Takeda Y, Dynan W S
Program in Gene Regulation, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA, USA.
Front Biosci. 2001 Nov 1;6:D1412-22. doi: 10.2741/takeda.
Autoantibodies against cellular components are commonly present in sera from patients with systemic rheumatic diseases and may play an important role in pathogenesis. The Ku protein was recognized 20 years ago as a major target of autoantibodies in a subset of Japanese patients with scleroderma-polymyositis overlap syndrome, and anti-Ku antibodies have since been shown to occur in 10-20% of patients with these and other systemic rheumatic diseases, including systemic lupus erythematosus. Ku functions physiologically in the repair of DNA double-strand breaks, where it carries out the initial recognition of damaged DNA ends. The three dimensional structure of the Ku-DNA complex has recently been solved, and helps illuminate the relationship between the autoimmune epitopes and other features of the protein. In addition to Ku, three other polypeptides in the same DNA repair pathway have more recently been identified as autoantigens: the DNA-dependent protein kinase catalytic subunit, DNA ligase IV, and XRCC4. Two hypotheses have been invoked to explain the ability of these proteins to elicit an autoimmune response in susceptible individuals. One is that DNA damage induces formation of nucleoprotein complexes that present novel composite or conformational epitopes. The other is that cleavage of these proteins by caspases or Granzyme B leads to presentation of immunocryptic peptides capable of stimulating autoreactive T lymphocytes. In the case of DNA double-strand break repair proteins, there is evidence that both of these mechanisms may be at work. Because of their role in the maintenance of genome stability, DNA double-strand break repair proteins have been the subject of intense study, and a wealth of new structural, biochemical and functional information makes them excellent models for investigation of the humoral autoimmune response.
针对细胞成分的自身抗体通常存在于系统性风湿性疾病患者的血清中，并且可能在发病机制中起重要作用。20年前，Ku蛋白在一部分日本硬皮病 - 多发性肌炎重叠综合征患者中被确认为自身抗体的主要靶标，此后已证明抗Ku抗体在这些患者以及其他系统性风湿性疾病（包括系统性红斑狼疮）的10% - 20%的患者中出现。Ku在DNA双链断裂的修复中发挥生理功能，在那里它对受损的DNA末端进行初始识别。Ku - DNA复合物的三维结构最近已被解析，这有助于阐明自身免疫表位与该蛋白质其他特征之间的关系。除了Ku之外，同一DNA修复途径中的其他三种多肽最近也被鉴定为自身抗原：DNA依赖性蛋白激酶催化亚基、DNA连接酶IV和XRCC4。已经提出了两种假说来解释这些蛋白质在易感个体中引发自身免疫反应的能力。一种假说是DNA损伤诱导核蛋白复合物的形成，这些复合物呈现新的复合或构象表位。另一种假说是半胱天冬酶或颗粒酶B对这些蛋白质的切割导致能够刺激自身反应性T淋巴细胞的免疫隐蔽肽的呈递。就DNA双链断裂修复蛋白而言，有证据表明这两种机制可能都在起作用。由于它们在维持基因组稳定性中的作用，DNA双链断裂修复蛋白一直是深入研究的对象，大量新的结构、生化和功能信息使它们成为研究体液自身免疫反应的优秀模型。
