背景:肠上皮细胞(IECs)可作为对抗潜在敌对腔抗原和共生微生物群的强大屏障。上皮屏障功能障碍增强肠通透性,导致与自身免疫性和慢性炎症性疾病相关的漏肠综合征(LGS)。然而,LGS与系统性疾病之间的因果关系尚不清楚.Ap1m2编码网格蛋白衔接子蛋白复合物1亚基mu2,这有助于极化蛋白质向基底外侧膜的运输,并有助于建立上皮屏障功能。
方法:我们产生了具有低肠屏障完整性的IEC特异性Ap1m2缺陷(Ap1m2ΔIEC)小鼠作为LSG模型,并检查了全身影响。
结果:Ap1m2ΔIEC小鼠自发出现IgA肾病(IgAN)样特征,其特征是IgA-IgG免疫复合物和补体因子在肾小球中沉积。由于IECs中聚合免疫球蛋白受体的下调和错误分类,Ap1m2缺乏显着增强了血清中异常糖基化的IgA。此外,Ap1m2缺乏通过减弱IL-22-STAT3信号导致肠道菌群失调。肠道菌群失调是IgAN的发病机理,因为抗生素治疗减少了Ap1m2ΔIEC小鼠中异常糖基化的IgA产生和肾脏IgA沉积。
结论:IEC屏障功能障碍和随后由AP-1B缺乏引起的菌群失调会引起IgA在小鼠肾脏中的沉积。我们的发现为LGS和IgAN之间的病理联系提供了实验证据。
背景:AMED,AMED-CREST,JSPS科学研究补助金,JSTCREST,富士蛋白质研究基金会,和庆应义大学促进下一代研究项目计划。
BACKGROUND: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions.
METHODS: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact.
RESULTS: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA-IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice.
CONCLUSIONS: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN.
BACKGROUND: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.