Nephrology Research Laboratory, Nijmegen Centre for Molecular Life Sciences, Department of Nephrology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Autoimmunity. 2012 Jun;45(4):290-7. doi: 10.3109/08916934.2012.664668. Epub 2012 Apr 2.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by the formation of autoantibodies against nuclear components. Disturbed apoptosis and reduced clearance of apoptotic material have been assigned a role in the pathogenesis of SLE. During apoptosis, apoptotic blebs are formed, in which SLE autoantigens are clustered. In vitro, apoptotic blebs can induce maturation of dendritic cells (DC), which in turn can stimulate IL-17 production by T cells. Here, we investigated the effects of administration of apoptotic blebs, separate or in combination with dendritic cells, on disease progression and autoantibody production in lupus and normal mice.
A preparation of apoptotic blebs, with or without DC, was intravenously administered to MRL/lpr and CBA mice at weeks 7, 9, and 11 of age. T-cell responses against autoantigens present in blebs were examined by delayed type hypersensitivity reactions. Disease progression of the mice was evaluated by determining proteinuria and the titers of anti-DNA, anti-histone, and anti-nucleosome autoantibodies in plasma.
Repeated administration of apoptotic blebs, with or without DC, had no effect on the course of proteinuria or on anti-DNA, anti-histone and anti-nucleosome autoantibody levels in MRL/lpr mice. Intravenous injections of apoptotic blebs resulted in a decrease in the DTH response towards s.c. administered blebs in MRL/lpr mice and in reduced anti-nucleosome antibody titers in CBA mice. These tolerizing effects were lost when apoptotic blebs were administered together with syngeneic DC after 2 hours of co-incubation.
In contrast to previous studies with apoptotic cells, and deviating from our in vitro findings with apoptotic blebs, we observed no stimulating effect of the administration of apoptotic blebs on disease progression in MRL/lpr lupus mice. The tolerogenic effects that were observed may be associated with rapid removal of i.v. administered blebs by phagocytes in an immune-silencing way.
系统性红斑狼疮（SLE）是一种自身免疫性疾病，其特征是形成针对核成分的自身抗体。凋亡紊乱和凋亡物质清除减少被认为在 SLE 的发病机制中起作用。在凋亡过程中，形成凋亡泡，其中包含 SLE 自身抗原。在体外，凋亡泡可以诱导树突状细胞（DC）的成熟，而树突状细胞反过来又可以刺激 T 细胞产生 IL-17。在这里，我们研究了给予凋亡泡（单独或与树突状细胞联合）对狼疮和正常小鼠疾病进展和自身抗体产生的影响。
在 7、9 和 11 周龄时，将包含或不包含树突状细胞的凋亡泡制剂通过静脉内给予 MRL/lpr 和 CBA 小鼠。通过迟发型超敏反应检查针对存在于泡中的自身抗原的 T 细胞反应。通过确定蛋白尿和血浆中抗 DNA、抗组蛋白和抗核小体自身抗体的滴度来评估小鼠的疾病进展。
重复给予凋亡泡（单独或与树突状细胞联合）对 MRL/lpr 小鼠蛋白尿的病程或对 DNA、组蛋白和核小体自身抗体水平没有影响。静脉内注射凋亡泡导致 MRL/lpr 小鼠对皮下给予的泡的 DTH 反应降低，并导致 CBA 小鼠的抗核小体抗体滴度降低。当凋亡泡与 2 小时共孵育后给予同基因树突状细胞时，这些耐受作用丧失。
与先前关于凋亡细胞的研究相反，并且与我们体外关于凋亡泡的研究结果相反，我们没有观察到给予凋亡泡对 MRL/lpr 狼疮小鼠疾病进展的刺激作用。观察到的耐受作用可能与吞噬细胞以免疫沉默方式快速清除静脉内给予的泡有关。
