Andersson Ulf, Harris Helena Erlandsson
Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital at Solna, S-171 76 Stockholm, Sweden.
Biochim Biophys Acta. 2010 Jan-Feb;1799(1-2):141-8. doi: 10.1016/j.bbagrm.2009.11.003.
HMGB1 is a ubiquitous nuclear protein that can be released by any damaged cell or by activated macrophages and certain other cell types. HMGB1 has been successfully therapeutically targeted in multiple preclinical models of infectious and sterile diseases including arthritis. Extracellular HMGB1 mediates inflammation via induction of cytokine and metalloproteinase production and recruitment and activation of dendritic cells needed for priming of naïve T helper type 1 lymphocytes. HMGB1 can bind endogenous molecules such as IL-1beta and nucleosomes and exogenous agents like endotoxin and microbial DNA. These complexes synergistically increase the capacity for activation of adaptive and innate immunity. HMGB1-nucleosome complexes induce autoantibody formation against double-stranded DNA and nucleosomes, which does not occur if HMGB1 is absent. These antibodies are central in the pathogenesis of systemic lupus erythematosus and patients with active disease have both increased HMGB1 and HMGB1-nucleosome levels in circulation. Furthermore, HMGB1 is strongly bipolar charged, enabling cell membrane passage and intracellular transport of complexed molecules including DNA. Rheumatoid arthritis patients have excessive extracellular HMGB1 levels in joints and serum. The HMGB1 release is caused by cytokines, activated complement and hypoxia. The most prominent HMGB1 protein and mRNA expression arthritis is present in pannus regions, where synovial tissue invades articular cartilage and bone. HMGB1 promotes the activity of proteolytic enzymes, and osteoclasts need HMGB1 for functional maturation. Neutralizing HMGB1 therapy in preclinical models of arthritis confers striking protection against structural damage. This review summarizes selected aspects of HMGB1 biology relevant for induction and propagation of some autoimmune conditions.
高迁移率族蛋白B1（HMGB1）是一种普遍存在的核蛋白，可由任何受损细胞、活化的巨噬细胞及某些其他细胞类型释放。在包括关节炎在内的感染性和无菌性疾病的多种临床前模型中，HMGB1已成为成功的治疗靶点。细胞外HMGB1通过诱导细胞因子和金属蛋白酶的产生以及募集和激活初始1型辅助性T淋巴细胞启动所需的树突状细胞来介导炎症。HMGB1可结合内源性分子如白细胞介素-1β和核小体以及外源性物质如内毒素和微生物DNA。这些复合物协同增强适应性免疫和先天性免疫的激活能力。HMGB1-核小体复合物诱导针对双链DNA和核小体的自身抗体形成，若没有HMGB1则不会发生这种情况。这些抗体在系统性红斑狼疮的发病机制中起核心作用，患有活动性疾病的患者循环中的HMGB1和HMGB1-核小体水平均升高。此外，HMGB1带有强双极性电荷，能够使包括DNA在内的复合分子通过细胞膜并进行细胞内转运。类风湿关节炎患者关节和血清中的细胞外HMGB1水平过高。HMGB1的释放是由细胞因子、活化的补体和缺氧引起的。在血管翳区域存在最显著的HMGB1蛋白和mRNA表达，血管翳区域的滑膜组织会侵入关节软骨和骨骼。HMGB1促进蛋白水解酶的活性，破骨细胞功能成熟需要HMGB1。在关节炎临床前模型中，中和HMGB1疗法可显著预防结构损伤。本综述总结了与某些自身免疫性疾病的诱导和传播相关的HMGB1生物学的选定方面。
