T-max: maximising insights from severe combined immunodeficiency and related disorders

T淋巴细胞(T细胞)是一种特殊类型的白细胞，对人类免疫系统至关重要。我们知道这一点的部分原因是，不幸出生时没有T细胞的婴儿会患上严重的感染，而这些感染几乎不会影响健康的儿童。这种非常罕见的疾病被称为严重联合免疫缺陷(SCID)，在20世纪60年代末骨髓移植发展之前，它曾被判处死刑。如今，干细胞移植可以挽救大多数儿童的生命，只要他们的病情在感染之前得到确认。出于这个原因，我们现在开始使用一项与其他筛查一起进行的测试来筛查新生儿的SCID，该测试是在一周大时已经收集的干血斑点上进行的。如果T细胞数量低，婴儿将接受进一步的检测和治疗，以保护他们免受感染，直到免疫系统恢复正常。通常，出生时T细胞水平低是因为我们其中一个基因的拼写错误。由DNA组成的基因提供了制造单个蛋白质的指令。在SCID中，单个基因的错误意味着T细胞缺少一种它们离不开的蛋白质。结果，T细胞不能正常发育，导致免疫系统耗尽。科学家们已经通过研究这个过程可能出错的许多方式，研究了健康的T细胞是如何发展的。事实证明，许多不同基因中的拼写错误可以阻止T细胞的发育。这在一定程度上是因为T细胞以如此惊人的方式发育！准确地知道导致新的SCID病例的是哪个基因出了问题，这是非常有帮助的。它指导患者的治疗方式，进一步使预测家庭内未来怀孕的风险成为可能。有时，科学家能够设计出在不进行干细胞移植的情况下替换缺失部分的方法，例如在某些情况下通过基因治疗或酶替代。这些聪明的治疗依赖于准确地知道哪个基因出了问题，因为这是需要替换的那个。令人沮丧的是，大约十分之一的SCID病例无法从遗传学上解释，即使使用非常现代的基因组测序技术也是如此。在这个研究项目中，我们将试图找出T细胞发育失败的原因，以及我们可以做些什么。其中一些患者可能在“旧的”SCID基因中有新的拼写错误，可能隐藏在DNA的某些部分，这些部分有能力关闭邻近的基因。为了让我们有更好的机会找到这些基因，我们将使用新的和强大的DNA分子读取方法，更广泛地研究每个SCID基因，并检查患者骨髓细胞中的基因是否打开或关闭。其他患者在新基因中会有拼写错误，这些错误以前没有与SCID有关--它们不在任何教科书名单上。我们已经通过筛查既往SCID患者的拼写错误找到了一些强有力的候选者。我们还有更多的工作要做，以了解为什么受影响的基因对T细胞如此重要，因为它们在许多其他组织中也很活跃。为了提供帮助，我们将研究试管中细胞中的每个拼写错误，并找出它是如何干扰相关蛋白质的结构和功能的。我们还将研究相同基因中的相同拼写错误是否会导致老鼠版的SCID。如果我们能确定这些事情，我们就会学到一些关于T细胞如何工作的新的和重要的东西。我们应该能够更好地在未来的婴儿中诊断出同样类型的SCID，并向他们的父母提供答案。我们和其他人将努力寻找新的、更好的方法，在不进行干细胞移植的情况下挽救T细胞发育。

T lymphocytes (T cells) are a special type of white blood cell that is crucial to the human immune system. We know this partly because babies who are unlucky enough to be born without T cells get terribly sick with infections that barely affect healthy children. This very rare condition, called severe combined immunodeficiency ("SCID"), used to be a death sentence until the development of bone marrow transplantation from the late 1960s onwards. Nowadays, stem cell transplantation can save most of these children, as long as their condition is recognised before infection takes hold. For this reason, we now are starting to screen newborn babies for SCID using a test carried out alongside other screens on the dried blood spot already collected at a week of age. If T cell numbers are low, babies undergo further testing and treatment to protect them from infection until the immune system can be put right. Usually, being born with low levels of T cells happens because of spelling mistakes in one of our genes. Genes, which are made of DNA, provide the instructions to make individual proteins. In SCID, mistakes in a single gene mean that T cells are missing a protein they can't do without. As a result, the T cells can't develop properly, leaving the immune system depleted. Scientists have worked out a lot about how healthy T cells develop from studying the many ways this process can go wrong. It turns out that spelling mistakes in many different genes can prevent T cells from developing. This is partly because T cells develop in such a remarkable way! It can be very helpful to know exactly which gene has gone wrong to cause a new case of SCID. It guides the way a patient is treated and furthermore, makes it possible to predict the risk to future pregnancies within the family. Sometimes scientists have been able to design ways of replacing the missing part without a stem cell transplant, for instance by gene therapy or enzyme replacement in some cases. These types of clever treatment rely on knowing exactly which gene has gone wrong, since that is the one that needs to be replaced.It's frustrating then that around 1 in 10 cases of SCID can't be explained genetically, even using the very modern technique of genome sequencing. In this research project, we will try to get to the bottom of why T cell development fails there and what we might be able to do about it. Some of these patients might have new sorts of spelling mistakes in "old" SCID genes, perhaps hidden in parts of the DNA that have the power to turn off neighbouring genes. To give us a better chance of finding these we will look more widely around each SCID gene using new and powerful ways of reading along DNA molecules, and check whether genes are turned on or off in patient's bone marrow cells. Other patients will have spelling mistakes in new genes that haven't been linked to SCID before - they aren't on any textbook list. We have already found some strong candidates by screening for spelling mistakes in past patients with SCID. We have more work to do to understand why the affected genes are so important for T cells, because they are active in lots of other tissues too. To help, we will study each spelling mistake in cells in the test tube, and find out how it disturbs the structure and function of the related protein. We also will study whether the same spelling mistakes in the same genes can cause the mouse version of SCID. If we can be sure of these things, we will have learned something new and important about how T cells work. We should be in a better position to diagnose the same sort of SCID in future babies and provide answers to their mums and dads. We and others will be working hard to find new and better ways to rescue T cell development without a stem cell transplant.