Haas C, Ryffel B, Le Hir M
Institute of Toxicology, University of Zürich, Switzerland.
J Immunol. 1997 Jun 1;158(11):5484-91.
MRL/lpr mice develop lymphoproliferation and accelerated autoimmune glomerulonephritis from which they ultimately die. To investigate the role of IFN-gamma in the manifestation of the disease, we generated MRL/lpr mice lacking the IFN-gamma receptor (MRL/lpr gammaR -/-). The absence of IFN-gamma signaling had no effect on generalized lymphoproliferation, expansion of CD4- CD8- double-negative T cells, or hypergammaglobulinemia. By contrast, glomerulonephritis as detected by proteinuria and histology was absent in MRL/lpr gammaR -/- mice. While serum IgG1 anti-dsDNA Abs were increased in all three strains of MRL/lpr mice (gammaR +/+, +/-, -/-), those of the IgG2a and IgG3 isotypes were low in MRL/lpr gammaR -/- mice. Immune complexes and C3 deposition were dramatically reduced in the glomerular capillaries of MRL/lpr gammaR -/- mice compared with MRL/lpr gammaR +/+ and +/- mice. Therefore, IFN-gamma plays a key regulatory role in the development of nephritis in MRL/lpr mice. Low levels of IFN-gamma-dependent IgG2a and IgG3 autoantibodies in MRL/lpr gammaR -/- mice might protect them from the pathogenic features of IgG3 cryoglobulins and complement-activating IgG2a and IgG3.
MRL/lpr小鼠会发生淋巴细胞增生，并加速自身免疫性肾小球肾炎的发展，最终导致死亡。为了研究γ干扰素在该疾病表现中的作用，我们培育出了缺乏γ干扰素受体的MRL/lpr小鼠（MRL/lpr γR -/-）。γ干扰素信号缺失对全身性淋巴细胞增生、CD4-CD8双阴性T细胞扩增或高球蛋白血症均无影响。相比之下，MRL/lpr γR -/-小鼠未出现通过蛋白尿和组织学检测到的肾小球肾炎。虽然在所有三株MRL/lpr小鼠（γR +/+、+/ -、-/-）中血清IgG1抗双链DNA抗体均升高，但MRL/lpr γR -/-小鼠中IgG2a和IgG3同种型的抗体水平较低。与MRL/lpr γR +/+和+/ -小鼠相比，MRL/lpr γR -/-小鼠肾小球毛细血管中的免疫复合物和C3沉积显著减少。因此，γ干扰素在MRL/lpr小鼠肾炎的发展中起关键调节作用。MRL/lpr γR -/-小鼠中低水平的γ干扰素依赖性IgG2a和IgG3自身抗体可能使其免受IgG3冷球蛋白以及补体激活型IgG2a和IgG3致病特征的影响。
