By Mary Carmichael
Newsweek
Updated: 1:00 p.m. ET Jan. 21, 2007
Jan. 21, 2007 - The immune system is what keeps most people's bodies healthy and free of disease, but for as many as 23 million Americans, it is a cause of disease, too. In autoimmune disorders, the system goes haywire, mistaking the body's own tissues for foreign invaders and destroying them. Drugs for these conditions, which include type 1 diabetes, multiple sclerosis and lupus, have been elusive. But on Sunday, scientists are reporting in the journal Nature that they have found a set of 30 genes that go awry in autoimmune disorders—and that could be potential targets for cures. NEWSWEEK's Mary Carmichael spoke with two of the discoverers, Richard Young, a biologist at the Massachusetts Institute of Technology's Whitehead Institute, and Alexander Marson, an M.D./Ph.D. student in Young's lab. Excerpts:
NEWSWEEK: What do these 30 genes normally do in a healthy person's body?
Richard Young: There was a very, very important discovery made about a decade ago, which was that a specialized class of "regulatory T cells" was controlling the immune system's arms of attack. Now, the million-dollar question is why this wonderful system that keeps you healthy might turn against you and begin to attack your own body. And it turns out that in these autoimmune disorders, there are genetic defects in the regulatory T cells, which would otherwise be a check on the rest of the immune system.
These regulatory T cells can't keep the system in line, and it starts attacking things it shouldn't?
Alexander Marson: Yes. In mice, if you remove all the regulatory T cells, what you see is a massive, multiorgan autoimmune disease. In some common human autoimmune disorders, like multiple sclerosis, there's not a total lack of these cells, but there's a subtler dysfunction. The regulatory T cells are present, but they don't work as well at turning off the other immune cells and preventing them from attacking the body.
What exactly is wrong with the genes in these regulatory T cells? What are they doing that they shouldn't be doing?
Young: In autoimmune disorders, most of these genes are less active than they normally would be. What Alex and his colleagues discovered is that this turns the regulatory T cells' activities down, so they're not as aggressive or powerful as they normally would be. Now, it was only three years ago that scientists discovered the "brain" of the regulatory T cells, or the gene that tells them how to do their job. This is a gene called Foxp3.
So Foxp3 is the immune system's big boss, and the 30 genes you've found inside the regulatory T cells are the middle managers?
Young: Right. Until now, it was not known exactly how Foxp3 was giving these T cells directions—which genes it was controlling in order to do that.
And these are the 30 genes, the ones that aren't following the proper directions. So you think this dysfunction is the basis not just for one disorder, but a whole host of autoimmune diseases?
Marson: Yes, regulatory T cells appear to be key in preventing type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, as well as autoimmune thyroid disorders. Dysregulation of the genes controlling those cells could contribute to a wide range of autoimmune conditions.
That's a huge number of people—the pharmaceutical industry must be very excited about this discovery.
Young: The imperative in the pharmaceutical industry, when you're thinking about investing nearly a billion dollars in a program, is to have deep knowledge of the molecular pathways you're going to be focused on. There's this sea of noise that's hard to get through when you're looking for drug targets, unless you have a very small group of genes to look at. Here, we have that—we have the opportunity to take many, many, many autoimmune diseases and search more quickly because we've narrowed down the genes that are involved. Considering what drives the industry, this gives them a real leg up on developing cures.
What if you narrowed it down further? Could a drug for all of these disorders be aimed at Foxp3, the master controller of these 30 genes?
Young: It's an option. If you find some secret sauce that will modify Foxp3's activities and you've shown that this is critical to a broad spectrum of disorders, that's going to be a great thing. Let's say for the sake of speculation that in one of these diseases, Foxp3 itself is not working at adequate levels or is slightly defective. That would make it a single target we could go after and see if we could tune it up. On the other hand, it could turn out—as it usually does—that life's more complex than that. For each one of the diseases, there may be some subset of the 30 target genes that aren't working right, and we'd have to use another, more specific approach in each disorder.
Marson: One of the key next steps is to take each of these 30 genes and figure out what they're doing within the T cells. There's evidence that they play important roles, but the molecular underpinning of that is really still unknown. The other thing will be to look for chemicals that mimic the function of Foxp3. There may be some that are already known, but hopefully there will be more to be discovered in the future.
Could you also manipulate these genes in healthy people to suppress the immune system if you needed to, the way doctors do now in organ transplantations?
