Potential role of decoy B7-H4 in the pathogenesis of rheumatoid arthritis: a mouse model informed by clinical data.
Potential role of decoy B7-H4 in the pathogenesis of rheumatoid arthritis: a mouse model informed by clinical data.
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DOI：
10.1371/journal.pmed.1000166
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发表时间：
2009-10
期刊：
影响因子：
15.8
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Azuma T;Zhu G;Xu H;Rietz AC;Drake CG;Matteson EL;Chen L
Lieping Chen 及其同事发现可溶性 B7-H4 与类风湿性关节炎严重程度之间存在关联，他们使用小鼠模型来证明可溶性 B7-H4 会阻断细胞表面 B7-H4 的抑制功能。类风湿性关节炎（RA）的一个致病标志是靶组织和器官中持续的炎症反应。众所周知，T 细胞和自身抗体介导的免疫反应发挥着关键作用。对这一观察结果的可能解释是自身免疫反应的负调节丧失。在这里，我们试图研究 B7-CD28 信号通路的细胞表面抑制分子 B7-H4 是否可能在 RA 的发病机制中发挥作用。在一项使用针对人 B7-H4 分子的单克隆抗体对临床便利样本进行的横断面研究中，我们在 65% 的 RA 患者 (n = 68) 的血清中检测到高水平的可溶性 B7-H4 (sH4)，而在健康供体中只有 13% (n = 24)。在横断面分析中，sH4 升高与疾病严重程度评分 (DAS28) 增加相关。在 RA 小鼠模型中，sH4 的转基因表达或 B7-H4 的基因缺失加速了胶原诱导的关节炎的进展，同时伴随着 T 细胞和 B 细胞介导的自身免疫反应的增强以及中性粒细胞活性的增加。激动剂（一种 B7-H4-免疫球蛋白 Fc 融合蛋白）的体内表达可显着抑制小鼠模型中的疾病进展。我们在小鼠中的研究结果表明，sH4 作为诱饵分子阻断细胞表面 B7-H4 的抑制功能，导致胶原诱导的关节炎恶化。如果可以证实 RA 患者 sH4 水平与疾病活动性之间的初步相关性反映了类似的机制，那么这些发现将为治疗方法提供一个新的目标。 请参阅本文后面的编辑摘要 类风湿性关节炎 (RA) 是一种由异常免疫反应引起的慢性疾病。在 RA 中，人体自身的免疫系统主要攻击关节，导致其内壁发炎，但也会影响体内的其他组织和器官。发达国家约有 1% 的人口患有 RA，它会导致长期的关节损伤，导致严重的疾病和残疾。患者患有慢性疼痛、关节功能丧失和活动能力丧失。 RA 的病因尚不清楚，也没有已知的治疗方法。然而，中性粒细胞（一种对炎症很重要的免疫细胞）被认为有助于引发 RA。了解 RA 发展背后的主要机制以及人体免疫系统出现问题的位置，不仅对于寻找该疾病的新疗法至关重要，而且对于辅助诊断、帮助患者接受治疗以控制其经常衰弱的症状至关重要。免疫系统的调节对于防止过度活跃是必要的。调节免疫反应的正常信号的中断可能导致正常组织的破坏。先前的研究表明，B7 蛋白家族与免疫细胞表面的 CD28 信号蛋白相互作用，是免疫反应的重要调节因子。人们还发现 B7 蛋白以可溶形式存在，与类风湿疾病的发展有关，但其确切作用尚不清楚。在当前的研究中，研究人员检查了 B7 家族的成员 B7-H4（通常充当免疫反应的抑制剂），以了解该信号分子是否影响免疫反应以及在 RA 的发展中发挥作用。研究人员收集了 68 名 RA 患者和 24 名健康志愿者的血液，并测量了可溶性 B7-H4（也称为 sH4）的水平。他们在 65% 的 RA 患者的血液中发现了 sH4，而健康人的这一比例仅为 13%。 RA 患者的 sH4 水平 (96.1 ng/ml) 显着高于健康人 (<5 ng/ml)。此外，在患有最严重类型的 RA 的患者中发现了最高水平的 sH4，这是通过标准指数评分来衡量的，该指数评分包括总体健康状况、肿胀关节的数量和炎症的程度。然后，研究人员使用 RA 小鼠模型来探索 sH4 对 RA 的影响。首先，他们向小鼠注射携带 sH4 基因的质粒（可用于将基因转移到生物体中的圆形 DNA 片段），并观察 sH4 的过度表达如何影响关节炎的发展。他们还研究了删除小鼠 B7-H4 基因如何影响症状。 sH4 的过度表达和 B7-H4 的缺失都会引起小鼠炎症；症状出现得更早，也更严重。此外，sH4 的作用被证明依赖于中性粒细胞。最后，研究人员通过使用一种蛋白质来模拟 B7-H4 的正常信号传导，从而抑制免疫反应，成功阻止了小鼠疾病的发展。这些发现表明信号分子 B7-H4 可能参与 RA 的发生。 B7-H4通常作为免疫反应的抑制剂来抑制炎症，但是当其作用被阻断时，免疫反应就不再被抑制，并且会发生不适当的和增强的免疫反应。 sH4 被认为充当诱饵，阻止 B7-H4 与其受体结合，从而阻止向免疫系统发出抑制信号。 sH4 的过度表达会使 RA 小鼠模型的症状恶化。有趣的是，RA 患者中也存在高水平的 sH4，并且与疾病严重程度的增加相关。这项研究并未将 sH4 确定为 RA 的病因，但暗示 sH4 是该疾病炎症加剧进展的一个原因。免疫系统信号分子有潜力成为治疗 RA 和其他自身免疫性疾病的新靶点。然而，还需要进一步的研究来测试 sH4 是否在人类 RA 的发展中具有直接作用。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.1000166。 MedlinePlus 有一个关于 RA 的主题页面，提供有关 RA 症状和治疗的广泛信息，并可获取相关临床试验和医学文献。国家类风湿关节炎协会（英国）是一家以患者为主导的慈善机构，为 RA 患者提供信息、教育和支持。关节炎基金会（美国）是一家全国性非营利组织，支持公共卫生教育和研究经费，并为关节炎患者提供信息资源。 http://www.arthritis.org/
