2nd Department of Internal Medicine, Semmelweis University, 1088 Budapest, Hungary.
World J Gastroenterol. 2013 Jul 28;19(28):4447-54. doi: 10.3748/wjg.v19.i28.4447.
Crohn's disease representing a clinical phenotype of inflammatory bowel disease is a polygenic immune disorder with complex multifactor etiology. Recent genome-wide association studies of susceptibility loci have highlighted on the importance of the autophagy pathway, which previously had not been implicated in disease pathology. Autophagy represents an evolutionarily highly conserved multi-step process of cellular self-digestion due to sequestration of excessive, damaged, or aged proteins and intracellular organelles in double-membranous vesicles of autophagosomes, terminally self-digested in lysosomes. Autophagy is deeply involved in regulation of cell development and differentiation, survival and senescence, and it also fundamentally affects the inflammatory pathways, as well as the innate and adaptive arms of immune responses. Autophagy is mainly activated due to sensors of the innate immunity, i.e., by pattern recognition receptor signaling. The interplay of genes regulating immune functions is strongly influenced by the environment, especially gut resident microbiota. The basic challenge for intestinal immune recognition is the requirement of a simultaneous delicate balance between tolerance and responsiveness towards microbes. On the basis of autophagy-related risk genetic polymorphisms (ATG16L1, IRGM, NOD2, XBP1) impaired sensing and handling of intracellular bacteria by innate immunity, closely interrelated with the autophagic and unfolded protein pathways seem to be the most relevant immunobiologic events. Autophagy is now widely considered as a key regulator mechanism with the capacity to integrate several aspects of Crohn's disease pathogenesis. In this review, recent advances in the exciting crosstalk of susceptibility coding variants-related autophagy and innate immunity are discussed.
克罗恩病是一种炎症性肠病的临床表型，是一种具有复杂多因素病因的多基因免疫紊乱。最近对易感性基因座的全基因组关联研究强调了自噬途径的重要性，而自噬途径以前与疾病病理无关。自噬是一种由于自噬体双层膜囊泡中隔离过多、受损或衰老的蛋白质和细胞内细胞器而导致的细胞自我消化的进化上高度保守的多步骤过程，最终在溶酶体中自我消化。自噬深度参与细胞发育和分化、存活和衰老的调节，它也从根本上影响炎症途径以及免疫反应的先天和适应性分支。自噬主要通过先天免疫传感器激活，即通过模式识别受体信号。调节免疫功能的基因相互作用强烈受到环境的影响，特别是肠道常驻微生物群。肠道免疫识别的基本挑战是需要在对微生物的耐受性和反应性之间同时保持微妙的平衡。基于与自噬相关的风险遗传多态性（ATG16L1、IRGM、NOD2、XBP1），先天免疫对细胞内细菌的感应和处理受损，与自噬和未折叠蛋白途径密切相关，这似乎是最相关的免疫生物学事件。自噬现在被广泛认为是一种关键的调节机制，具有整合克罗恩病发病机制几个方面的能力。在这篇综述中，讨论了与自噬和先天免疫相关的易感性编码变异体的令人兴奋的串扰的最新进展。
