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

炎症性肠病(IBD)，主要是克罗恩病，在儿科人群中得到越来越多的认识。一组患者在出生后的头几年出现肠道炎症，称为早发性IBD(EO-IBD)。最近的研究表明，EO-IBD的肠道病理可以源于单个疾病引起的基因变异，这些变异对肠道免疫稳态有很强的生物影响，如编码IL-10或IL-10受体α或β的基因突变。对结肠炎表型的原发免疫缺陷综合征的研究不仅有助于我们了解这些孤儿疾病的分子机制，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免疫缺陷，X-连锁淋巴增殖性综合征2型(XLP-2)。XLP-2综合征的特征是反复发作噬血细胞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。然而，到目前为止，XIAP缺乏如何导致肠道病理还不清楚。全基因组相关性研究表明，XIAP蛋白与多种免疫信号通路有关(如NOD2信号通路)，参与IBD的发病机制。鉴于XLP-2综合征中结肠炎的不完全外显性，更常见的修饰基因或多态可能与XIAP-基因突变的深刻生物学效应有关。对于肠道共生微生物的先天免疫反应是否受到XIAP缺乏症的影响尚不清楚。先天性免疫细胞对细菌的异常处理和细胞因子的产生可能导致适应性免疫细胞的不受控制的激活，最终易患结肠炎。因此，本研究项目的目的是调查XIAP缺乏的儿童，并剖析与IBD发病相关的信号通路。由于XIAP缺乏症是一种罕见的疾病，在儿科患者中具有潜在的严重病程，由于生物样本的有限，这项研究具有固有的局限性。为了克服这一问题，患者的体细胞将通过一组转录因子的强制表达而重新编程为多能状态，随后分化为免疫细胞。患者来源的诱导多能干细胞(IPSC)携带致病基因变异，并允许在体外建立疾病机制的模型。此外，对IPSC来源的免疫细胞的研究有可能直接比较细胞水平的免疫功能与XIAP基因不同突变患者的临床和免疫学表型的显著差异。

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.