Finding an association between soluble B7-H4 and rheumatoid arthritis severity, Lieping Chen and colleagues use a mouse model to show that the soluble form blocks the inhibitory function of cell-surface B7-H4. A pathogenic hallmark of rheumatoid arthritis (RA) is persistent inflammatory responses in target tissues and organs. Immune responses mediated by T cells and autoantibodies are known to play pivotal roles. A possible interpretation for this observation is a loss of negative regulation of autoimmune responses. Here we sought to investigate whether B7-H4, a cell surface inhibitory molecule of the B7-CD28 signaling pathway, may play a role in the pathogenesis of RA. In a cross-sectional study of a clinical convenience sample using monoclonal antibodies against human B7-H4 molecules, we detected high levels of the soluble form of B7-H4 (sH4) in the sera of 65% of patients with RA (n = 68) versus only 13% of healthy donors (n = 24). Elevated sH4 was associated with an increased disease severity score (DAS28) in a cross-sectional analysis. In a mouse model of RA, transgenic expression of sH4 or genetic deletion of B7-H4 accelerated the progression of collagen-induced arthritis, accompanied by enhanced T and B cell–mediated autoimmune responses as well as increased activity of neutrophils. Expression in vivo of an agonist, a B7-H4-immunoglobulin Fc fusion protein, profoundly suppressed disease progression in the mouse model. Our findings in mice indicate that sH4 acts as a decoy molecule to block the inhibitory functions of cell-surface B7-H4, leading to exacerbation of collagen-induced arthritis. If the preliminary correlation between sH4 levels and disease activity in patients with RA can be confirmed to reflect a similar mechanism, these findings suggest a novel target for treatment approaches. Please see later in the article for the Editors' Summary Rheumatoid arthritis (RA) is a chronic disease caused by abnormal immune responses. In RA, the body's own immune system mainly attacks the joints, causing inflammation in their lining, but can affect other tissues and organs in the body. About 1% of the population in developed countries suffer from RA, and it can result in long-term joint damage, causing significant illness and disability. Sufferers have chronic pain, loss of function of the joint, and loss of mobility. The cause of RA is unknown and there is no known cure. However, neutrophils (an immune cell important for inflammation) are thought to contribute to the initiation of RA. Understanding the primary mechanisms behind the development of RA, and where the body's immune system goes wrong, is fundamental not only to find new treatments for the disease but also to aid diagnosis to help patients get treatment to help control their often debilitating symptoms. Regulation of the immune system is necessary to prevent overactivity. Interruptions to the normal signals that moderate the immune response can lead to destruction of normal tissues. Previous studies have shown that the B7 family of proteins, which interact with CD28 signaling proteins on the surface of immune cells, are important regulators of the immune response. B7 proteins have also been found to exist in soluble forms that have been implicated in the development of rheumatoid diseases, but their exact role is not well understood. In the current study, researchers examined a member of the B7 family, B7-H4, which normally acts as an inhibitor of the immune response, to