Apoptotic cells, autoantibodies, and the role of HMGB1 in the subcellular localization of an autoantigen.
Apoptotic cells, autoantibodies, and the role of HMGB1 in the subcellular localization of an autoantigen.
复制标题
凋亡细胞、自身抗体以及 HMGB1 在自身抗原亚细胞定位中的作用。
DOI：
10.1016/j.jaut.2005.08.005
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发表时间：
2005
影响因子：
12.8
通讯作者：
Sullivan,KathleenE
中科院分区：
文献类型：
--
作者：
Sanford,AmyN;Dietzmann,Kelly;Sullivan,KathleenE
目前系统性红斑狼疮的进化模型假设有遗传易感性与环境或感染性触发因素相结合。这项研究调查了给予促炎症信号的凋亡细胞是否可以诱导狼疮的特征。在IACUC批准的一项研究中，BALB/c小鼠被注射了一种凋亡的Balb/c来源的髓系细胞系J774.1，无论是否带有DNA结合蛋白HMGB1，共注射了五次，为期16天。分别于治疗后6周和12周处死小鼠。用免疫荧光法评估肾脏疾病，用酶联免疫吸附试验检测自身抗体。用Western blotting鉴定自身抗原。注射了凋亡细胞的小鼠产生抗组蛋白、SSA、单链DNA和磷脂的抗体。对SSA和SSDNA的抗体持续存在；然而，对组蛋白和磷脂的抗体在12周时下降。肾脏中的IgG沉积在6周时被检测到，并持续到12周，主要是在同时接受凋亡细胞和HMGB1的动物中。小鼠的自身抗体是多样的，但接受凋亡细胞的小鼠对一种未知的78 kDa蛋白产生了特别高滴度的抗体。在HMGB1存在的情况下，该蛋白被外化到J774.1细胞表面。接受带有HMGB1的凋亡J774.1细胞的小鼠出现了更广泛的肾脏免疫球蛋白沉积。虽然机制尚不清楚，但HMGB1的一个重要作用是改变了一种主要自身抗原的亚细胞分布，使该自身抗原可用于免疫反应。这是第一次描述炎性刺激改变潜在自身抗原的免疫可获得性。
A current model for the evolution of systemic lupus erythematosus hypothesizes that there is a genetic predisposition coupled with an environmental or infectious trigger. This study investigated whether apoptotic cells given with a proinflammatory signal could induce features of lupus. Balb/c mice were injected with an apoptotic Balb/c-derived myeloid cell line, J774.1, either with or without the DNA-binding protein HMGB1 for five injections over 16 days in an IACUC approved study. Mice were sacrificed at 6 weeks and 12 weeks after treatment. Renal disease was assessed by immunofluorescence and autoantibodies were defined by ELISA. Western blotting was performed to characterize autoantigens. Mice injected with apoptotic cells developed antibodies to histones, SSA, ssDNA, and phospholipids. Antibodies to SSA and ssDNA persisted; however, antibodies to histones, and phospholipid declined at 12 weeks. IgG deposits in the kidney were detected at 6 weeks and persisted through 12 weeks primarily in animals that received both apoptotic cells and HMGB1. Autoantibodies in mice were diverse but the mice that received apoptotic cells developed particularly high titer antibodies to an unknown 78kDa protein. This protein became externalized on the surface of J774.1 cells in the presence of HMGB1. Mice that received apoptotic J774.1 cells with HMGB1 developed more extensive renal IgG deposition. While the mechanism is uncertain, an important effect of HMGB1 was to alter the subcellular distribution of a major autoantigen, making the autoantigen accessible for immune responses. This is the first description of an inflammatory stimulus altering the immunologic availability of a potential autoantigen.