PDF(Pubmed)
Abstract：
Inflammatory bowel disease (IBD) is a multifactorial disorder triggered by imbalances of the microbiome and immune dysregulations in genetically susceptible individuals. Several mouse and human studies have demonstrated that multimeric inflammasomes are critical regulators of host defense and gut homeostasis by modulating immune responses to pathogen- or damage-associated molecular patterns. In the context of IBD, excessive production of pro-inflammatory Interleukin-1β has been detected in patient-derived intestinal tissues and correlated with the disease severity or failure to respond to anti-tumor necrosis factor therapy. Correspondingly, genome-wide association studies have suggested that single nucleotide polymorphisms in inflammasome components might be associated with risk of IBD development. The relevance of inflammasomes in controlling human intestinal homeostasis has been further exemplified by the discovery of very early onset IBD (VEO-IBD) patients with monogenic defects affecting different molecules in the complex regulatory network of inflammasome activity. This review provides an overview of known causative monogenic entities of VEO-IBD associated with altered inflammasome activity. A better understanding of the molecular mechanisms controlling inflammasomes in monogenic VEO-IBD may open novel therapeutic avenues for rare and common inflammatory diseases.
摘要：
炎症性肠病（IBD）是一种多因素疾病，由遗传易感个体中微生物组的失衡和免疫失调引发。一些小鼠和人类研究表明，多聚炎性体通过调节对病原体或损伤相关分子模式的免疫反应，是宿主防御和肠道稳态的关键调节剂。在IBD的背景下，在患者来源的肠组织中检测到促炎性白细胞介素-1β的过度产生,并与疾病的严重程度或对抗肿瘤坏死因子治疗的反应失败相关.相应地,全基因组关联研究表明,炎性体成分中的单核苷酸多态性可能与IBD发展风险相关.炎症小体在控制人类肠道内稳态中的相关性已经通过发现具有影响炎症小体活性的复杂调节网络中的不同分子的单基因缺陷的极早发作IBD(VEO-IBD)患者而得到进一步例证。这篇综述概述了与炎症小体活性改变相关的VEO-IBD的已知致病单基因实体。更好地了解单基因VEO-IBD中控制炎性体的分子机制可能会为罕见和常见的炎性疾病开辟新的治疗途径。
