Identification of New Pathogenic Players in Lupus: Autoantibody-Secreting Cells Are Present in Nephritic Kidneys of (NZBxNZW)F1 Mice
Identification of New Pathogenic Players in Lupus: Autoantibody-Secreting Cells Are Present in Nephritic Kidneys of (NZBxNZW)F1 Mice
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DOI：
10.4049/jimmunol.0902595
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Muller, Sylviane
中科院分区：
文献类型：
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作者：
Lacotte, Stephanie;Dumortier, Helene;Muller, Sylviane
系统性红斑狼疮的一个重要标志是产生针对核AGS的自身抗体，其中包括核小体及其成分、DNA和病史。人们普遍认为，这些自身抗体中的一些在狼疮的发病机制中起了很大作用，因为它们具有诱发肾炎的潜能。然而，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小鼠在疾病过程中对组蛋白H2B的自身免疫反应，包括淋巴器官和肾脏，并评估了其在狼疮致病中的潜在参与。我们发现，组蛋白H_2B的N-末端区域是循环自身抗体的优先靶点，其出现的动力学与疾病的发展呈正相关。此外，自身免疫前(NZBxNZW)F1小鼠用H_2B肽1-25免疫会加速疾病的发生。从患病的(NZBxNZW)F1小鼠的肾脏洗脱液中确实含有与该多肽反应的Ig G抗体，并且在肾炎肾脏中检测到的含银沉淀物中的特定抗体探针可以与该H 2B序列结合。最后，与正常对照组和幼龄前自身免疫(NZBxNZW)F1小鼠相比，脾和骨髓中分泌与多肽1-25反应的自身抗体的细胞频率显著增加，最重要的是从病理生理学的角度来看，在肾病(NZBxNZW)F1小鼠的肾脏中，局部升高。总之，我们的结果证明了在(NZBxNZW)F1小鼠中存在针对组蛋白H2 B N末端区域的全身性和局部性B细胞反应，并强调了这一核域在狼疮病理中的潜在意义。免疫学杂志，2010,184：3937-3945。
An important hallmark of systemic lupus erythematosus is the production of autoantibodies specific for nuclear Ags, among which nucleosomes and their constituents, DNA and histories. 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. The Journal of Immunology, 2010,184: 3937-3945.