Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including Akkermansia muciniphila. IgA1 was deglycosylated by A. muciniphila both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1^KI-CD89^tg) that underwent intestinal colonization by A. muciniphila developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by A. muciniphila in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins—a risk locus for IgA nephropathy—inhibited growth of A. muciniphila in vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of A. muciniphila in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.

中文翻译：

---

肠道微生物群翻译后修饰自身免疫性肾小球肾炎中的 IgA1

获得性自身免疫中自我耐受破坏的机制仍不清楚。免疫球蛋白 A (IgA) 肾病是一种获得性自身免疫性疾病，其中去糖基化的 IgA1（IgA 亚类 1）自身抗原被 IgG 自身抗体识别，形成免疫复合物沉积在肾脏中，导致肾小球肾炎。在 IgA 肾病患者的肠道微生物群中，粘蛋白降解细菌的相对丰度增加，包括嗜粘蛋白阿克曼氏菌 (Akkermansia muciniphila)。 IgA1在体外和小鼠肠腔中均被A. muciniphila去糖基化。这产生了新表位，可以被 IgA 肾病患者血清中的自身反应性 IgG 识别。表达人 IgA1 和人 Fc α 受体 I (α1 ^KI -CD89 ^{tg ) 的小鼠在肠道内被}A. muciniphila定植后，出现了加重的 IgA 肾病表型。在小鼠肠腔中，IgA1 被A. muciniphila去糖基化后，IgA1 通过逆转录胞吞作用穿过肠上皮进入循环系统，并沉积在小鼠肾脏的肾小球中。人类 α-防御素（IgA 肾病的危险位点）在体外抑制 A. muciniphila的生长。在 IgA 肾病患者中，观察到的 α-防御素 6 粪便浓度与对照参与者肠道中A. muciniphila数量之间的负相关性消失了。这项研究表明，肠道微生物群失调会导致 IgA 肾病患者和该疾病的小鼠模型中自身抗原的产生。