Impact of Ageing on Humoral Immune Protection from Infection

随着个人年龄的增长，免疫系统的变化往往意味着老年人在接种疫苗时不会形成长期保护，在再次遇到病毒和细菌时很容易再次感染。这一事实在SARS-CoV-2大流行中得到了强调，但众所周知这种情况由来已久。为了实现长期保护，需要不断产生针对感染性病原体的抗体。在我们的身体里，只有一种细胞类型能产生抗体。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抗体的产生至关重要，是疫苗接种成功和再感染控制的基础。浆细胞在次级淋巴组织中产生，如脾和淋巴结，一些在骨髓中找到安全的避难所，在那里它们可以存活几个月、几年、几十年。尽管浆细胞至关重要，但我们目前还不知道：i)如何区分存活时间长的浆细胞和不存活的浆细胞；ii)浆细胞的长期存活是在其生成时或迁移到骨髓后发生的，还是两者兼而有之；iii)骨髓中的哪些细胞和信号支持浆细胞的生存；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在一定程度上是由于技术限制，因此到目前为止，大多数研究都是在体外进行的，在许多情况下没有转化为体内。关键的是，我们一直缺乏一种工具来鉴定和分离纯的、真正长寿的浆细胞。在我的实验室取得的一项突破中，我们在小鼠身上产生了一种基因工具，并对其进行了表征，该工具首次允许对体内和骨髓中的浆细胞进行特定的遗传操作、时间戳和命运映射。使用这一工具，我们已经生成了由驻留在骨髓中的真正长寿的PC表达的非常特殊的基因图谱，并确定了可能使我们能够识别这些细胞的候选基因。我们已经制定了一项计划，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生存的细胞和信号的理解是触手可及的。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IL6的分子，该分子在老年人中异常表达，与浆细胞病理有关。我们将测试IL6的表达是否是老年人免疫失调的基础，并建立新的系统，以便于在骨髓细胞和浆细胞之间的串扰中研究IL6。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。

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.