Oral tolerance, an important feature of the mucosal immune system, appears to protect against immune-mediated disease by blunting production of systemic IgG and IgM antibody directed toward immunogens chronically present at mucosal surfaces. In this study, we explored the role of oral tolerance and mucosal immunoregulation in an experimental model of IgA nephropathy (IgAN), an important form of nephritis in humans. Cyclophosphamide and estradiol were used to inhibit the expression of oral tolerance, which otherwise develops after chronic oral presentation of Ag. BALB/c mice given drinking water containing 0.1% bovine gamma globulin (BGG) continuously for 14 wk were randomly assigned to groups given either 2 mg of cyclophosphamide i.p., 2 mg of estradiol s.c. or both drugs. Groups of control mice received neither BGG nor drugs. In three separate experiments, a low percentage of saline-treated orally immunized mice had microscopic hematuria (0 to 20%), as did nonimmunized controls (0 to 20%). However, 58 to 83% of mice given estradiol and/or cyclophosphamide at appropriate times developed significant hematuria. If drugs were given at suboptimal times, only 25 to 56% of mice developed hematuria. Drug-treated immunized mice also had more serum IgG and IgM anti-BGG antibodies than control and saline groups. Immunofluorescence showed significantly more glomerular deposits of IgG, IgM, and C3 in drug-treated immunized mice compared to saline-treated immunized and normal untreated control mice. Hematuria and glomerular deposits of IgG, IgM, and C3 paralleled serum IgG and IgM antibody. All immunized mice showed significant mesangial IgA and BGG deposits and there were no differences in such deposits between saline- and drug-treated immunized mice. We suggest that blunting of oral tolerance with promotion of systemic IgG and IgM antibody production leads to nephritis in chronically orally immunized mice and that glomerular immune complexes containing IgG and/or IgM promote complement deposition and hematuria in IgAN. Analogous defects in oral (or more generally mucosal) tolerance could play a role in the genesis of symptomatic human IgAN.

译文

:口腔耐受是粘膜免疫系统的一个重要特征,它似乎通过减弱针对长期存在于粘膜表面的免疫原的全身性IgG和IgM抗体的产生,来保护自身免受免疫介导的疾病的侵害。在这项研究中,我们探讨了口服耐受性和粘膜免疫调节在IgA肾病(IgAN)(一种人类肾炎的重要形式)实验模型中的作用。环磷酰胺和雌二醇被用来抑制口腔耐受的表达,否则这种耐受会在长期口服银后产生。连续14周连续喝含0.1%牛γ-球蛋白(BGG)的饮用水的BALB / c小鼠被随机分为两组,分别给予2 mg环磷酰胺i.p.,2 mg雌二醇s.c.或同时使用这两种药物。对照组小鼠既不接受BGG也不接受药物。在三个独立的实验中,经盐水处理的经口免疫小鼠中有低百分比的患者出现镜下血尿(0%至20%),而未免疫的对照小鼠则为0%至20%。但是,在适当的时间接受雌二醇和/或环磷酰胺的小鼠中有58%至83%出现了明显的血尿。如果在次佳的时间服用药物,则只有25%到56%的小鼠会出现血尿。药物治疗的免疫小鼠也比对照组和生理盐水组具有更多的血清IgG和IgM抗BGG抗体。免疫荧光显示与盐水处理的免疫小鼠和正常未处理的对照小鼠相比,在药物处理的免疫小鼠中IgG,IgM和C3的肾小球沉积明显更多。血尿和IgG,IgM和C3的肾小球沉积物与血清IgG和IgM抗体平行。所有免疫的小鼠均显示出明显的肾小球系膜IgA和BGG沉积物,盐水和药物处理的免疫小鼠之间的沉积物无差异。我们建议通过口服全身免疫的小鼠促进全身性IgG和IgM抗体产生的口服耐受性减退会导致肾炎,而含有IgG和/或IgM的肾小球免疫复合物会促进IgAN中的补体沉积和血尿。口腔(或更常见的粘膜)耐受性的类似缺陷可能在有症状的人类IgAN的发生中起作用。

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