Young: Sure. In the same vein that you can imagine the loss of function of these genes, you can think of situations where you'd like to turn down the immune response, like in transplantation. There are already drugs that do that, of course, but the best evidence we have so far is that those drugs are working in a different way, on different genes than the ones we've discovered. Then again, sometimes if you discover new genes and then you go and test what the known drugs are doing, you're often surprised that they're doing multiple things and are involved in pathways you didn't anticipate.
Marson: One of the major drugs that's used to suppress the immune system now is cyclosporin, which inhibits a protein called NFAT. We and others have evidence that Foxp3 is also inhibiting that protein.
Young: Many of these genes are operating together with others, collaborating in the control of regulatory T-cell function. They're like drinking buddies. So it may turn out that the connection is a whole lot closer than we've imagined.
Young says the discovery will give drug makers 'a real leg up' in curing autoimmune diseases
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Scientists link 30 genes to multiple sclerosis and other autoimmune diseases.
科学家发现和多发性硬化及其它自身免疫性疾病相关的30个基因
By Mary Carmichael
Newsweek
Updated: 1:00 p.m. ET Jan. 21, 2007
Mary Carmichael
每周新闻
更新时间：2007年1月21日 下午1：00
Jan. 21, 2007 - The immune system is what keeps most people's bodies healthy and free of disease, but for as many as 23 million Americans, it is a cause of disease, too. In autoimmune disorders, the system goes haywire, mistaking the body's own tissues for foreign invaders and destroying them. Drugs for these conditions, which include type 1 diabetes, multiple sclerosis and lupus, have been elusive. But on Sunday, scientists are reporting in the journal Nature that they have found a set of 30 genes that go awry in autoimmune disorders—and that could be potential targets for cures. NEWSWEEK's Mary Carmichael spoke with two of the discoverers, Richard Young, a biologist at the Massachusetts Institute of Technology's Whitehead Institute, and Alexander Marson, an M.D./Ph.D. student in Young's lab. Excerpts:
2007年1月21日－免疫系统的作用是保持机体健康和免受疾病侵袭，但是对于多达2300万的美国人来说，免疫系统却是他们生病的成因。自身免疫性疾病中，免疫系统功能紊乱，把自身组织误认为是外来的侵袭物并且破坏它们。用于治疗这些病包括1型糖尿病、多发性硬化和狼疮的药物通常是难于取得肯定的疗效。但是在星期天，科学家们在《自然》杂志上报道他们发现了一组30个基因在自身免疫性疾病中发生异常－－这可能是治疗对策中的潜在目标。NEWSWEEK的Mary Carmichael 和其他两个发现者，美国麻省理工学院粟粒疹研究所的生物学家Richard Young和Young实验室的博士生Alexander Marson,对于这个成果进行了谈话。摘要如下：
NEWSWEEK: What do these 30 genes normally do in a healthy person's body?
Richard Young: There was a very, very important discovery made about a decade ago, which was that a specialized class of "regulatory T cells" was controlling the immune system's arms of attack. Now, the million-dollar question is why this wonderful system that keeps you healthy might turn against you and begin to attack your own body. And it turns out that in these autoimmune disorders, there are genetic defects in the regulatory T cells, which would otherwise be a check on the rest of the immune system.
NEWSWEEK：正常情况下，这30个基因在健康机体中是起什么作用的？
Richard Young: 大约10年前，有一项非常非常重要的发现，即一类叫做“调节性T细胞”的特殊细胞控制免疫系统不攻击自身细胞。现在，对于为什么这个保持你健康的完美系统可能回过头来开始攻击你机体自身产生了诸多的疑问。并且结果发现，在这些自身免疫性疾病中，调节性T细胞具有遗传缺陷，在免疫系统的其他
These regulatory T cells can't keep the system in line, and it starts attacking things it shouldn't?
这些调节性T细胞不能保证系统正常工作，并且它开始攻击它不该攻击的东西？
Alexander Marson: Yes. In mice, if you remove all the regulatory T cells, what you see is a massive, multiorgan autoimmune disease. In some common human autoimmune disorders, like multiple sclerosis, there's not a total lack of these cells, but there's a subtler dysfunction. The regulatory T cells are present, but they don't work as well at turning off the other immune cells and preventing them from attacking the body.
