Sekiguchi Debora R, Jainandunsing Sandra M, Fields Michele L, Maldonado Michael A, Madaio Michael P, Erikson Jan, Weigert Martin, Eisenberg Robert A
Department of Medicine, Division of Rheumatology, Wistar Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Immunol. 2002 Apr 15;168(8):4142-53. doi: 10.4049/jimmunol.168.8.4142.
Anti-dsDNA Abs are specific diagnostic markers of systemic lupus erythematosus, and are also implicated in kidney pathology. Anti-dsDNA B cells have been shown to be tolerized in nonautoimmune mice. The immunodysregulation that causes these cells to break tolerance is presumably part of the fundamental defects in systemic lupus erythematosus. To explore these mechanisms, we used the chronic graft-versus-host model mediated by MHC class II differences. Induction of chronic graft-vs-host in anti-DNA H chain knockin (3H9.KI) transgenic mice on a nonautoimmune background resulted in specific activation of anti-dsDNA B cells, as evidenced by high titers of soluble Ab in sera and a high frequency (70%) of anti-dsDNA B cell clones recovered as hybridomas. In addition, the lambda(+)-anti-dsDNA B cells developed increased expression of cell surface activation markers, and concentrated in the T cell area of the follicle with an Ab-forming cell-compatible phenotype. Genetic analysis of the hybridoma clones showed strong evidence of secondary rearrangements of the L chain associated with anti-dsDNA reactivity. Thus, our study indicates that alloreactive T cell help can break tolerance in a complex manner, involving several events.
抗双链DNA抗体是系统性红斑狼疮的特异性诊断标志物，也与肾脏病变有关。抗双链DNA B细胞在非自身免疫小鼠中已被证明处于耐受状态。导致这些细胞打破耐受的免疫失调可能是系统性红斑狼疮基本缺陷的一部分。为了探究这些机制，我们使用了由MHC II类差异介导的慢性移植物抗宿主模型。在非自身免疫背景的抗DNA重链敲入（3H9.KI）转基因小鼠中诱导慢性移植物抗宿主反应，导致抗双链DNA B细胞特异性活化，血清中高滴度的可溶性抗体以及作为杂交瘤回收的抗双链DNA B细胞克隆的高频率（70%）证明了这一点。此外，λ(+)抗双链DNA B细胞表面活化标志物的表达增加，并集中在具有抗体形成细胞兼容表型的滤泡T细胞区。对杂交瘤克隆的基因分析显示，与抗双链DNA反应性相关的轻链二次重排有强有力的证据。因此，我们的研究表明，同种异体反应性T细胞辅助可以以复杂的方式打破耐受，涉及多个事件。
