【独家翻译】研究人员发现确认导致狼疮发作的一种酶

来源：贝斯以色列女执事医疗中心

翻译：Pearl Chen（翻译志愿者）

Summary:

Researchers have identified an enzyme that is significantly elevated in mouse models of systemic lupus erythematosus and in blood samples of patients with lupus. The new findings demonstrate that inhibition of the SHP-2 enzyme can significantly diminish lupus symptoms – including skin lesions, enlarged spleen and kidney failure – and suggest that development of a SHP-2 inhibitor drug could offer a new therapeutic approach for this often debilitating disease.

摘要：

研究人员发现有一种酶，在全身性红斑狼疮的小鼠模型和患者的狼疮血样中都有明显升高。新的研究结果表明SHP-2酶的抑制因子能够有效减轻狼疮症状，包括皮损，脾脏肿大与肾功能衰竭等症状。同时研究还指出，SHP-2抑制剂药物的开发将会为这种使人衰弱的疾病提供一个新的治疗方法。

Researchers at Beth Israel Deaconess Medical Center (BIDMC) have identified an enzyme that is significantly elevated in mouse models of systemic lupus erythematosus and in blood samples of patients with lupus. Published online in The Journal of Clinical Investigation, the new findings demonstrate that inhibition of the SHP-2 enzyme can significantly diminish lupus symptoms -- including skin lesions, enlarged spleen and kidney failure -- and suggest that development of a SHP-2 inhibitor drug could offer a new therapeutic approach for this often debilitating disease.

在贝斯以色列女执事医疗中心的研究人员发现有一种酶，在全身性红斑狼疮的小鼠模型和患者的狼疮血样中都有明显升高。在临床研究期刊上在线发表的一份新的研究结果表明SHP-2酶的抑制因子能够有效减轻狼疮症状，包括皮损，脾脏肿大与肾功能衰竭等症状。同时研究还指出，SHP-2抑制剂药物的开发将会为这种使人衰弱的疾病提供一个新的治疗方法。

Systemic lupus erythematosus is a chronic autoimmune disease that causes widespread inflammation and tissue damage to organ systems throughout the body. There is no cure for the disease, which primarily strikes young women in their 20s and 30s and affects an estimated 1.5 million individuals in the United States and at least 5 million worldwide.

全身性红斑狼疮是一种慢性的自身免疫性疾病，会导致广泛的炎症和组织损伤，损害全身器官系统的健康。这种疾病主要会在20岁到30岁左右的年轻女性中发作，感染者在美国范围内约有150万人，全国范围内则至少有500万人，而且，它没有治愈的方法。

"SHP-2 can lead to an overproduction of cytokine molecules," explained senior author Maria Kontaridis, PhD, Interim Director of the Basic Cardiology Research Program in the CardioVascular Institute at BIDMC and Assistant Professor of Medicine at Harvard Medical School (HMS). "In patients with lupus, we know that cytokines trigger inflammation, contribute to immune cell dysfunction, and lead to organ damage."

“SHP-2会造成细胞因子分子的生产过剩”资深作者Maria Kontaridis博士解释道，她是贝斯以色列女执事医疗中心的心血管研究所的有关心脏病基础研究发展的临时主任，同时也是哈弗医学院（HMS）的医学助理教授，“通过狼疮患者我们可以知道，细胞因子引发的炎症，会导致免疫细胞功能障碍，引起器官损伤。”

Kontaridis, whose mother battled lupus for more than 25 years -- has spent more than a decade studying genetic mutations in a class of enzymes known as protein tyrosine phosphatases. Her previous work has revealed that mutations in these proteins alter cellular signaling pathways, leading to the development of a group of rare congenital heart diseases known as RASopathies. Several years ago, after learning that more than 50 children with a RASopathy disorder called Noonan syndrome had also developed lupus, Kontaridis hypothesized that there might be a correlation between phosphatase activity and systemic autoimmunity.

Kontaridis博士花了十年以上来研究一类被称为蛋白酪氨酸磷酸酶的基因突变，而她的母亲也曾与狼疮疾病抗争25年之久。Kontaridis博士之前的研究揭示了这些蛋白质的突变会改变细胞信号途径，从而引起一组罕见的先天性心脏病的发作，这种病也就是RASopathies。几年前，Kontaridis博士在了解到超过50名孩子有RASopathy障碍则被称为Noonan综合征，同时还会触发狼疮病症之后，便推测在磷酸酶活性和系统性自身免疫之间有一定的关联性。

Preliminary tests of lupus mouse models revealed that SHP-2 enzyme activity was elevated four-to-six-fold compared with a group of control mice. "We then validated this finding in humans by examining blood cells isolated from lupus patients and found SHP-2 activity was also significantly higher than normal," said first author Jianxun Wang, PhD, a postdoctoral fellow in the Kontaridis laboratory and an Instructor in Medicine at HMS.

