we investigated experimental Lewis rat models displaying both disease types, which were only dependent on the autoantigen peptide used for immunization. Retinal S-Antigen-peptide PDSAg induces chronic, monophasic disease, whilst interphotoreceptor retinoid-binding protein (IRBP)-peptide R14 causes a spontaneously relapsing-remitting course. R14-mediated uveitis can be re-induced by immunization; PDSAg-induced disease is even preventable by prior CFA-injection. T cells with different antigen specificities preferentially infiltrate the eyes from different sites, e.g. choroid or retinal vessels, they remain in the retina after resolution of inflammation for many weeks. The major inflammatory cell populations in the eyes during rat uveitis are CD4 or CD8 monocytes/macrophages. Chemokine mutants only suppress PDSAg-mediated EAU, while IFN-α-treatment ameliorated R14-, but worsened PDSAg-induced disease. Comparison of T cells revealed upregulated expression of 26 genes related to various signal transduction pathways upstream and downstream of IFN-γ only in T cells causing relapsing EAU. Intraocular injection of IFN-γ induces synchronized relapses in R14-mediated uveitis, while VEGF-expression of PDSAg-specific T cells causing chronic disease induced chorioretinal neovascularization that is suppressed by anti-CD146 antibody. Intraocular T cells from rat eyes during EAU express IL-17, IFN-γ or IL-10, with dynamic changes of the cell populations during the disease course, differing in both disease types. Immunization of animals with a mixture of both antigens suppressed relapses, indicating a dominance of the monophasic disease. Understanding the exact pathogenesis of both disease courses is key to developing novel therapies for autoimmune diseases.
自身免疫性疾病通常表现为复发缓解或慢性进行性病程。为了了解潜在的免疫发病机制，我们研究了表现出这两种疾病类型的实验性 Lewis 大鼠模型，这些模型仅依赖于用于免疫的自身抗原肽。视网膜 S 抗原肽 PDSAg 诱导慢性单相疾病，而光感受器间视黄醇结合蛋白 (IRBP)-肽 R14 导致自发复发缓解过程。R14 介导的葡萄膜炎可通过免疫再诱导；PDSAg 诱导的疾病甚至可以通过预先注射 CFA 来预防。具有不同抗原特异性的 T 细胞优先从不同部位浸润眼睛，例如脉络膜或视网膜血管，它们在炎症消退后仍在视网膜中持续数周。大鼠葡萄膜炎期间眼睛中的主要炎症细胞群是 CD4 或 CD8 单核细胞/巨噬细胞。趋化因子突变体仅抑制 PDSAg 介导的 EAU，而 IFN-α 治疗改善了 R14-，但恶化了 PDSAg 诱导的疾病。对 T 细胞的比较显示，仅在引起复发 EAU 的 T 细胞中，与 IFN-γ 上游和下游的各种信号转导途径相关的 26 个基因表达上调。眼内注射 IFN-γ 可诱导 R14 介导的葡萄膜炎同步复发，而导致慢性疾病的 PDSAg 特异性 T 细胞的 VEGF 表达诱导脉络膜视网膜新生血管形成，该新生血管形成被抗 CD146 抗体抑制。EAU 期间大鼠眼内 T 细胞表达 IL-17、IFN-γ 或 IL-10，在疾病过程中细胞群体的动态变化，在两种疾病类型中均有所不同。用两种抗原混合物免疫动物可抑制复发，表明单相疾病占主导地位。了解这两种疾病过程的确切发病机制是为自身免疫性疾病开发新疗法的关键。
