The interaction of mesenchymal stromal cells and activated B cells in the context of fibrosis-associated autoimmune diseases, under special consideration of systemic sclerosis and CREST syndrome

在系统性硬化症和 CREST 综合征的特殊考虑下，间充质基质细胞和活化 B 细胞在纤维化相关自身免疫性疾病背景下的相互作用

• 批准号: 394518511
• 负责人: Dr. Theresa Tretter, Ph.D.
• 金额: --
• 依托单位: Klinik für Hämatologie, Onkologie und Rheumatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/394518511?language=en
• 关键词: interaction; mesenchymal; stromal; cells; activated

Systemic Sclerosis (SSc) is a rare autoimmune disease, belonging to the group of collagenoses. SSc is characterized by progressive fibrosis of skin and internal organs and - in a subgroup of patients- additionally by increased calcifications (CREST syndrome). Current medications can delay fibrosis, however not really stop it. Fibrosis is the main determinant for mortality in SSc. Therefore a better basic understanding of SSc-associated fibrosis is of utmost importance to improve treatment options. The bidirectional cross-talk of activated immune cells and stromal cells, such as fibroblasts is considered a central mechanism in pathophysiology of SSc and other matrix remodeling autoimmune diseases. However, so far this interaction has not been sufficiently investigated. Specifically the participation of B cells in this process has long been considered to merely encompass production of pathological auto-antibodies, thereby supporting fibrosis in a direct or indirect manner. However several hints indicate that B cells can actively take part in the disease by other properties, such as their ability to secrete cytokines. For example improvement of the SSc symptoms upon B cell depleting therapy in patients is not necessarily paralleled by a reduction of antibody titers. And in vitro experiments from our own lab demonstrate that human B cells can activate fibroblasts from a non-inflammatory environment via secretion of soluble factors such as TNF-alpha and IL-1ß. Such activated fibroblasts increase their own cytokine production, including IL-8, IL-6 and TGFß up to 100fold above baseline concentration.Moreover our unpublished preliminary work to this project also revealed that B cells can modulate functions of multipotent mesenchymal stromal cells (MSC), including their differentiation capacity.These results together with additional observations, led us to the hypothesis that activated B cells may also contribute to pathogenesis and/or progression of SSc via their secretion of cytokines.The testing of this hypothesis includes: 1) the detailed elaboration of the bidirectional interaction of B cells and dermal fibroblasts (of healthy individuals and SSc lesions) under special consideration of SSc-specific conditions. 2) the investigation in how far activated B cells influence the differentiation of fibroblasts and MSC, - thereby contributing to aberrant fibrosis and calcification (CREST-syndrome), 3) the analysis of the B cell- mediated signaling pathways in fibroblasts and MSC and potential options for intervention, 4) the confirmation for antibody-independent influence of activated B cells on SSc-associated fibrosis by means of a 3-dimensional skin model. Our aim is to better elucidate the concept of B cells as modulators of fibrosis in SSc, as an autoimmune disease that is hardly understood, often aggressive and with few therapeutic options.

系统性硬化症（SSc）是一种罕见的自身免疫性疾病，属于胶原蛋白群。SSc的特征是皮肤和内脏器官进行性纤维化，在一个亚组患者中，还伴有钙化增加（CREST综合征）。目前的药物可以延缓纤维化，但不能真正阻止它。纤维化是SSc死亡率的主要决定因素。因此，更好地了解ssc相关纤维化对改善治疗方案至关重要。活化的免疫细胞和基质细胞（如成纤维细胞）的双向串扰被认为是SSc和其他基质重塑自身免疫性疾病病理生理的中心机制。然而，到目前为止，这种相互作用还没有得到充分的研究。特别是B细胞在这一过程中的参与一直被认为仅仅包括病理性自身抗体的产生，从而以直接或间接的方式支持纤维化。然而，一些迹象表明，B细胞可以通过其他特性积极参与疾病，例如它们分泌细胞因子的能力。例如，患者在B细胞消耗疗法后SSc症状的改善并不一定与抗体滴度的降低相一致。我们自己实验室的体外实验表明，人类B细胞可以通过分泌可溶性因子，如tnf - α和IL-1ß，在非炎症环境中激活成纤维细胞。这些被激活的成纤维细胞增加了自身细胞因子的产生，包括IL-8、IL-6和TGFß，达到基线浓度的100倍以上。此外，我们未发表的该项目的初步工作还揭示了B细胞可以调节多能间充质基质细胞（MSC）的功能，包括其分化能力。这些结果与其他观察结果一起，使我们提出这样的假设，即活化的B细胞也可能通过分泌细胞因子参与SSc的发病和/或进展。对这一假设的检验包括：1)在特殊考虑SSc特异性条件下，详细阐述B细胞和真皮成纤维细胞（健康个体和SSc病变）的双向相互作用。2)研究活化的B细胞在多大程度上影响成纤维细胞和间充质干细胞的分化，从而导致异常纤维化和钙化（crest综合征）；3)分析成纤维细胞和间充质干细胞中B细胞介导的信号通路以及潜在的干预方案；4)通过三维皮肤模型证实活化的B细胞对ssc相关纤维化的抗体独立影响。我们的目的是更好地阐明B细胞作为SSc纤维化调节剂的概念，SSc是一种难以理解的自身免疫性疾病，通常具有侵袭性且治疗选择很少。