Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
J Autoimmun. 2010 May;34(3):J178-206. doi: 10.1016/j.jaut.2009.11.013. Epub 2009 Dec 23.
Autoimmunity to ubiquitously expressed macromolecular nucleic acid-protein complexes such as the nucleosome or the spliceosome is a characteristic feature of systemic autoimmune diseases. Disease-specificity and/or association with clinical features of some of these autoimmune responses suggest pathogenic involvement which, however, has been proven in only a few cases so far. Although the mechanisms leading to autoimmunity against nucleic acid-containing complexes are still far from being fully understood, there is increasing experimental evidence that the nucleic acid component may act as a co-stimulator or adjuvans via activation of nucleic acid-binding receptor systems such as Toll-like receptors in antigen-presenting cells. Dysregulated apoptosis and inappropriate stimulation of nucleic acid-sensing receptors may lead to loss of tolerance against the protein components of such complexes, activation of autoreactive T cells and formation of autoantibodies. This has been demonstrated to occur in systemic lupus erythematosus and seems to represent a general mechanism that may be crucial for the development of systemic autoimmune diseases. This review provides a comprehensive overview of the most thoroughly-characterized nucleic acid-associated autoantigens, describing their structure and biological function, as well as the nature and pathogenic importance of the reactivities directed against them. Furthermore, recent advances in immunotherapy such as antigen-specific approaches targeted at nucleic acid-binding antigens are discussed.
自身免疫对广泛表达的大分子核酸-蛋白复合物的免疫，如核小体或剪接体，是系统性自身免疫性疾病的一个特征。这些自身免疫反应中的一些具有疾病特异性和/或与临床特征相关，提示其具有致病性，但迄今为止仅在少数情况下得到证实。尽管导致针对含核酸复合物的自身免疫的机制仍远未完全了解，但越来越多的实验证据表明，核酸成分可能通过激活抗原呈递细胞中的核酸结合受体系统，如 Toll 样受体，作为共刺激剂或佐剂发挥作用。凋亡失调和核酸感应受体的不当刺激可能导致对这些复合物的蛋白成分失去耐受性，从而激活自身反应性 T 细胞并形成自身抗体。这在系统性红斑狼疮中已经得到证实，似乎代表了一种普遍机制，可能对系统性自身免疫性疾病的发展至关重要。本文综述了最全面描述的核酸相关自身抗原，描述了它们的结构和生物学功能，以及针对这些抗原的反应的性质和致病性重要性。此外，还讨论了免疫治疗的最新进展，如针对核酸结合抗原的抗原特异性方法。
