Elucidation of properties and mechanism of development of autoimmune diseases in new congenic MRL/MpJ-lprcg/lprcg mice

我们<cg>在CBA/KIJms（CBA）小鼠中发现的新的淋巴增殖性和自身免疫性lpr^基因通过12次回交转移到MRL/MpJ（MRL）背景上。所得到的同源MRL-lpr^<cg>/lpr^<cg>小鼠发展出以CD 4 -8-、Thy-1+、B220+淋巴样细胞（DN T细胞）扩增为特征的淋巴组织增生性疾病。肾脏组织学显示，MRL-lpr^<cg>/lpr^<cg>小鼠发生的肾小球肾炎与MRL-lpr/lpr小鼠的肾小球肾炎难以区分，尽管前者的发生率略低。肾小球免疫复合物沉积在MRL-lpr^<cg>/lpr^<cg>和MRL-lpr/lpr小鼠中几乎相同。MRL-lpr ^ /lpr^的血清IG、循环免疫复合物和自身抗体水平<cg><cg>与MRL-lpr/lpr相当甚至更高。比较有肾小球肾炎的MRL-lpr^<cg>/lpr^<cg>与无肾小球肾炎的CBA-lpr^<cg>/lpr^<cg>，发现MRL-lpr^ /lpr^与MRL-lpr/lpr^一样，其类特异性自身抗体应答中IgM到IgG的类别转换和血清IG水平均增强<cg><cg>。MRL-lpr ^<cg>/+小鼠的淋巴结和脾脏明显较大，没有异常DN T细胞的聚集。值得注意的是，在MRL-lpr^ /+和-lpr^ /lpr^中肾小球肾炎的发生率和严重程度相似<cg><cg><cg>，提示DN T细胞在肾脏疾病中没有参与。这些结果共同表明，lpr^<cg>通过与lpr相同的机制诱导肾小球肾炎和MRL背景下的血清学异常，正如从两个突变基因之间的等位性所预期的，并且新建立的同源MRL-lpr^<cg>/lpr^<cg>小鼠将为研究小鼠自身免疫提供独特的模型。

The novel lymphoproliferative and autoimmune lpr^<cg> gene, which we discovered in the CBA/KIJms (CBA) mice, was transferred onto the MRL/MpJ (MRL) background by 12 backcrosses. The resulting congenic MRL-lpr^<cg>/lpr^<cg> mice developed lymphoproliferative disease characterized by expansion of CD4-8-, Thy-1+, B220+ lymphoid cells (DN T cells). The histology of the kidney revealed that MRL-lpr^<cg>/lpr^<cg> mice developed glomerulonephritis indistinguishable from that in MRL-lpr/lpr although its frequency was slightly lower in the former. Glomerular immune complex deposition was almost the same in MRL-lpr^<cg>/lpr^<cg> and MRL-lpr/lpr mice. The levels of serum Ig, circulating immune complexes and autoantibodies in MRL-lpr^<cg>/lpr^<cg> were comparable to or even higher than those in MRL-lpr/lpr. Comparison between MRL-lpr^<cg>/lpr^<cg> with glomerulonephritis and CBA-lpr^<cg>/lpr^<cg> without it evidenced that the IgM-to-IgG class switch in class-specific autoantibody responses and serum Ig levels were enhanced in MRL-lpr^<cg>/lpr^<cg> as in MRL-lpr/lpr, Moreover, the function of the heterozygous lpr was investigated. MRL-lpr^<cg>/+ mice had significantly larger lymph nodes and spleens free from accumulation of anomalous DN T cells. Noticeably, the incidence and severity of gromeluronephritis were similar in MRL-lpr^<cg>/+ and -lpr^<cg>/lpr^<cg>, suggestive of no involvement of DN T cells in renal disease. These results taken together indicate that the lpr^<cg> functions through the same mehanism as lpr in induction of glomerulonephritis and serological abnormalities on the MRL background as expected from the allelism between both mutant genes and that the newly established conenic MRL-lpr^<cg>/lpr^<cg> mouse will provide a unique model for reserach into autoimmunity in mice.