Deciphering the stage specific impact of cellular and humoral components modulating the onset of RA

解读调节 RA 发病的细胞和体液成分的阶段特异性影响

• 批准号: 418295817
• 负责人: Dr. Anja Lux
• 金额: --
• 依托单位: Department Biologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418295817?language=en
• 关键词: Deciphering; stage; specific; impact; cellular

Autoantibodies play a central role in a variety of autoimmune diseases, including inflammatory arthritis. Of note, autoantibodies may be present years before the onset of clinical disease, suggesting that checkpoints modulating autoantibody pathology must be in place. Among these potential immune checkpoints, modulation of autoantibody activity via IgG glycosylation or altering the expression of activating versus inhibitory Fcg-receptors on innate immune effector cells may play a key role to switch autoantibodies from a non-pathogenic to a pathogenic form. Thus, the central aim of project B2 was to decipher the molecular and cellular changes occurring during the early phase of the disease in a spontaneous mouse model of inflammatory arthritis (KBxN mice). By broadly analysing changes in humoral and cellular immune function during the indolent and early phase of the disease our study generated a highly detailed, time-resolved map of the molecular and cellular changes during the pre- and early phase of inflammatory arthritis. We demonstrate that the appearance of GPI specific autoantibodies was preceded by a global change of serum glycosylation towards pro-inflammatory glycoforms and an expansion of plasma cells before the onset of joint inflammation. The change in serum IgG glycosylation was paralleled or even preceded by waves of pro-inflammatory cytokines including IL1, IL17, and IL27, while TNF and IL-6 levels were increasing steadily and closely correlated with intensifying clinical disease. In line with the early increase in IL1 an increased expression CD54 (ICAM-1) was noted on T cells and inflammatory monocytes before disease initiation, while changes in FcR expression occurred only during active disease. Based on the results of the first funding period we will focus on identifying which of these early changes in immune system function play a key role in orchestrating the later phases of disease during the second funding period. In addition, we will continue to use the clinical samples and develop a humanized mouse model to translate our findings to the human immune system.

自身抗体在包括炎症性关节炎在内的各种自身免疫性疾病中发挥核心作用。值得注意的是，自身抗体可能在临床疾病发生前几年就出现了，这表明调节自身抗体病理的检查点必须到位。在这些潜在的免疫检查点中，通过糖基化来调节自身抗体的活性或改变天然免疫效应细胞上激活和抑制的FCG受体的表达，可能在将自身抗体从非致病形式转变为致病形式中起到关键作用。因此，项目B2的中心目标是破译自发性炎性关节炎小鼠模型(KBxN小鼠)在疾病早期阶段发生的分子和细胞变化。通过广泛分析疾病惰性和早期阶段体液和细胞免疫功能的变化，我们的研究生成了炎性关节炎前期和早期阶段分子和细胞变化的非常详细的、时间分辨的地图。我们证明，在GPI特异性自身抗体出现之前，血清糖基化向促炎糖型的整体改变以及在关节炎症开始之前浆细胞的扩张。血清Ig G糖基化水平的变化与IL 1、IL 17、IL 2 7等促炎细胞因子的波动平行甚至先于其后，而肿瘤坏死因子和IL 6水平持续升高，且与临床病情加重密切相关。与IL-1早期升高相一致，T细胞和炎性单核细胞在发病前表达增加，而Fc-R的表达仅在活动期发生变化。根据第一个资助期的结果，我们将重点确定这些免疫系统功能的早期变化中的哪些在第二个资助期内协调疾病的后期阶段发挥关键作用。此外，我们将继续使用临床样本，并开发人源化的小鼠模型，将我们的发现转化为人类免疫系统。