Kuroki Aki, Moll Thomas, López-Hoyos Marcos, Fossati-Jimack Liliane, Ibnou-Zekri Nabila, Kikuchi Shuichi, Merino Jesús, Merino Ramón, Izui Shozo
Department of Pathology, CMU, Geneva, Switzerland.
Eur J Immunol. 2004 Apr;34(4):1077-84. doi: 10.1002/eji.200424859.
The presence of rheumatoid factors (RF) is a characteristic feature of patients with rheumatoid arthritis, but not systemic lupus erythematosus. In this study, we have explored the role of the anti-apoptotic Bcl-2 protein and the Y-linked autoimmune acceleration (Yaa) mutation in the production of IgG RF in comparison with IgG anti-DNA autoimmune responses. Analysis in C57BL/6 mice, in their F1 hybrids with lupus-prone NZW mice, and in bone marrow chimeras containing mixtures of C57BL/6 bcl-2-transgenic and BXSB non-transgenic cells demonstrated that an enforced Bcl-2 expression in B cells promoted the induction of IgG anti-DNA production in these mice, while significant IgG RF responses were observed only in mice developing high levels of gp70-anti-gp70 immune complexes and lethal glomerulonephritis. Moreover, in contrast to a synergistic interaction between the Yaa mutation and Bcl-2 overexpression on IgG anti-DNA production, the Yaa mutation failed to enhance the production of IgG RF induced in bcl-2-transgenic mice. Our results reveal that defects in the regulation of B cell apoptosis play a critical role in the production of IgG RF, and that the Yaa mutation differentially modulates RF and anti-DNA autoimmune responses, likely related to the nature of autoantigens involved in each autoimmune response.
类风湿因子（RF）的存在是类风湿关节炎患者的一个特征性表现，但系统性红斑狼疮患者则不然。在本研究中，我们探讨了抗凋亡Bcl-2蛋白和Y连锁自身免疫加速（Yaa）突变在IgG RF产生中的作用，并与IgG抗DNA自身免疫反应进行了比较。对C57BL/6小鼠、其与易患狼疮的NZW小鼠的F1杂种以及含有C57BL/6 bcl-2转基因和BXSB非转基因细胞混合物的骨髓嵌合体进行分析，结果表明，B细胞中Bcl-2的强制表达促进了这些小鼠中IgG抗DNA的产生，而仅在产生高水平gp70-抗gp70免疫复合物和致死性肾小球肾炎的小鼠中观察到显著的IgG RF反应。此外，与Yaa突变和Bcl-2过表达对IgG抗DNA产生的协同相互作用相反，Yaa突变未能增强bcl-2转基因小鼠中诱导的IgG RF的产生。我们的结果表明，B细胞凋亡调节缺陷在IgG RF的产生中起关键作用，并且Yaa突变对RF和抗DNA自身免疫反应有不同的调节作用，这可能与每种自身免疫反应中涉及的自身抗原的性质有关。
