Multi-scale analysis of B cell responses in ageing

免疫系统是一个复杂的系统，由许多不同类型的细胞和分子组成，它们相互作用，保护我们免受传染病的侵害。它必须能够识别我们遇到的许多不同的外来实体，但不会对“自我”做出反应。因此，这是一个非常小心平衡的系统。随着年龄的增长，这种平衡被打破了，我们变得更容易感染传染病（当我们感染疾病时，我们就会变得更差）。我们通常依靠疫苗来保护我们免受疾病的侵害，但它的效果并不好。另一方面，我们也更容易患炎症，以及炎症可能与心血管疾病和阿尔茨海默病等病因有关的疾病。因此，理解为什么老年人的免疫系统会随着年龄的增长而失效是一个巨大的挑战。当我们接种疫苗时，免疫系统产生抗体，这些抗体与外来分子（抗原）结合，具有多种功能，是许多疫苗决定疫苗是否有效的主要指标。抗体是由B细胞产生的，在接种疫苗后，我们留下了记忆B细胞，它们知道如何产生我们需要的抗体，以防我们遇到我们接种过疫苗的疾病。在老年时，我们产生的有效抗体会减少，而我们确实拥有的一些抗体会对“自身”抗原产生反应。因此，在抗体产生过程中的某个地方，平衡系统发生了变化。我们已经证明，某些类型的B细胞会随着年龄的增长而发生变化，但我们不知道它们的功能是什么。我们将使用我们独特的细胞分析仪（能够测量每个细胞35种不同的参数）来准确识别哪些类型的B细胞随着年龄的变化而变化。我们之前的研究也表明，在老年人中，产生抗体的细胞种类较少。这种多样性的丧失与健康状况不佳有关。多样性在疫苗应答中很重要，因为对应答中数千个抗体基因的测序表明，涉及许多不同类型的抗体基因。然而，我们还发现，在应答细胞群中，抗体基因（CDRH3）的一部分具有有利的特征，该基因编码抗体的一部分，该部分对结合外来抗原很重要。因此，即使反应看起来不同，抗体之间也有一些共同的序列特征——即使是针对不同的外来抗原。我们假设，有利的CDRH3特征是那些能够结合多种外源抗原（多特异性）的结构，并且这些特征将在疫苗挑战中占主导地位。然而，需要对多特异性加以限制，因为这可能导致自身反应性——我们可以制造针对外来病原体的抗体，但它也可能意外地与自身抗原结合，导致自身免疫性疾病。由于缺乏外来抗原特异性和获得自身反应性是老年人抗体的特征，因此多反应性的利弊之间的平衡可能在老年时受到干扰。疫苗反应涉及许多其他因素，我们不知道所有因素的细节。因此，我们将使用统计力学来建立B细胞反应的模型，使我们能够在不知道其下面的详细相互作用的情况下，在群体水平上观察事件。我们将模拟B细胞反应的动力学，结合实验室调查确定的值。我们将仔细研究这些数据，以确定可能具有多特异性的CDRH3特征的值，我们将在实验室中生产一些抗体，以测试我们对给定CDRH3序列是否具有多特异性的预测。我们希望，一个解释外来抗原特异性和自身反应性之间平衡的模型的产生和验证，将使我们能够专注于我们可能改变的因素，以纠正老年人的平衡。

The immune system is a complex system, made up of many different types of cells and molecules that interact together to protect us from infectious disease. It has to be able to recognise the many different foreign entities that we come across but without reacting to "self". Hence it is a system that is in very careful balance. With age this balance is disturbed, we become more prone to infectious disease (and when we catch a disease we are more poorly as a result). Vaccination, that normally we rely on to help protect us from disease, does not work as well. On the other hand we also are more likely to suffer from inflammation, and diseases where inflammation may have a part in their aetiology such as cardiovascular disease and Alzheimer's disease. Hence understanding why the older immune system fails with age is a big challenge.When we are vaccinated the immune system makes antibodies, which bind to the foreign molecule (antigen), have a variety of functions and are the chief readout for many vaccines to decide if the vaccine has worked or not. The antibodies are made by B cells, and after vaccination we are left with memory B cells that know how to make the antibodies we need in case we meet the disease we were vaccinated against. In old age we make less effective antibodies, and some of the antibodies that we do have react to "self" antigens. So somewhere in the antibody - generation process the balanced system has changed. We have shown that some types of B cell are changed with age, but we don't know what their function is. We will use our unique cell analyser (capable of measuring 35 different parameters per cell) to identify exactly which types of B cell are changed with age. We have also previously shown that in older people the repertoire of the antibody-producing cells is less diverse. This loss of diversity is associated with poor health. Diversity is important in a vaccine response, as sequencing of thousands of antibody genes in a response shows that many different types of antibody genes are involved. However, we also found that within a population of responding cells there are favoured characteristics of a section of the antibody gene (CDRH3) which codes for the part of the antibody that is important in binding the foreign antigen. So even though the response looks diverse, there are some common sequence characteristics between antibodies - even for different foreign antigens.We hypothesise that favoured CDRH3 characteristics are ones that make a structure that is capable of binding to multiple foreign antigens (polyspecific), and that these will predominate in a vaccine challenge. However, there needs to be a limit on polyspecificity as this could lead to self-reactivity - we could make an antibody to a foreign pathogen but it might accidentally also bind to a self-antigen and cause autoimmune disease. Since lack of foreign antigen specificity and gain of self-reactivity are features of antibodies from older people, the balanced trade-off between the advantages and disadvantages of polyreactivity may be disturbed in old age.Many other factors are involved in a vaccine response, and we don't know the details of them all. Hence we will use statistical mechanics to make a model of the B cell response, enabling us to look at events on a population level without knowing the detailed interactions below it. We will model the dynamics of a B cell response, incorporating values determined from laboratory investigation. The data will be carefully looked at to define values for CDRH3 characteristics that might be polyspecific, and we will produce some antibodies in the lab to test our predictions of whether a given CDRH3 sequence would be polyspecific or not. We hope that production and validation of a model that explains the balance between foreign antigen specificity and self-reactivity will then enable us to focus on factors that we might change to redress the balance in older age.