狼疮小鼠模型的初步测试揭示了，与对照组小鼠相比，它们的SHP-2酶的活性会增强4到6倍。“我们接下来将这一发现在人身上进行验证，通过测试从狼疮患者身上取得的血细胞样本，我们同样也发现相比于普通人，狼疮患者体内的SHP-2酶活性强度明显要高。”第一作者王建勋博士说道，他是Kontaridis实验室的博士后研究员，同时也是HMS医学讲师。

The investigators next conducted a series of biochemical analyses to identify the mechanisms by which SHP-2 is involved in the development of lupus and made use of a novel inhibitor of the SHP-2 enzyme to show that its inhibition could lead to the amelioration of the disease. "The mice were remarkably changed as a result of the drug treatment," said Kontaridis. "The animals' lifespans were increased, characteristic skin lesions were eliminated, the enlarged spleens were reduced in size -- and most remarkably -- the kidneys were normalized."

研究者又进行了一系列的生化分析来确认SHP-2酶参与狼疮发作的机制，并且利用一种新型的SHP-2酶抑制剂来证明这种抑制剂有利于狼疮疾病的改善。“在药物的治疗下，实验组的小鼠病情得到了明显的改善，”Kontaridis博士说道。“它们的寿命均得到延长，特征性皮损得到改善，脾脏肿大体积减少，最显著的一点是，肾脏功能开始正常化。”

When the investigators went on to study what was happening at the molecular level, they discovered that SHP-2 predominantly affected the proliferation of double-negative T cells, candidate markers of immune dysregulation.

当研究者继续研究在分子水平上到底发生了什么的时候，他们发现SHP-2主要影响了双阴性T细胞的增殖和免疫失调的候选标记。

"We know these T cells are responsible for the secretion of specific cytokines, and we think these cytokines are what induce the infiltration of inflammatory cells into the target tissues in animal models of lupus," said Kontaridis. "We identified two specific cytokines regulated by SHP-2 in lupus -- IL17 A/F and interferon gamma -- both of which we think mediate the pathogenicity of SLE and cause the disease-associated inflammation and organ damage."

“我们知道T细胞是负责某些特定细胞因子的分泌的，而我们认为这些细胞因子就是诱导炎症细胞浸润在动物模型中靶组织的因子，”Kontaridis博士说道。“我们确认了两种在狼疮中由SHP-2调节的特定细胞因子——IL17 A / F和干扰素γ，我们认为这两者都能够调节全身性红斑狼疮的致病性，并且引起疾病相关的炎症和器官损伤。”

"Treatment of patients with SLE has lagged behind other conditions and, unfortunately, is still limited to the use of immunosuppressive drugs," said George Tsokos, MD, Chief of Rheumatology at BIDMC and a coauthor on the paper. "The identification of novel targets such as this one shows promise that the development of a small molecule drug inhibitors, such as for SHP-2, will allow for the initiation of clinical trials in patients with lupus."

“全身性红斑狼疮患者的治疗还是很落后的，同时，不幸的是治疗还受制于免疫抑制药物的使用，”医学博士George Tsokos说道，他是贝斯以色列女执事医疗中心风湿科的院长，也是这篇文章的合作作者，“像这类新目标的确立体现了小分子药物抑制剂，比如SHP-2的抑制剂的开发将会开启狼疮患者的临床试验这样的可能性。”

"My own mother's 26-year long battle with lupus motivated me and inspired this investigation," said Kontaridis. "Our findings, and others like this, give great hope that one day soon there will be newer and better treatment options available for the millions of patients that suffer with this disease."

“我母亲26年与狼疮的抗争史是我研究的动机和灵感，”Kontaridis博士说道。“我们的研究结果，包括其他人的，给数以百计的患者带来了极大的希望，也许有一天就会有更新更好的治疗方案提供给他们。”

Story Source:

The above post is reprinted from materials provided by Beth Israel Deaconess Medical Center. Note: Materials may be edited for content and length.

故事来源：

上述职位由贝斯以色列女执事医疗中心提供的材料转载