Shi Xiaoyan, Xie Chun, Chang Sooghee, Zhou Xin J, Tedder Thomas, Mohan Chandra
University of Texas Southwestern Medical School, Dallas, TX 75390-8884, USA.
Arthritis Rheum. 2007 Sep;56(9):3057-69. doi: 10.1002/art.22825.
B cell hyperactivity is a common denominator in murine and human systemic lupus erythematosus. Some susceptibility genes in lupus are associated with B cell hyperactivity, but others are clearly not. While the Sle1 lupus susceptibility locus of NZM2410/NZW origin leads to chromatin-focused autoimmunity, genetically engineered overexpression of CD19 leads to "generalized" B cell hyperactivity. We undertook this study to determine the degree to which generalized B cell hyperactivity can amplify lupus pathogenesis.
To elucidate the impact of generalized B cell hyperactivity on Sle1-triggered autoimmunity, B6 mice bearing the human CD19 transgene were rendered congenic for the Sle1(z) genetic locus and phenotyped for serologic, cellular, and pathologic evidence of lupus.
As expected, B6.Sle1.hCD19(Tg/Tg) mice, homozygous at Sle1 and bearing the hCD19 transgene, exhibited high levels of IgM and IgG anti-DNA/antiglomerular autoantibodies, skewed B cell subsets, and profoundly activated B and T cells. Despite exhibiting glomerular IgM, IgG, and complement deposits, these mice did not exhibit accelerated mortality or any clinical evidence of renal dysfunction.
Generalized B cell hyperactivity may augment humoral autoimmunity, but this may not suffice to engender end-organ disease in lupus. These findings allude to the presence of an additional distal checkpoint that dissociates pathogenic autoantibody formation and renal immunoglobulin deposition from the progression to clinical nephritis in lupus.
B细胞功能亢进是小鼠和人类系统性红斑狼疮的一个共同特征。狼疮中的一些易感基因与B细胞功能亢进有关，但其他一些基因显然并非如此。虽然源自NZM2410/NZW的Sle1狼疮易感基因座会导致染色质聚焦的自身免疫，但通过基因工程过表达CD19会导致“全身性”B细胞功能亢进。我们进行这项研究以确定全身性B细胞功能亢进在多大程度上会加剧狼疮的发病机制。
为了阐明全身性B细胞功能亢进对Sle1引发的自身免疫的影响，使携带人CD19转基因的B6小鼠在Sle1(z)基因座上同源，并对狼疮的血清学、细胞和病理学证据进行表型分析。
正如预期的那样，在Sle1位点纯合且携带hCD19转基因的B6.Sle1.hCD19(Tg/Tg)小鼠表现出高水平的IgM和IgG抗DNA/抗肾小球自身抗体、B细胞亚群失衡以及B细胞和T细胞的深度活化。尽管这些小鼠表现出肾小球IgM、IgG和补体沉积，但它们并未表现出加速死亡或任何肾功能障碍的临床证据。
全身性B细胞功能亢进可能会增强体液自身免疫，但这可能不足以导致狼疮的终末器官疾病。这些发现暗示存在一个额外的远端检查点，该检查点将致病性自身抗体的形成和肾脏免疫球蛋白沉积与狼疮进展为临床肾炎区分开来。
