Ray S K, Putterman C, Diamond B
Department of Microbiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2019-24. doi: 10.1073/pnas.93.5.2019.
The immune system's ability to distinguish self and nonself is essential for both host defense against foreign agents and protection of self-antigens from autoimmune destruction. Such discrimination is complicated by extensive structural homology shared between foreign and self antigens. One hypothesis to explain the development of an autoimmune response is that some B cells activated by foreign antigen acquire, through somatic mutation, specificity for both the eliciting foreign antigen and self antigen. If such clones arise frequently, there must be a mechanism for their elimination. We have analyzed the extent of autoreactivity arising in a nonautoimmune host during the response to a foreign antigen. To overcome the process of apoptosis in primary B cells that might routinely eliminate autoreactive clones, we generated B-cell hybridomas from spleen cells of immunized mice by using a fusion partner constitutively expressing bcl-2. Multiple lines were obtained that recognize simultaneously the hapten phosphorylcholine and the self antigen double-stranded DNA. This dual specificity was not present early but was detected by day 10 after immunization. Some of these cross-reactive antibodies deposit in kidneys in a pattern similar to what is seen in autoimmune disease. These results demonstrate that autoantibodies arise at a high frequency as part of a response to foreign antigen. It has previously been shown that autoreactivity is regulated by central deletion; these data demonstrate a need for negative selection in peripheral lymphoid organs also, to regulate autoantibodies acquiring their self-specificity by somatic mutation.
免疫系统区分自身和非自身的能力对于宿主抵御外来病原体以及保护自身抗原免受自身免疫破坏至关重要。然而，由于外来抗原与自身抗原之间存在广泛的结构同源性，这种区分变得复杂。一种解释自身免疫反应发生的假说是，一些被外来抗原激活的B细胞通过体细胞突变获得了对引发外来抗原和自身抗原的特异性。如果这种克隆频繁出现，那么必然存在一种机制来消除它们。我们分析了非自身免疫宿主在对外来抗原的反应过程中产生的自身反应性程度。为了克服原代B细胞中可能常规消除自身反应性克隆的凋亡过程，我们通过使用组成性表达bcl-2的融合伙伴，从免疫小鼠的脾细胞中生成了B细胞杂交瘤。获得了多个同时识别半抗原磷酰胆碱和自身抗原双链DNA的细胞系。这种双重特异性在早期并不存在，但在免疫后第10天被检测到。其中一些交叉反应性抗体以与自身免疫疾病中所见相似的模式沉积在肾脏中。这些结果表明，作为对外来抗原反应的一部分，自身抗体以高频率产生。先前已经表明自身反应性受中枢清除调节；这些数据表明在外周淋巴器官中也需要进行阴性选择，以调节通过体细胞突变获得自身特异性的自身抗体。
