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

自身抗体在包括炎症性关节炎在内的多种自身免疫性疾病中发挥着核心作用。值得注意的是，自身抗体可能在临床疾病发病前几年就存在，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IgG糖基化或改变先天免疫效应细胞上激活或抑制fcg受体的表达来调节自身抗体活性可能在将自身抗体从非致病性转变为致病性方面发挥关键作用。因此，B2项目的中心目标是破译自发性炎症性关节炎小鼠模型（KBxN小鼠）疾病早期发生的分子和细胞变化。通过广泛分析在疾病的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症性关节炎前期和早期阶段的分子和细胞变化的非常详细的、时间分辨的地图。我们证明，GPI特异性自身抗体的出现之前，血清糖基化向促炎糖型的整体变化和浆细胞的扩张在关节炎症发作之前。血清IgG糖基化的变化与il - 1、il - 17、il - 27等促炎细胞因子的波动平行，甚至在此之前，而TNF、IL-6水平稳步上升，且与临床疾病的加重密切相关。与IL1的早期升高一致，在疾病开始前，T细胞和炎症单核细胞中CD54 （ICAM-1）表达升高，而FcR表达的变化仅发生在活动性疾病期间。基于第一个资助期的结果，我们将重点确定免疫系统功能的哪些早期变化在第二个资助期的疾病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小鼠模型，将我们的发现转化为人类免疫系统。

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.