Alexander Marson: 是的，在小鼠中，如果你去除所有的调节性T细胞，你将看到的是多器官性、严重的自身免疫性疾病。在一些常见的人类自身免疫性疾病如多发性硬化中，并不是完全缺失这些细胞，但是它们存在一定的功能缺陷。调节性T细胞尽管存在，但是它们并不禁止其他免疫细胞的从而防止它们攻击自身。
What exactly is wrong with the genes in these regulatory T cells? What are they doing that they shouldn't be doing?
Young: In autoimmune disorders, most of these genes are less active than they normally would be. What Alex and his colleagues discovered is that this turns the regulatory T cells' activities down, so they're not as aggressive or powerful as they normally would be. Now, it was only three years ago that scientists discovered the "brain" of the regulatory T cells, or the gene that tells them how to do their job. This is a gene called Foxp3.
那在调节性T细胞中这些基因具体出什么问题了？它们产生了什么不该产生的作用？
Young:相对于正常机体，在自身免疫性疾病中这些基因大多数活性降低。Alex和他的同事发现这使得调节性T细胞活性下降，因此它们没有像正常情况下那么具有攻击性和强有力。3年前科学家才发现调节性T细胞的“中枢”，或者说，指导调节性T细胞“工作”的基因。这个基因是Foxp3。
So Foxp3 is the immune system's big boss, and the 30 genes you've found inside the regulatory T cells are the middle managers?
Young: Right. Until now, it was not known exactly how Foxp3 was giving these T cells directions—which genes it was controlling in order to do that.
所以Foxp3是免疫系统的“老大”，而你们发现的在调节性T细胞中的那30个基因是“中间管理者”？
And these are the 30 genes, the ones that aren't following the proper directions. So you think this dysfunction is the basis not just for one disorder, but a whole host of autoimmune diseases?
并且是这30个基因不发挥正常的作用。所以你认为这个功能障碍是疾病的基础，不是疾病所表现的一个症状而是控制产生疾病的成因？
Marson: Yes, regulatory T cells appear to be key in preventing type 1 diabetes, lupus, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease, as well as autoimmune thyroid disorders. Dysregulation of the genes controlling those cells could contribute to a wide range of autoimmune conditions.
Marson：是的，调节性T细胞是防止1型糖尿病，狼疮，多发性硬化发生，类风湿性关节炎，炎性肠病还有自身免疫性甲状腺疾病的关键细胞，控制这些细胞的基因失调可能导致广泛的自身免疫性病发生。
That's a huge number of people—the pharmaceutical industry must be very excited about this discovery.
非常多的人－制药工业肯定对这个发现非常感兴趣。
Young: The imperative in the pharmaceutical industry, when you're thinking about investing nearly a billion dollars in a program, is to have deep knowledge of the molecular pathways you're going to be focused on. There's this sea of noise that's hard to get through when you're looking for drug targets, unless you have a very small group of genes to look at. Here, we have that—we have the opportunity to take many, many, many autoimmune diseases and search more quickly because we've narrowed down the genes that are involved. Considering what drives the industry, this gives them a real leg up on developing cures.
Young:当你考虑投资近10亿美元到一个项目中是，制药行业必须对你将集中投入研究的分子通路有一个深入的了解。如果你没有只集中在很小一组基因
的话，当你寻找药物靶点时将会有很多的干扰因素阻碍你。
What if you narrowed it down further? Could a drug for all of these disorders be aimed at Foxp3, the master controller of these 30 genes?
如果你进一步局限基因的数量会怎么样呢？针对所有这些疾病的药物能够能否靶向这30个基因的“总指挥”Foxp3呢？
Young: It's an option. If you find some secret sauce that will modify Foxp3's activities and you've shown that this is critical to a broad spectrum of disorders, that's going to be a great thing. Let's say for the sake of speculation that in one of these diseases, Foxp3 itself is not working at adequate levels or is slightly defective. That would make it a single target we could go after and see if we could tune it up. On the other hand, it could turn out—as it usually does—that life's more complex than that. For each one of the diseases, there may be some subset of the 30 target genes that aren't working right, and we'd have to use another, more specific approach in each disorder.