find out whether this signaling molecule affects the immune response and has a role in the development of RA. The researchers collected blood from 68 patients with RA and 24 healthy volunteers, and measured levels of soluble B7-H4, also known as sH4. They found sH4 in blood from 65% of patients with RA, compared with only 13% of healthy people. The levels of sH4 were significantly higher in RA patients (96.1 ng/ml) compared to healthy people (<5 ng/ml). Moreover, the highest levels of sH4 were found in patients with the most severe forms of RA, as measured by a standard index score that includes general health, the number of swollen joints, and the amount of inflammation. The researchers then used a mouse model of RA to explore how sH4 might contribute to RA. First, they injected mice with plasmids (circular pieces of DNA that can be used to transfer genes into organisms) carrying the gene for sH4 and looked at how overexpression of sH4 affected the development of arthritis. They also looked at how deleting the B7-H4 gene in mice affected symptoms. Both overexpression of sH4 and deletion of B7-H4 caused inflammation in the mice; symptoms appeared earlier and were more severe. Furthermore, the effects of sH4 were shown to be dependent on neutrophils. Finally, the researchers successfully prevented the development of disease in mice by using a protein to mimic the normal signaling by B7-H4, which inhibits the immune response. These findings suggest that the signaling molecule B7-H4 may be involved in the development of RA. B7-H4 normally acts as an inhibitor of the immune response to suppress inflammation, but when its action is blocked the immune response is no longer suppressed, and an inappropriate and increased immune reaction occurs. sH4 is thought to act as a decoy that blocks binding of B7-H4 to its receptor, thereby preventing an inhibitory signal to the immune system. Overexpression of sH4 worsens the symptoms in the mouse model of RA. Intriguingly, high levels of sH4 were also present in RA patients and were associated with increased severity of disease. This study does not establish sH4 as a cause of RA but implicates sH4 as a cause in the progression of increased inflammation in this disease. Immune system signaling molecules have potential as novel targets for treatment of RA and other autoimmune disorders. However, further studies are needed to test whether sH4 has a direct role in the development of RA in humans. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000166. MedlinePlus has a topic page on RA providing extensive information on symptoms and treatment for RA and access to related clinical trials and medical literature The National Rheumatoid Arthritis Society (UK) is a patient-led charity to provide information, education, and support for people with RA The Arthritis Foundation (US) is a national not-for-profit organization that supports public health education and research funding, and provides informational resources for people with arthritis http://www.arthritis.org/
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