Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases.
Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases.
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DOI：
10.3389/fimmu.2016.00036
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发表时间：
2016
影响因子：
7.3
通讯作者：
Yu CY
中科院分区：
文献类型：
--
作者：
Lintner KE;Wu YL;Yang Y;Spencer CH;Hauptmann G;Hebert LA;Atkinson JP;Yu CY
补体系统由效应蛋白、调节因子和受体组成，参与宿主对病原体的防御。补体系统的激活，通过经典途径(CP)，早已被认为是免疫复合体介导的组织损伤，最明显的是系统性红斑狼疮(SLE)。矛盾的是，CP早期成分的完全缺陷，如人类报告的纯合子基因缺陷所证明的，与发展为SLE或狼疮样疾病的风险密切相关。同样，由于基因拷贝数(GCN)变异和/或针对CP成分或调节蛋白的自身抗体的存在导致获得性缺陷的同型缺陷在SLE患者中相对常见。应用准确的检测方法和严格的数据验证，在欧洲和东亚SLE中，总C4的低GCNS和C4a的杂合子和纯合子缺陷被显示为中到大效应大小的危险因素，而总C4或C4a的高拷贝数作为流行的保护因素。在这里，我们总结了目前与遗传缺陷和缺陷相关的知识，以及获得性C1q、C1r、C1s、C4a/C4b和C2蛋白缺陷在SLE的发病机制和预后中的作用，以及其他系统性自身免疫性疾病的简要介绍。随着补体系统越来越多地被发现与自身免疫性疾病和免疫介导性疾病有关，它已经成为一个有吸引力的治疗靶点。我们强调了最近的发展，并对未来的研究和治疗应用提出了一个平衡的观点，重点是人类系统性自身免疫性疾病中CP的早期成分。
The complement system consists of effector proteins, regulators, and receptors that participate in host defense against pathogens. Activation of the complement system, via the classical pathway (CP), has long been recognized in immune complex-mediated tissue injury, most notably systemic lupus erythematosus (SLE). Paradoxically, a complete deficiency of an early component of the CP, as evidenced by homozygous genetic deficiencies reported in human, are strongly associated with the risk of developing SLE or a lupus-like disease. Similarly, isotype deficiency attributable to a gene copy-number (GCN) variation and/or the presence of autoantibodies directed against a CP component or a regulatory protein that result in an acquired deficiency are relatively common in SLE patients. Applying accurate assay methodologies with rigorous data validations, low GCNs of total C4, and heterozygous and homozygous deficiencies of C4A have been shown as medium to large effect size risk factors, while high copy numbers of total C4 or C4A as prevalent protective factors, of European and East-Asian SLE. Here, we summarize the current knowledge related to genetic deficiency and insufficiency, and acquired protein deficiencies for C1q, C1r, C1s, C4A/C4B, and C2 in disease pathogenesis and prognosis of SLE, and, briefly, for other systemic autoimmune diseases. As the complement system is increasingly found to be associated with autoimmune diseases and immune-mediated diseases, it has become an attractive therapeutic target. We highlight the recent developments and offer a balanced perspective concerning future investigations and therapeutic applications with a focus on early components of the CP in human systemic autoimmune diseases.