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

口服耐受性是粘膜免疫系统的重要特征,似乎可以通过钝化针对慢性存在于粘膜表面的免疫原的全身性IgG和IgM抗体的产生来预防免疫介导的疾病。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) 实验模型中的作用,IgA肾病是人类肾炎的重要形式。环磷酰胺和雌二醇用于抑制口服耐受性的表达,否则口服耐受性会在Ag的慢性口服表现后发展。连续14周饮用含有0.1% 牛丙种球蛋白 (BGG) 的BALB/c小鼠被随机分配到给予2 mg环磷酰胺i.p.,2 mg雌二醇的组。或者两种药物。对照组小鼠既未接受BGG也未接受药物。在三个单独的实验中,低百分比的经生理盐水处理的经口服免疫的小鼠具有显微镜下血尿 (0至20%),与未免疫的对照 (0至20%) 一样。然而,在适当的时间给予雌二醇和/或环磷酰胺的小鼠中有58至83% 出现明显的血尿。如果在次优时间给予药物,只有25至56% 的小鼠出现血尿。药物处理的免疫小鼠的血清IgG和IgM抗BGG抗体也比对照组和盐水组多。免疫荧光显示,与盐水处理的免疫小鼠和正常未经处理的对照小鼠相比,药物处理的免疫小鼠中IgG,IgM和C3的肾小球沉积明显更多。IgG,IgM和C3的血尿和肾小球沉积物与血清IgG和IgM抗体平行。所有免疫小鼠均显示出明显的系膜IgA和BGG沉积物,并且在盐水和药物处理的免疫小鼠之间此类沉积物没有差异。我们建议,通过促进全身IgG和IgM抗体产生而使口服耐受性减弱会导致慢性口服免疫小鼠的肾炎,而含有IgG和/或IgM的肾小球免疫复合物会促进IgAN的补体沉积和血尿。口腔 (或更一般的粘膜) 耐受性的类似缺陷可能在有症状的人IgAN的发生中起作用。

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