Young:这是个选择。如果你发现了修饰Foxp3活性的秘方并提示对一系列病症能起关键作用的话，那将是一件很了不起的事情。推测起见，我们可以说至少对于这些疾病中的一种，Foxp3自身并没有发挥足够的作用或者说功能轻度缺陷。这使它成为单一靶点，我们可以追踪看我们是否可以上调它的功能。对于这些疾病的每一种，可能存在功能不正常的这30个靶基因的亚单位，在每个疾病中，我们得使用另外的，更加具体的方法。
Marson: One of the key next steps is to take each of these 30 genes and figure out what they're doing within the T cells. There's evidence that they play important roles, but the molecular underpinning of that is really still unknown. The other thing will be to look for chemicals that mimic the function of Foxp3. There may be some that are already known, but hopefully there will be more to be discovered in the future.
Marson：下一个关键的步骤是把这30个基因一个一个单独拿出来研究其对T细胞发挥的作用。有证据表明它们发挥可重要的作用，但是分子学基础仍未明确。另外一件事是寻找模拟Foxp3功能的化学物质。可能有一些已经被认识，但是希望将来能够发现更多。
Could you also manipulate these genes in healthy people to suppress the immune system if you needed to, the way doctors do now in organ transplantations?
如果有需要的话，是否你也可以通过控制健康人机体中的这些基因来抑制免疫系统，就像现在在器官移植中医生做的那样。
Young: Sure. In the same vein that you can imagine the loss of function of these genes, you can think of situations where you'd like to turn down the immune response, like in transplantation. There are already drugs that do that, of course, but the best evidence we have so far is that those drugs are working in a different way, on different genes than the ones we've discovered. Then again, sometimes if you discover new genes and then you go and test what the known drugs are doing, you're often surprised that they're doing multiple things and are involved in pathways you didn't anticipate.
Young：当然。你可以想象在同样的静脉中这些基因功能的丧失，你能想到在什么情况下你想下调免疫应答，比如在移植中。当然已经有许多的药物可以发挥那样的效果，但是到目前为止我们最好的证据是这些药物以不同的方式作用在我们所发现的这些基因上，并针对在不同的基因发挥作用。以后同样，有时当你发现新的基因然后去试验这些已知药物的作用时，你常常会惊讶于它们发挥了多种作用并且参与了你预想不到的信号途径。
Marson: One of the major drugs that's used to suppress the immune system now is cyclosporin, which inhibits a protein called NFAT. We and others have evidence that Foxp3 is also inhibiting that protein.
一种常用来抑制免疫系统的药物是环胞素A,它抑制NFAT蛋白。我们和其他研究人员发现Foxp3也可以抑制此蛋白。
Young: Many of these genes are operating together with others, collaborating in the control of regulatory T-cell function. They're like drinking buddies. So it may turn out that the connection is a whole lot closer than we've imagined.
Young:这些基因中的许多基因相互作用，协同调控调节性T细胞的功能。它们就像“酒友”。因此很可能结果是这些联系形成一个比我们想象的更为紧密的整体。
科学家发现和多发性硬化及其它自身免疫性疾病相关的30个基因
Mary Carmichael
每周新闻
更新时间：2007年1月21日 下午1：00
2007年1月21日－免疫系统的作用是保持机体健康和免受疾病侵袭，但是对于多达2300万的美国人来说，免疫系统却是他们生病的成因。自身免疫性疾病中，免疫系统功能紊乱，把自身组织误认为是外来的侵袭物并且破坏它们。用于治疗这些病包括1型糖尿病、多发性硬化和狼疮的药物通常是难于取得肯定的疗效。但是在星期天，科学家们在《自然》杂志上报道他们发现了一组30个基因在自身免疫性疾病中发生异常－－这可能是治疗对策中的潜在目标。NEWSWEEK的Mary Carmichael 和其他两个发现者，美国麻省理工学院粟粒疹研究所的生物学家Richard Young和Young实验室的博士生Alexander Marson,对于这个成果进行了谈话。摘要如下：
