The role of interleukin (IL)-10 in the pathogenesis of autoimmune uveitis in mice and man

眼内炎症（葡萄膜炎）是失明的常见原因。在病因学上，葡萄膜炎可以分为感染性和自身免疫性形式，两种形式之间存在一些关联，如HLA-B27阳性葡萄膜炎的情况。由于在每次感染期间都有自身抗原的释放，因此身体通过外周耐受机制（包括调节细胞群和细胞因子如白细胞介素（IL）-10）来防止随后的自身免疫反应的发展。这个网络的失败可能解释了自身免疫性疾病和先前感染之间的已知关联。我们在人类葡萄膜炎（实验性自身免疫性葡萄膜炎（EAU））小鼠模型中的初步工作表明，预先暴露于完全弗氏佐剂（CFA）形式的细菌产物（类似于先前的感染）可改善EAU。这种保护性特征严重依赖于IL-10，并与髓源性抑制细胞（MDSC）的扩增有关。该项目的目的是阐明这种保护作用的机制，特别是MDSC的作用和IL-10的细胞来源。基于这些发现，我们想探讨IL-10产生失调的假说，特别是在感染期间，易患随后的自身免疫性葡萄膜炎。我们的初步研究结果支持，在EAU模型中，IL-10缺陷小鼠在预暴露于细菌产物然后进行EAU诱导后会出现葡萄膜炎，但在通过细菌诱导的IL-10受到保护的野生型小鼠中则不会出现葡萄膜炎。除了外周MDSC，视网膜中的常驻巨噬细胞作为小胶质细胞存在，并在EAU期间获得活化状态。将分析该群体通过IL-10对EAU的免疫调节的贡献。将在EAU中评价通过玻璃体内应用IL-10的局部递送作为葡萄膜炎的新治疗手段，由于该细胞因子的多效性特征，能够实现局部免疫抑制而没有潜在的全身副作用。最后，将在HLA-B27阳性葡萄膜炎患者中检查血清和外周血单核细胞和淋巴细胞中IL-10的分泌模式，作为发生葡萄膜炎的易感性的推定标志物。

Intraocular inflammation (uveitis) is a common cause of blindness. Etiologically, uveitis can be divided into infectious and autoimmune forms, with some associations between both forms, as in the case of HLA-B27 positive uveitis. Since there is a release of self antigens during every infection, the body prevents the development of subsequent autoimmune reactions by peripheral tolerance mechanisms including regulatory cell populations and cytokines such as interleukin (IL)-10. Failure of this network may explain the known association between autoimmune disorders and preceding infections. Our preliminary work in the murine model of human uveitis, experimental autoimmune uveitis (EAU), has shown that pre-exposure with bacterial products (analogous to a preceding infection) in form of complete freund´s adjuvant (CFA) ameliorates EAU. This protective feature critically depends on IL-10 and is associated with an expansion of myeloid derived suppressor cells (MDSC). The aim of this project now is to elucidate the mechanisms of this protective effect, particularly the role of MDSC and the cellular source of IL-10. Based on these findings we want to explore the hypothesis that dysregulation of IL-10 production, especially during infections, predisposes to subsequent autoimmune uveitis. Our initial findings support that in the EAU model, uveitis develops in IL-10 deficient mice after pre-exposure with bacterial products followed by EAU induction, but not in wild-type mice that are protected through bacteria-induced IL-10. In addition to peripheral MDSC, resident macrophages in the retina are present as microglia and aquire an activated state during EAU. The contribution of this population to immunoregulation of EAU via IL-10 will be analyzed. Local delivery by intravitreal application of IL-10 will be evaluated in EAU as a novel therapeutical means for uveitis, enabling a local immunosuppression without potential systemic side-effect due to the pleiotropic profile of this cytokine. Finally, secretion patterns of IL-10 in serum and peripheral blood monocytes and lymphocytes as putative markers of susceptibility for developing uveitis will be examined in patients with HLA-B27 positive uveitis.