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

自身抗体在包括炎性关节炎在内的多种自身免疫性疾病中起着核心作用。值得注意的是，自身抗体可能在临床疾病发作前数年就存在，这表明调节自身抗体病理学的检查点必须到位。在这些潜在的免疫检查点中，通过IgG糖基化调节自身抗体活性或改变先天性免疫效应细胞上活化性与抑制性Fcg受体的表达可能在将自身抗体从非致病性转变为致病性形式中起关键作用。因此，项目B2的中心目标是在自发性炎症性关节炎小鼠模型（KBxN小鼠）中破译疾病早期发生的分子和细胞变化。通过广泛分析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分子和细胞变化的高度详细的时间分辨图。我们证明GPI特异性自身抗体的出现之前，血清糖基化向促炎性糖型的全球变化和浆细胞的扩张，关节炎症发作之前。血清IgG糖基化水平的变化与IL 1 β、IL 17和IL 27等促炎细胞因子的波动同步甚至先于其变化，而TNF α和IL-6水平则持续升高，并与临床疾病的加重密切相关。在疾病开始之前，在T细胞和炎性单核细胞上观察到与IL 1 β早期增加一致的CD 54（ICAM-1）表达增加，而Fc γ R表达的变化仅发生在活动性疾病期间。根据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内对疾病的后期阶段起着关键作用。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.