Gubbels Melanie R, Jørgensen Trine N, Metzger Troy E, Menze Katherine, Steele Heather, Flannery Shannon A, Rozzo Stephen J, Kotzin Brian L
Division of Clinical Immunology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
J Immunol. 2005 Nov 1;175(9):6190-6. doi: 10.4049/jimmunol.175.9.6190.
The lupus-like disease that develops in hybrids of NZB and NZW mice is genetically complex, involving both MHC- and non-MHC-encoded genes. Studies in this model have indicated that the H2d/z MHC type, compared with H2d/d or H2z/z, is critical for disease development. C57BL/6 (B6) mice (H2b/b) congenic for NZB autoimmunity 2 (Nba2), a NZB-derived susceptibility locus on distal chromosome 1, produce autoantibodies to nuclear Ags, but do not develop kidney disease. Crossing B6.Nba2 to NZW results in H2b/z F1 offspring that develop severe lupus nephritis. Despite the importance of H2z in past studies, we found no enhancement of autoantibody production or nephritis in H2b/z vs H2b/b B6.Nba2 mice, and inheritance of H2z/z markedly suppressed autoantibody production. (B6.Nba2 x NZW)F1 mice, compared with MHC-matched B6.Nba2 mice, produced higher levels of IgG autoantibodies to chromatin, but not to dsDNA. Although progressive renal damage with proteinuria only occurred in F1 mice, kidneys of some B6.Nba2 mice showed similar extensive IgG and C3 deposition. We also studied male and female B6.Nba2 and F1 mice with different MHC combinations to determine whether increased susceptibility to lupus among females was also expressed within the context of the Nba2 locus. Regardless of MHC or the presence of NZW genes, females produced higher levels of antinuclear autoantibodies, and female F1 mice developed severe proteinuria with higher frequencies. Together, these studies help to clarify particular genetic and sex-specific influences on the pathogenesis of lupus nephritis.
NZB和NZW小鼠杂交后代中出现的狼疮样疾病在遗传上较为复杂，涉及MHC编码基因和非MHC编码基因。对该模型的研究表明，与H2d/d或H2z/z相比，H2d/z MHC类型对疾病发展至关重要。C57BL/6（B6）小鼠（H2b/b）携带来源于NZB的位于1号染色体远端的自身免疫易感位点NZB自身免疫2（Nba2），会产生针对核抗原的自身抗体，但不会发展为肾病。将B6.Nba2与NZW杂交产生H2b/z F1后代，这些后代会发展为严重的狼疮性肾炎。尽管在过去的研究中H2z很重要，但我们发现H2b/z与H2b/b的B6.Nba2小鼠相比，自身抗体产生或肾炎并未增强，并且H2z/z的遗传显著抑制了自身抗体的产生。与MHC匹配的B6.Nba2小鼠相比，（B6.Nba2×NZW）F1小鼠产生了更高水平的针对染色质而非双链DNA的IgG自身抗体。虽然只有F1小鼠出现了伴有蛋白尿的进行性肾损伤，但一些B6.Nba2小鼠的肾脏也显示出类似广泛的IgG和C3沉积。我们还研究了具有不同MHC组合的雄性和雌性B6.Nba2和F1小鼠，以确定雌性对狼疮易感性增加是否也在Nba2位点的背景下表现出来。无论MHC如何或是否存在NZW基因，雌性产生的抗核自身抗体水平更高，并且雌性F1小鼠出现严重蛋白尿的频率更高。总之，这些研究有助于阐明对狼疮性肾炎发病机制的特定遗传和性别特异性影响。
