Waters Samuel T, McDuffie Marcia, Bagavant Harini, Deshmukh Umesh S, Gaskin Felicia, Jiang Chao, Tung Kenneth S K, Fu Shu Man
The University of Virginia Specialized Center of Research on Systemic Lupus Erythematosus, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
J Exp Med. 2004 Jan 19;199(2):255-64. doi: 10.1084/jem.20031519. Epub 2004 Jan 12.
In lupus-prone NZM2328 mice, a locus Cgnz1 on chromosome 1 was linked to chronic glomerulonephritis, severe proteinuria, and early mortality in females. A locus Adnz1 on chromosome 4 was linked to antinuclear antibody (ANA) and anti-double stranded DNA (dsDNA) antibody (Ab) production. In this investigation, two congenic strains, NZM2328.C57L/Jc1 (NZM.C57Lc1) and NZM2328.C57L/Jc4 (NZM.C57Lc4), were generated by replacing the respective genetic intervals containing either Cgnz1 or Adnz1 with those from C57L/J, a nonlupus-prone strain. The NZM.C57Lc1 females had markedly reduced incidence of chronic glomerulonephritis and severe proteinuria. NZM.C57Lc4 females had chronic glomerulonephritis and severe proteinuria without circulating ANA, anti-dsDNA, and antinucleosome Ab. These data confirm the linkage analysis. Unexpectedly, NZM.C57Lc1 females had little anti-dsDNA and related Ab, suggesting the presence of a second locus Adnz2 on chromosome 1. The diseased NZM.C57Lc4 kidneys had immune complexes by immunofluorescence and electron microscopy. The eluates from these kidneys did not contain ANA, anti-dsDNA, and antinucleosome Ab, indicative of the presence of non-anti-dsDNA nephritogenic Ab. Thus, breaking tolerance to dsDNA and chromatin is not required for the pathogenesis of lupus nephritis. These results reaffirm that anti-dsDNA and related Ab production and chronic glomerulonephritis are under independent genetic control. These findings have significant implications in the pathogenesis of systemic lupus erythematosus.
在易患狼疮的新西兰混合2328（NZM2328）小鼠中，1号染色体上的Cgnz1位点与慢性肾小球肾炎、严重蛋白尿以及雌性小鼠的早期死亡有关。4号染色体上的Adnz1位点与抗核抗体（ANA）和抗双链DNA（dsDNA）抗体（Ab）的产生有关。在本研究中，通过用非易患狼疮品系C57L/J的相应基因区间替换包含Cgnz1或Adnz1的各自基因区间，产生了两个同源近交系，即NZM2328.C57L/Jc1（NZM.C57Lc1）和NZM2328.C57L/Jc4（NZM.C57Lc4）。NZM.C57Lc1雌性小鼠慢性肾小球肾炎和严重蛋白尿的发病率显著降低。NZM.C57Lc4雌性小鼠患有慢性肾小球肾炎和严重蛋白尿，但没有循环的ANA、抗dsDNA和抗核小体抗体。这些数据证实了连锁分析。出乎意料的是，NZM.C57Lc1雌性小鼠几乎没有抗dsDNA及相关抗体，这表明1号染色体上存在第二个位点Adnz2。患病的NZM.C57Lc4小鼠肾脏通过免疫荧光和电子显微镜检查发现有免疫复合物。这些肾脏的洗脱液中不含有ANA、抗dsDNA和抗核小体抗体，这表明存在非抗dsDNA致肾炎抗体。因此，狼疮性肾炎的发病机制并不需要打破对dsDNA和染色质的耐受性。这些结果再次证实，抗dsDNA及相关抗体的产生和慢性肾小球肾炎受独立的基因控制。这些发现对系统性红斑狼疮的发病机制具有重要意义。
