Impact of Ageing on Humoral Immune Protection from Infection

随着年龄的增长，免疫系统的变化通常意味着老年人在接种疫苗时不会形成长期保护，并且在再次遇到病毒和细菌时容易再次感染。SARS-CoV-2大流行突出了这一事实，但人们早就知道这一点。为了实现长期保护，需要持续产生针对感染因子的抗体。在我们的身体中，只有一种细胞类型可以产生抗体。这些是终末分化的B细胞，也称为抗体产生细胞和浆细胞。因此，浆细胞的长期存活对于抗体产生至关重要，并且是疫苗接种成功和再感染控制的基础。浆细胞产生于次级淋巴组织，如脾脏和淋巴结，一些浆细胞在骨髓中找到安全港，在那里它们存活数月，数年，数十年。尽管浆细胞至关重要，但我们目前不知道i）如何区分长寿的浆细胞与不长寿的浆细胞; ii）浆细胞的长期存活是否发生在产生时或在其迁移到骨髓后，或两者兼而有之; iii）骨髓中的哪些细胞和信号支持浆细胞的存活; iii）浆细胞的存活与浆细胞的存活之间的关系。iv）浆细胞的长期存活如何受到衰老的影响。这种令人惊讶的知识缺乏部分是由于技术限制，因此迄今为止大多数研究都是在体外进行的，而不是在许多情况下转化为体内研究。关键的是，我们缺乏一种工具，可以识别和分离纯的真正长寿的浆细胞。在我实验室的一项突破中，我们在小鼠中产生并表征了一种遗传工具，该工具首次允许在骨髓中对浆细胞进行体内特异性遗传操作、时间戳和命运作图。使用这个工具，我们已经产生了真正长寿的PC在骨髓中表达的基因的非常概况，并确定了其他方面的候选基因，可能使我们能够识别这些细胞。我们已经制定了一个计划，以测试这些基因，并定义长寿浆细胞的标记，并将研究长寿浆细胞的异质性。因为我们现在可以识别真正长寿的PC，所以对骨髓中支持浆细胞存活的细胞和信号的理解是可以实现的。我们将绘制细胞图并研究它们与浆细胞之间的串扰。我们还将研究一种名为IL 6的分子，该分子在老年人中异常表达，并与浆细胞病理学有关。我们将测试IL 6表达是否是老年人免疫失调的基础，并建立新的系统，以便于研究IL 6在骨髓细胞和浆细胞之间的相互作用。由于长寿浆细胞的生物学尚不清楚，该项目可能会释放出真正新颖的治疗策略，以增强老年人的保护性免疫力。

As individuals age, changes in the immune system often mean that older individuals do not form long-term protection when vaccinated and easily become reinfected upon reencounter with virus and bacteria. This fact was highlighted by the SARS-CoV-2 pandemic, but known to be the case for long. To achieve long-term protection antibodies against the infectious agent need to be continuously produced. In our body only one cell type can produce antibodies. These are terminally differentiated B cells, also called antibody producing cells and plasma cells. As consequence, the long-term survival of plasma cells is critical for antibody production and underlies vaccination success and re-infection control. Plasma cells are produced in secondary lymphoid tissues like spleen and lymph nodes and some find safe harbour in the bone marrow where they survive for months, years, decades. Despite the critical importance of plasma cells, we currently do not know i) how to distinguish plasma cells that live-long from those that do not; ii) whether long-term survival of a plasma cells occurs at generation or following its migration to the bone marrow, or both; iii) which cells and signals in the bone marrow support the survival of plasma cells; iv) how the long-term survival of plasma cells is impacted by ageing. This surprising lack of knowledge is in part due to technical limitations and for that reason most studies so far have been performed in vitro, not translating on many occasions to in vivo. Critically we have lacked a tool permitting the identification and isolation of pure truly long-lived plasma cells. In a breakthrough of my laboratory, we have generated and characterised a genetic tool in the mouse that allowed for the first time specific genetic manipulation, time-stamping and fate mapping of plasma cells in vivo, in the bone marrow. Using this tool we have generated the very profile of genes expressed by truly long-lived PCs residing in the bone marrow and identified among other aspects candidate genes that may allow us to identify these cells. We have set a plan to test these genes and define markers of long-lived plasma cells and will study long-lived plasma cell heterogeneity. Because we now can identify truly long-lived PCs, the understanding of the cells and signals in the bone marrow that support plasma cell survival is in reach. We will map the cells and study the crosstalk between them and plasma cells. We will also study a molecule called IL6 that is found abnormally expressed in aged individuals and is associated with plasma cell pathology. We will test if IL6 expression underlies immune dysregulation in aged individuals and set-up new systems to allow easy study of IL6 in the crosstalk between bone marrow cells and plasma cells. Because the biology of long-lived plasma cells is not understood this project may unleash truly novel therapeutic strategies to enhance protective immunity in aged individuals.