The IMMaged study: understanding the balance of immunity and immune disease in an aged immune system

随着年龄的增长，我们的免疫系统会发生变化，导致对疫苗和感染的保护反应减弱，同时增加了身体对自身的“自身免疫”反应，导致无益的炎症或疾病。我们知道这些变化发生了，但不知道是什么使它们发生的，也不知道当它们发生时我们如何改进它们。更好地了解免疫老化可以让我们设计出更好的疫苗，确定谁最需要疫苗，或者更好地治疗老年人的炎症性疾病。要了解老年人的免疫系统如何以不同的方式工作，首先有必要描述发生的变化：换句话说，找出“正常”衰老的样子。作为一项国际合作的一部分，我们仔细收集并测量了数千人免疫系统的许多不同方面，以描述发生的变化。这包括对血液中不同细胞类型和蛋白质水平的测量，以及对感染和身体自身蛋白质的保护水平（“自身反应”反应）。从这项研究中我们发现，免疫衰老在70岁以后发生得更快，而且在不同的人身上变化的速度也不同。这意味着同一年龄的人可能有非常不同的免疫年龄。我们还发现，他们的免疫年龄与他们的寿命有关，这表明免疫年龄可能对我们在晚年保持健康至关重要。在我们测量的所有免疫变化中，只有少数与免疫年龄密切相关。我们现在利用这些信息设计了一个更详细的实验，旨在更多地了解什么可能导致免疫衰老。我们想要详细了解免疫老化过程中发生了什么。为了做到这一点，我们计划把重点放在年龄相同，但免疫年龄非常不同的人身上。我们不仅想了解它们之间的不同之处，还想了解它们的免疫系统如何对相同的“挑战”做出不同的反应。为此，我们将确定两组年龄相近但免疫年龄差异很大的人，并在他们接种标准流感和COVID加强疫苗之前、期间和之后采集血液样本：我们只需要在他们接种加强疫苗时采集血液样本，就像他们在任何情况下都会做的那样。从血液样本中，我们将纯化一系列不同的免疫细胞类型——包括那些我们认为与免疫年龄有关的细胞，以及其他可能起作用的细胞。然后，我们可以详细分析这些免疫细胞群，测量每个细胞的哪些基因被激活，哪些蛋白质存在，以及它们使用的抗体或免疫受体的类型。这是有帮助的，因为产生的详细信息水平使我们能够识别与“较老”免疫反应相关的细胞，即使是那些我们可能没有想到的重要细胞（因为我们可以测量每个细胞中的所有基因）。我们还可以利用这些信息来弄清楚两组人的细胞反应是如何不同的。我们可以在实验的每个时间点（例如，在他们接种疫苗之前）这样做，但我们也可以观察随着时间的推移发生的变化，比较接种疫苗前后。在他们接种疫苗后，我们将测量他们做出的反应有多有效，以及他们对自己身体的蛋白质产生“不正确”反应的程度。通过把所有这些信息放在一起，我们的目标是确定控制有益和有害免疫平衡的免疫老化的变化。我们相信，这是更好地了解老年人应该如何使用药物来影响这种平衡的第一步：提高老年人对抗感染、癌症和对疫苗作出反应的能力，提高我们治疗炎症性疾病的能力。这可能会对老年人的生活持续时间和质量产生巨大影响。

Our immune systems change as we get older, resulting in weaker protective responses to vaccines and infections and at the same time increasing 'autoimmune' responses in which the body reacts against itself, causing unhelpful inflammation or disease. We know these changes occur, but not what makes them happen or how we might improve them when they do. A better understanding of immune ageing could allow us to design better vaccines, identify who needs them most or better treat inflammatory disease in older people. To understand how the immune system works differently in older people, it is first necessary to describe the changes occurring: in other words, to find out what 'normal' ageing looks like. As part of an international effort, we have carefully collected and measured many different aspects of the immune system in thousands of people to describe what changes occur. This included measures of different cell types and protein levels in the blood alongside levels of protection against infection and against the body's own proteins (the 'autoreactive' responses). From this study we found that immune ageing occurred much more rapidly after 70 years of age and also changed at different rates in different people. This meant that people of a given age could have very different immune ages. We also found that their immune age was linked to their lifespan, suggesting that immune age might be critical for keeping us healthy in later years. Of all the immune changes we measured, only a few were strongly linked to immune age. We have now used this information to design a much more detailed experiment, aiming to understand more about what might be responsible for immune ageing. We want to understand in detail what happens in immune ageing. To do this, we plan to focus on people who have the same age, but very different immune ages. We want to understand not only what is different between them, but also how their immune systems respond differently to the same 'challenge'. To do this we will identify two groups of people with similar ages but very different immune ages and take blood samples before, during and after they receive their standard influenza and COVID booster vaccinations: we only need take blood samples while they have booster shots just as they would do in any case. From the blood samples we will purify a range of different immune cell types - both those we have linked to immune age and others likely to contribute. We can then analyse these immune cell populations in minute detail, measuring for each individual cell which genes are switched on, which proteins are present and the type of antibody or immune receptors they use. This is helpful as the level of detailed information generated allows us to identify the cells linked to 'older' immune responses, even those we may not have suspected were important (as we can measure all genes in every cell). We can also use this information to work out how cells are responding differently in the two groups of people. We can do this at each timepoint of the experiment (for example, before they get their vaccine) but we can also look at changes occurring over time, comparing before and after vaccination. After they receive their vaccine we will measure how effective a response they have made and also the extent to which they have produced an 'incorrect' response against their own body's proteins. By putting together all of this information we aim to identify changes in immune ageing that control the balance between helpful and harmful immunity. We believe this is the first step towards a better understanding of how medications should be used in the elderly to influence that balance: improving older peoples' ability to fight infection, cancer and to respond to vaccines and improving our ability to treat inflammatory disease also. This could have a huge impact on the duration and quality of life in ageing.