HERV-K immunity, a trigger of citrullination in rheumatoid arthritis?

项目总结/摘要 我们研究的主要目的是阐明最接近的分子机制，启动， 类风湿性关节炎（RA）是一种严重的全身性自身免疫性疾病， 世界范围内的人口。这个R21的提议将解决新的假设， 内源性逆转录病毒的蛋白质，称为HERV-K，触发体液和细胞免疫应答， 可能是瓜氨酸蛋白增加和抗瓜氨酸化蛋白抗体产生的上游 （ACPA）是RA的特征。这里显示的是初步数据，我们有了令人兴奋的发现， 高比例的RA患者具有针对HERV-K包膜（Env）和/或Gag蛋白的自身抗体，通常 滴度很高基于此，我们希望解决关于HERV潜在作用的两个基本问题- RA中的K免疫：RA患者对HERV-K产生了什么样的免疫反应，为什么？有没有 抗HERV-K免疫和瓜氨酸蛋白之间的联系，因此，ACPA的发展？ 我们的具体目标是： 具体目的1：表征RA中的抗HERV-K免疫。在这里，我们将确定哪些患者抗体 识别，如果它们中和Env的配体结合特性，如果它们识别天然Env优于 变性，我们将克隆患者抗Env mAb。我们还将询问是否存在HERV-K特异性T细胞， 其中HERV-K被表达。 具体目标2. HERV-K免疫会导致瓜氨酸吗？在这个目标中，我们将询问Env是否是瓜氨酸化的， 如果患者的T细胞抗体识别瓜氨酸化Env.我们还将测试是否杀死表达Env的中性粒细胞 会引发瓜氨酸反应 虽然以前在RA血液和滑液中检测到HERV-K mRNA，但我们的研究提出了这种可能性。 这些发现是令人兴奋的，代表了探索RA发病机制的新领域。的高患病率 抗Env和抗Gag（自身）抗体与RA发病有关。 因此，如果我们的工作模型甚至在方向上是正确的，我们可能会在一个重要的领域向前迈进， 方式HERV-K参与RA可能为开发新的治疗方法提供新的机会 治疗这种疾病与目前批准的RA治疗不同，这些治疗是相对非特异性的免疫治疗。 抑制剂，新的药物专门针对上游致病分子机制的RA可能是 更有效，安全责任更少。

Project Summary/Abstract The main purpose of our research is to elucidate the most proximal molecular mechanisms that initiate, and likely continue to perpetuate, rheumatoid arthritis (RA), a severe systemic autoimmune disorder affecting ~1% of the population world-wide. This R21 proposal will address the novel hypothesis that aberrant expression of proteins of an endogenous retrovirus, termed HERV-K, triggers a humoral and cellular immune response, which may be upstream of the increased protein citrullination and development of anti-citrullinated protein antibodies (ACPA) that are characteristic of RA. Shown here as Preliminary Data, we have made the exciting discovery that a high proportion of RA patients have autoantibodies against HERV-K envelope (Env) and/or Gag proteins, often with high titers. Based on this, we wish to address two fundamental questions about the potential role of HERV- K immunity in RA: What kind of immune response do RA patients mount against HERV-K and why? Is there a connection between anti-HERV-K immunity and protein citrullination and, hence, the development of ACPA? Our specific aims are: SPECIFIC AIM 1: To characterize anti-HERV-K immunity in RA. Here, we will establish what patient antibodies recognize, if they neutralize the ligand-binding properties of Env, if they recognize native Env better than denatured, and we will clone patient anti-Env mAbs. We will also ask if HERV-K specific T cells are present and where HERV-K is expressed. SPECIFIC AIM 2. Does HERV-K immunity lead to citrullination? In this Aim, we will ask if Env is citrullinated or if patient antibodies of T cells recognize citrullinated Env. We will also test if killing of Env-expressing neutrophils will trigger a citrullination reaction. Although HERV-K mRNA has been detected in RA blood and synovial fluid before, the possibilities raised by our findings are exciting and represent new territory in the exploration of RA pathogenesis. The high prevalence of anti-Env and anti-Gag (auto)antibodies in RA patients suggests that they may be related to RA pathogenesis. Hence, if our working models are even directionally correct, we may move the field forward in a significant manner. HERV-K involvement in RA may present new opportunities for the development of novel therapeutics for this disease. Unlike the currently approved therapies for RA, which are relatively non-specific immune suppressants, new drugs specifically targeted to the upstream pathogenic molecular mechanisms of RA may be more efficacious and have fewer safety liabilities.