XIAP Deficiency and Intestinal Inflammation: Study of an Orphan Disease and Pathways relevant for Inflammatory Bowel Disease

XIAP 缺乏和肠道炎症：孤儿疾病和炎症性肠病相关途径的研究

• 批准号: 240816342
• 负责人: Privatdozent Dr. Tobias Schwerd
• 金额: --
• 依托单位: Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/240816342?language=en
• 关键词: XIAP; Deficiency; Intestinal; Inflammation; Study

Inflammatory bowel disease (IBD), mainly Crohn's disease, is increasingly recognized in the pediatric population. A subgroup of patients suffers from onset of intestinal inflammation during the first years of life, called early-onset IBD (EO-IBD). Recent studies demonstrated that intestinal pathology of EO-IBD can derive from single disease causing genetic variants with strong biologic impact on intestinal immune homeostasis, like mutations in the genes encoding IL-10 or IL-10 receptor alpha or beta. Studies of primary immunodeficiency syndromes with colitis-phenotype contribute to our understanding of molecular mechanisms in those orphan diseases but more importantly, reveal pathways relevant for IBD in general.Mutations in the X-linked inhibitor of apoptosis protein (XIAP)-gene cause the rare primary immunodeficiency, X-linked lymphoproliferative syndrome type 2 (XLP-2). XLP-2 syndrome is characterized by recurrent episodes of hemophagocytic lymphohistiocytosis and splenomegaly. One fifth of patients develops severe IBD-like immunopathology. However, so far it is not understood how XIAP-deficiency leads to intestinal pathology. XIAP protein is associated with several immune signaling pathways implicated in IBD pathogenesis by genome-wide association studies (e.g. NOD2 signaling). Given the incomplete penetrance of colitis in XLP-2 syndrome, more common modifier genes or polymorphisms may contribute to the profound biologic effect of mutations in XIAP-gene. It remains elusive whether innate immune responses towards commensal microorganisms of the gut are affected by XIAP-deficiency. Aberrant bacterial handling and cytokine production by innate immune cells may lead to uncontrolled activation of adaptive immune cells and ultimately predispose to colitis. Thus, the aim of this research project is to investigate children with XIAP-deficiency and dissect signalling pathways relevant for IBD pathogenesis. As XIAP-deficiency is a rare disease with a potentially severe disease course in pediatric patients, the study has inherent limitations due to the limited availability of biological specimens. To overcome this problem, somatic cells of patients will be reprogrammed into a state of pluripotency by the forced expression of a set of transcription factors and subsequently, differentiated into immune cells. Patient-derived induced pluripotent stem cells (iPSC) carry the disease-causing genetic variants and allow to model disease mechanism in vitro. In addition, studies with iPSC-derived immune cells hold the potential to directly compare immune function at the cellular level with the significant diversity of clinical and immunological phenotypes among patients with different mutations occurring in the XIAP-gene.

炎症性肠病（IBD），主要是克罗恩病，在儿科人群中越来越受到重视。一部分患者在生命的最初几年会出现肠道炎症，称为早发性 IBD (EO-IBD)。最近的研究表明，EO-IBD 的肠道病理可能源于单一疾病引起的遗传变异，对肠道免疫稳态具有强烈的生物学影响，例如编码 IL-10 或 IL-10 受体 α 或 β 的基因突变。对具有结肠炎表型的原发性免疫缺陷综合征的研究有助于我们了解这些孤儿疾病的分子机制，但更重要的是，揭示了与 IBD 相关的一般途径。 X 连锁凋亡抑制蛋白 (XIAP) 基因的突变导致罕见的原发性免疫缺陷，即 X 连锁淋巴增殖综合征 2 型 (XLP-2)。 XLP-2综合征的特征是反复发作的噬血细胞性淋巴组织细胞增多症和脾肿大。五分之一的患者出现严重的 IBD 样免疫病理学。然而，到目前为止，尚不清楚 XIAP 缺乏如何导致肠道病理。通过全基因组关联研究（例如 NOD2 信号传导），XIAP 蛋白与 IBD 发病机制中涉及的多种免疫信号传导途径相关。鉴于 XLP-2 综合征中结肠炎的不完全外显率，更常见的修饰基因或多态性可能有助于 XIAP 基因突变的深远生物学效应。针对肠道共生微生物的先天免疫反应是否受到 XIAP 缺陷的影响仍不清楚。先天免疫细胞异常的细菌处理和细胞因子产生可能导致适应性免疫细胞不受控制的激活，并最终诱发结肠炎。因此，该研究项目的目的是调查 XIAP 缺陷的儿童并剖析与 IBD 发病机制相关的信号通路。由于 XIAP 缺乏症是一种罕见疾病，在儿科患者中可能会出现严重的病程，因此由于生物标本的可用性有限，该研究具有固有的局限性。为了克服这个问题，患者的体细胞将通过一组转录因子的强制表达被重新编程为多能状态，并随后分化为免疫细胞。源自患者的诱导多能干细胞 (iPSC) 携带致病遗传变异，可在体外模拟疾病机制。此外，对 iPSC 衍生免疫细胞的研究有可能在细胞水平上直接比较免疫功能与 XIAP 基因发生不同突变的患者的临床和免疫表型的显着多样性。