Altered T follicular helper responses in human autoimmune diseases

自身抗体的产生是自身免疫性疾病的一个标志。最近在人类和老鼠身上的数据表明 T滤泡辅助细胞(TFH)的过度表达，这是一种专门帮助B细胞 生发中心(GCs)与自身免疫有关。然而，导致疾病的免疫机制 在人类自身免疫性疾病中，TFH的夸大反应在很大程度上仍不清楚。我们的初步研究 提示在人类自身免疫性疾病中与TFH反应过度有关的共同机制。 我们确定了两个来自抗原提呈细胞的促进TFH反应的候选因子。更改后的 自身免疫性疾病中的TFH反应也可能与T卵泡调节失调有关 (TFR)来源于胸腺来源的调节性T细胞(Tregs)。在这个协作项目中，我们 假设改变的APC促进TFH反应，同时抑制TFR反应，从而有助于 与人类自身免疫性疾病的发病机制有关。我们将分享我们既定的研究方法 将人类Tfh细胞转移到其他中心，以便新诊断的未经治疗的患者具有广泛的 自身免疫性疾病可以在各个中心进行分析。具体目标是目标1：确定 自身免疫性疾病患者外周血中TFH细胞亚群的变化目的2：测定Tfh的变化 自身免疫性疾病炎症组织中细胞和CD11c+APC的表达目标3：确定是否 炎症组织中的APC能够诱导幼稚和记忆的CD4+T细胞分化为 TFH细胞，以及目的4：确定自身免疫性疾病中TFR反应是否以及如何改变。在……里面 结论：我们可能能够揭示导致改变的Tfh/GC反应共享的免疫途径 由不同的自身免疫性疾病以及每种疾病特有的一种疾病引起。

Generation of autoantibodies is a hallmark of autoimmune diseases. Recent data in humans and mice show that overrepresentation of T follicular helper (Tfh) cells, a CD4+ T cell subset specialized in helping B cells in germinal centers (GCs), is associated with autoimmunity. Yet, the immune mechanisms that cause exaggerated Tfh response in human autoimmune diseases remain largely unknown. Our preliminary studies suggest a common mechanism associated with exaggerated Tfh responses in human autoimmune disease. We identified two candidate factors derived from antigen-presenting cells promoting Tfh responses. Altered Tfh response in autoimmune diseases might be also associated with dysregulated of T follicular regulatory (Tfr) cells that originate from thymus-derived regulatory T cells (Tregs). In this Collaborative Project, we hypothesize that Altered APCs promotes Tfh response while suppressing Tfr response thereby contributing to the pathogenesis of human autoimmune diseases. We will share our established methods for the studies of human Tfh cells to other Centers, so that newly diagnosed untreated patients with a broad range of autoimmune diseases can be analyzed across the Centers. The specific aims are AIM 1: To determine the alteration in Tfh cell subsets in blood in autoimmune diseases. AIM 2: To determine the alteration in Tfh cells and CD11c+ APCs in inflammatory tissues in autoimmune diseases. AIM 3: To determine whether APCs in inflammatory tissues are capable of inducing naive and memory CD4+ T cells to differentiate into Tfh cells, and AIM 4: To determine whether and how Tfr response is altered in autoimmune diseases. In conclusion, we might be able to reveal immunological pathways that cause altered Tfh/GC response shared by different autoimmune diseases as well as unique one to each disease.