Jacobi Annett M, Zhang Jie, Mackay Meggan, Aranow Cynthia, Diamond Betty
The Center for Autoimmune and Musculoskeletal Diseases, Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York, USA.
PLoS One. 2009 Jun 2;4(6):e5776. doi: 10.1371/journal.pone.0005776.
DNA-reactive B cells play a central role in systemic lupus erythematosus (SLE); DNA antibodies precede clinical disease and in established disease correlate with renal inflammation and contribute to dendritic cell activation and high levels of type 1 interferon. A number of central and peripheral B cell tolerance mechanisms designed to control the survival, differentiation and activation of autoreactive B cells are thought to be disturbed in patients with SLE. The characterization of DNA-reactive B cells has, however, been limited by their low frequency in peripheral blood. Using a tetrameric configuration of a peptide mimetope of DNA bound by pathogenic anti-DNA antibodies, we can identify B cells producing potentially pathogenic DNA-reactive antibodies. We, therefore, characterized the maturation and differentiation states of peptide, (ds) double stranded DNA cross-reactive B cells in the peripheral blood of lupus patients and correlated these with clinical disease activity. Flow cytometric analysis demonstrated a significantly higher frequency of tetramer-binding B cells in SLE patients compared to healthy controls. We demonstrated the existence of a novel tolerance checkpoint at the transition of antigen-naïve to antigen-experienced. We further demonstrate that patients with moderately active disease have more autoreactive B cells in both the antigen-naïve and antigen-experienced compartments consistent with greater impairment in B cell tolerance in both early and late checkpoints in these patients than in patients with quiescent disease. This methodology enables us to gain insight into the development and fate of DNA-reactive B cells in individual patients with SLE and paves the way ultimately to permit better and more customized therapies.
DNA反应性B细胞在系统性红斑狼疮（SLE）中起核心作用；DNA抗体先于临床疾病出现，在已确诊疾病中与肾脏炎症相关，并促进树突状细胞活化和高水平的1型干扰素产生。旨在控制自身反应性B细胞存活、分化和活化的许多中枢和外周B细胞耐受机制在SLE患者中被认为受到干扰。然而，DNA反应性B细胞的特性一直受到其在外周血中低频率的限制。利用与致病性抗DNA抗体结合的DNA肽模拟表位的四聚体结构，我们可以识别产生潜在致病性DNA反应性抗体的B细胞。因此，我们对狼疮患者外周血中肽、（双链）双链DNA交叉反应性B细胞的成熟和分化状态进行了表征，并将其与临床疾病活动相关联。流式细胞术分析表明，与健康对照相比，SLE患者中四聚体结合B细胞的频率显著更高。我们证明了在从未接触抗原到接触过抗原的转变过程中存在一种新的耐受检查点。我们进一步证明，中度活动期疾病患者在未接触抗原和接触过抗原的细胞区室中都有更多的自身反应性B细胞，这与这些患者在早期和晚期检查点的B细胞耐受性损害比静止期疾病患者更大是一致的。这种方法使我们能够深入了解SLE个体患者中DNA反应性B细胞的发育和命运，并最终为更好、更个性化的治疗铺平道路。
