Centre National de la Recherche Scientifique, Institut de Biologie Moléculaire et Cellulaire, Immunologie et Chimie Thérapeutiques, Strasbourg, France.
J Immunol. 2010 Apr 1;184(7):3937-45. doi: 10.4049/jimmunol.0902595. Epub 2010 Feb 24.
An important hallmark of systemic lupus erythematosus is the production of autoantibodies specific for nuclear Ags, among which nucleosomes and their constituents, DNA and histones. It is widely admitted that some of these autoantibodies contribute largely in lupus pathogenesis because of their nephritogenic potential. However, the underlying mechanisms are still debated. In this study, we analyzed the autoimmune response against histone H2B during the course of the disease in lupus-prone (NZBxNZW)F1 mice, both in lymphoid organs and kidneys, and we assessed its potential involvement in lupus pathogenicity. We found that the N-terminal region of histone H2B represents a preferential target for circulating autoantibodies, which kinetics of appearance positively correlates with disease development. Furthermore, immunization of preautoimmune (NZBxNZW)F1 mice with H2B peptide 1-25 accelerates the disease. Kidney eluates from diseased (NZBxNZW)F1 mice do contain IgG Abs reacting with this peptide, and this H2B sequence was found to be accessible to specific Ab probes in Ag-containing deposits detected in nephritic kidneys. Finally, compared with control normal mice and to young preautoimmune (NZBxNZW)F1 animals, the frequency of cells secreting autoantibodies reacting with peptide 1-25 was significantly raised in the spleen and bone marrow and most importantly on a pathophysiological point of view, locally, in nephritic kidneys of diseased (NZBxNZW)F1 mice. Altogether our results demonstrate the existence in (NZBxNZW)F1 mice of both a systemic and local B cell response targeting the N-terminal region of histone H2B, and highlight the potential implication of this nuclear domain in lupus pathology.
系统性红斑狼疮的一个重要特征是产生针对核抗原的自身抗体，其中核小体及其成分、DNA 和组蛋白是特异性的。人们普遍认为，由于这些自身抗体具有肾炎形成能力，其中一些在狼疮发病机制中起主要作用。然而，其潜在的机制仍存在争议。在这项研究中，我们分析了狼疮易感（NZBxNZW）F1 小鼠疾病过程中淋巴器官和肾脏中针对组蛋白 H2B 的自身免疫反应，并评估了其在狼疮发病机制中的潜在作用。我们发现组蛋白 H2B 的 N 端区域是循环自身抗体的一个优先靶标，其出现的动力学与疾病的发展呈正相关。此外，用 H2B 肽 1-25 免疫预自身免疫（NZBxNZW）F1 小鼠可加速疾病的发生。来自患病（NZBxNZW）F1 小鼠的肾脏洗脱液确实含有与该肽反应的 IgG 抗体，并且在肾炎肾脏中检测到的含抗原沉积物中，该 H2B 序列可被特异性 Ab 探针检测到。最后，与对照正常小鼠和年轻的预自身免疫（NZBxNZW）F1 动物相比，在患病（NZBxNZW）F1 小鼠的脾脏和骨髓中以及更重要的是在肾脏中，分泌与肽 1-25 反应的自身抗体的细胞频率明显升高。总之，我们的结果证明了（NZBxNZW）F1 小鼠中存在针对组蛋白 H2B N 端区域的全身性和局部 B 细胞反应，并强调了该核域在狼疮病理学中的潜在作用。
