Degroote Roxane L, Uhl Patrizia B, Amann Barbara, Krackhardt Angela M, Ueffing Marius, Hauck Stefanie M, Deeg Cornelia A
Department of Veterinary Sciences, Ludwig-Maximilians-Universität München, 80539 Munich, Germany.
III. Medical Department, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.
J Proteomics. 2017 Feb 10;154:102-108. doi: 10.1016/j.jprot.2016.12.015. Epub 2017 Jan 3.
The membrane protein expression repertoire of cells changes in course of activation. In equine recurrent uveitis (ERU), a spontaneous autoimmune disease in horses with relapsing and ultimately blinding inner eye inflammation, CD4+ T lymphocytes are the crucial pathogenic cells activated in the periphery directly prior to an inflammatory episode. In order to find relevant changes in the membrane proteome associated to disease, we sorted CD4+ lymphocytes and compared protein abundance from the generated proteome datasets of both healthy horses and ERU cases. We detected formin like 1, a key player in actin dependent cellular processes such as phagocytosis, cell adhesion and cell migration, with significantly higher abundance in the CD4+ cell membrane proteome of horses with ERU. In transmigration experiments, we demonstrated higher migration rate of cells originating from diseased animals connecting formin like 1 to the migratory ability of cells. These findings are the first description of formin like 1 in association to processes involved in migration of inflammatory CD4+ T cells across the blood-retinal barrier in a spontaneous ocular autoimmune disease and suggest formin like 1 to play a role in the molecular mechanisms of ERU disease pathogenesis. Data are available via ProteomeXchange with identifier PXD005384.
This comparative proteomic study of membrane proteins of CD4+ T cells identified a novel protein, formin like 1, with expression on the plasma cell membrane of equine CD4+ T cells and a significant change of abundance on CD4+ T cells of horses with a spontaneous autoimmune disease. Functional studies in a cell culture model for transmigration at the blood-retinal barrier (BRB) unraveled a strong impact of formin like 1 on migratory processes of CD4+ T cells across the BRB, a key event in uveitis pathogenesis. These findings provide novel knowledge about changes in the CD4+ immune cell membrane proteome in a spontaneously and naturally occurring autoimmune disease in horses with high relevance for veterinary medicine. Additionally, this model has proven translational quality for human medicine and provides novel proteomic information on autoimmune uveitis in man.
细胞的膜蛋白表达谱在激活过程中会发生变化。在马复发性葡萄膜炎（ERU）中，这是一种马的自发性自身免疫性疾病，伴有反复发作并最终导致失明的眼内炎症，CD4+ T淋巴细胞是在炎症发作前直接在外周被激活的关键致病细胞。为了找到与疾病相关的膜蛋白质组的相关变化，我们对CD4+淋巴细胞进行了分选，并比较了健康马和ERU病例生成的蛋白质组数据集的蛋白质丰度。我们检测到formin样蛋白1，它是肌动蛋白依赖性细胞过程（如吞噬作用、细胞粘附和细胞迁移）中的关键参与者，在患有ERU的马的CD4+细胞膜蛋白质组中的丰度显著更高。在迁移实验中，我们证明了来自患病动物的细胞具有更高的迁移率，将formin样蛋白1与细胞的迁移能力联系起来。这些发现首次描述了formin样蛋白1与自发性眼部自身免疫性疾病中炎症性CD4+ T细胞跨血视网膜屏障迁移过程的关联，并表明formin样蛋白1在ERU疾病发病机制的分子机制中发挥作用。数据可通过ProteomeXchange获得，标识符为PXD005384。
这项对CD4+ T细胞膜蛋白的比较蛋白质组学研究鉴定出一种新蛋白质formin样蛋白1，它在马CD4+ T细胞的质膜上表达，并且在患有自发性自身免疫性疾病的马的CD4+ T细胞上丰度有显著变化。在血视网膜屏障（BRB）迁移的细胞培养模型中的功能研究揭示了formin样蛋白1对CD4+ T细胞跨BRB迁移过程的强烈影响，这是葡萄膜炎发病机制中的一个关键事件。这些发现提供了关于马自发性和自然发生的自身免疫性疾病中CD4+免疫细胞膜蛋白质组变化的新知识，对兽医学具有高度相关性。此外，该模型已证明对人类医学具有转化价值，并提供了关于人类自身免疫性葡萄膜炎的新蛋白质组信息。