NEWSWEEK：正常情况下，这30个基因在健康机体中是起什么作用的？
Richard Young: 大约10年前，有一项非常非常重要的发现，即一类叫做“调节性T细胞”的特殊细胞控制免疫系统不攻击自身细胞。现在，对于为什么这个保持你健康的完美系统可能回过头来开始攻击你机体自身产生了诸多的疑问。并且结果发现，在这些自身免疫性疾病中，调节性T细胞具有遗传缺陷，在免疫系统的其他
这些调节性T细胞不能保证系统正常工作，并且它开始攻击它不该攻击的东西？
Alexander Marson: 是的，在小鼠中，如果你去除所有的调节性T细胞，你将看到的是多器官性、严重的自身免疫性疾病。在一些常见的人类自身免疫性疾病如多发性硬化中，并不是完全缺失这些细胞，但是它们存在一定的功能缺陷。调节性T细胞尽管存在，但是它们并不禁止其他免疫细胞的从而防止它们攻击自身。
那在调节性T细胞中这些基因具体出什么问题了？它们产生了什么不该产生的作用？
Young:相对于正常机体，在自身免疫性疾病中这些基因大多数活性降低。Alex和他的同事发现这使得调节性T细胞活性下降，因此它们没有像正常情况下那么具有攻击性和强有力。3年前科学家才发现调节性T细胞的“中枢”，或者说，指导调节性T细胞“工作”的基因。这个基因是Foxp3。
所以Foxp3是免疫系统的“老大”，而你们发现的在调节性T细胞中的那30个基因是“中间管理者”？并且是这30个基因不发挥正常的作用。所以你认为这个功能障碍是疾病的基础，不是疾病所表现的一个症状而是控制产生疾病的成因？
Marson：是的，调节性T细胞是防止1型糖尿病，狼疮，多发性硬化发生，类风湿性关节炎，炎性肠病还有自身免疫性甲状腺疾病的关键细胞，控制这些细胞的基因失调可能导致广泛的自身免疫性病发生。
非常多的人－制药行业肯定对这个发现非常感兴趣。
Young:当你考虑投资近10亿美元到一个项目中是，制药行业必须对你将集中投入研究的分子通路有一个深入的了解。如果你没有只集中在很小一组基因
的话，当你寻找药物靶点时将会有很多的干扰因素阻碍你。
如果你进一步局限基因的数量会怎么样呢？针对所有这些疾病的药物能够能否靶向这30个基因的“总指挥”Foxp3呢？
Young:这是个选择。如果你发现了修饰Foxp3活性的秘方并提示对一系列病症能起关键作用的话，那将是一件很了不起的事情。推测起见，我们可以说至少对于这些疾病中的一种，Foxp3自身并没有发挥足够的作用或者说功能轻度缺陷。这使它成为单一靶点，我们可以追踪看我们是否可以上调它的功能。对于这些疾病的每一种，可能存在功能不正常的这30个靶基因的亚单位，在每个疾病中，我们得使用另外的，更加具体的方法。
Marson：下一个关键的步骤是把这30个基因一个一个单独拿出来研究其对T细胞发挥的作用。有证据表明它们发挥可重要的作用，但是分子学基础仍未明确。另外一件事是寻找模拟Foxp3功能的化学物质。可能有一些已经被认识，但是希望将来能够发现更多。
如果有需要的话，是否你也可以通过控制健康人机体中的这些基因来抑制免疫系统，就像现在在器官移植中医生做的那样。
Young：当然。你可以想象在同样的静脉中这些基因功能的丧失，你能想到在什么情况下你想下调免疫应答，比如在移植中。当然已经有许多的药物可以发挥那样的效果，但是到目前为止我们最好的证据是这些药物以不同的方式作用在我们所发现的这些基因上，并针对在不同的基因发挥作用。以后同样，有时当你发现新的基因然后去试验这些已知药物的作用时，你常常会惊讶于它们发挥了多种作用并且参与了你预想不到的信号途径。
一种常用来抑制免疫系统的药物是环胞素A,它抑制NFAT蛋白。我们和其他研究人员发现Foxp3也可以抑制此蛋白。
Young:这些基因中的许多基因相互作用，协同调控调节性T细胞的功能。它们就像“酒友”。因此很可能结果是这些联系形成一个比我们想象的更为紧密的整体。
标题处“相管”应为“相关”
Newsweek《新闻周刊》
which would otherwise be a check on the rest of the immune system
在免疫系统的其他
Young: Right. Until now, it was not known exactly how Foxp3 was giving these T cells directions—which genes it was controlling in order to do that.
So you think this dysfunction is the basis not just for one disorder, but a whole host of autoimmune diseases?
所以你认为这个功能障碍是疾病的基础，不是疾病所表现的一个症状而是控制产生疾病的成因？
Here, we have that—we have the opportunity to take many, many, many autoimmune diseases and search more quickly because we've narrowed down the genes that are involved. Considering what drives the industry, this gives them a real leg up on developing cures.
In the same vein that you can imagine the loss of function of these genes
你可以想象在同样的静脉中这些基因功能的丧失