Emancipator S N, Ovary Z, Lamm M E
Lab Invest. 1987 Sep;57(3):269-76.
We sought to determine if codeposits of IgG and IgM and glomerular complement, observed in most cases of human IgA nephropathy, might be important for inducing hematuria. All combinations of three binary variables, the protein immunogen, the duration of oral immunization, and the protein used for intravenous challenge, were accommodated by eight groups of BALB/c mice in an active model of IgA nephropathy. Mice drank 0.1% solutions of either of two proteins for either 6 or 14 weeks, and then were challenged intravenously with either the same protein or the alternate protein. After 6 weeks, all mice had significant increases of serum IgA, IgG, and IgM antibody to the oral immunogen. At 14 weeks, IgG and IgM antibodies were reduced, presumably due to the onset of oral tolerance, but IgA titers persisted. Nearly all mice had mesangial deposits of IgA and oral immunogen. However, only mice immunized for 6 weeks and challenged with the same protein had significant IgG and IgM deposits (100%), C3 deposits (76%), and significant microhematuria. To distinguish between the role of IgG/IgM codeposits and C3 in the pathogenesis of the hematuria, we induced passive IgA nephropathy with immune complexes of monoclonal IgA anti-dinitrophenyl antibody, dinitrophenyl-bovine albumin as antigen, and one of two monoclonal IgG antibodies specific for dinitrophenyl; one of the IgGs fixes complement, the other does not. Despite comparable mesangial deposits of IgA, IgG, and antigen, only mice given immune complexes containing the complement-fixing IgG had glomerular C3 and hematuria. Furthermore, when mice depleted of serum complement via cobra venom factor were given immune complexes containing the complement-fixing IgG, no glomerular complement was observed and no hematuria ensued. We conclude that IgG/IgM codeposits in murine IgA nephropathy do not directly cause hematuria but do induce the deposition of complement, which is in turn required for glomerular injury.
我们试图确定在大多数人类IgA肾病病例中观察到的IgG和IgM与肾小球补体的共沉积是否对诱发血尿至关重要。在IgA肾病的主动模型中，八组BALB/c小鼠涵盖了三种二元变量的所有组合，即蛋白质免疫原、口服免疫的持续时间以及用于静脉内激发的蛋白质。小鼠饮用两种蛋白质中任一种的0.1%溶液6周或14周，然后静脉内注射相同的蛋白质或另一种蛋白质。6周后，所有小鼠针对口服免疫原的血清IgA、IgG和IgM抗体均显著增加。在14周时，IgG和IgM抗体减少，推测是由于口服耐受的开始，但IgA滴度持续存在。几乎所有小鼠都有IgA和口服免疫原的系膜沉积。然而，只有免疫6周并用相同蛋白质激发的小鼠有显著的IgG和IgM沉积（100%）、C3沉积（76%）以及显著的微量血尿。为了区分IgG/IgM共沉积和C3在血尿发病机制中的作用，我们用单克隆IgA抗二硝基苯基抗体、二硝基苯基 - 牛血清白蛋白作为抗原以及两种对二硝基苯基特异的单克隆IgG抗体之一的免疫复合物诱导被动性IgA肾病；其中一种IgG可固定补体，另一种则不能。尽管IgA、IgG和抗原的系膜沉积相当，但只有给予含有可固定补体的IgG的免疫复合物的小鼠出现肾小球C3和血尿。此外，当通过眼镜蛇毒因子耗尽血清补体的小鼠给予含有可固定补体的IgG的免疫复合物时，未观察到肾小球补体，也未出现血尿。我们得出结论，小鼠IgA肾病中的IgG/IgM共沉积不会直接导致血尿，但会诱导补体沉积，而补体沉积反过来又是肾小球损伤所必需的。
