Understanding the link between bone marrow failure and chronic inflammation through the lens of VEXAS syndrome

随着年龄的增长，骨髓在血液和免疫系统中产生细胞的效率会降低。在某种程度上，这是由于骨髓细胞的基因组成随着年龄的增长而发生的变化。尽管这些遗传变化并不能统一地驱动强健和同质的疾病表型，但各种免疫细胞的功能改变会对血细胞产生和免疫系统应对挑战的能力产生全身性影响。因此，个体抵抗感染的能力会下降，更有可能产生破坏性的炎症，这一过程通常被称为“发炎”。尽管炎症与许多慢性疾病有关，但我们并不完全了解骨髓中特定的遗传变化是如何与炎症联系在一起的。这就是研究诸如VEXAS综合征（空泡，E1酶，x -连锁，自身炎症，体细胞）的关键所在。这种综合征是一种新发现的疾病，在血液干细胞及其免疫细胞后代的遗传密码发生特定变化的情况下，受影响的个体可能遭受骨髓衰竭和严重炎症。在大多数情况下，基因突变发生在UBA1，这是一种控制包括炎症在内的几种重要细胞功能的分子。由于特定基因变化、骨髓衰竭和炎症之间的这种明确联系，我们可以使用VEXAS综合征更详细地了解这些关系，并开发新的实验室测试来跟踪疾病演变并确定治疗方案。我们将通过研究VEXAS综合征获得的知识将有助于提高我们对炎症的整体理解，以及这一过程如何促进其他常见的慢性年龄相关疾病的发展。

As we age, the bone marrow becomes less effective in producing cells within the blood and the immune system. In part, this is due to changes that occur with age in the genetic make-up of bone marrow cells. Despite these genetic changes not uniformly driving a robust and homogenous disease phenotype, the functional alterations in various immune cells lead to systemic effects on blood cell production and the ability of the immune system to respond to challenges. As a result, individuals can become less able to fight infection and more likely to produce damaging levels of inflammation in a process frequently referred to as "inflammageing". Although inflammageing has been linked to many chronic diseases, we do not fully understand exactly how specific genetic changes in the bone marrow are linked to inflammation. This is where the study of conditions such as VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is critical. This syndrome is a newly discovered disorder in which affected individuals can suffer bone marrow failure and severe inflammation in the context of a specific change in the genetic code of blood stem cells and their immune cell progeny. In the majority of cases, the genetic mutation occurs in UBA1, a molecule that controls several important cell functions including inflammation. Because of this clear link between a specific genetic change, bone marrow failure and inflammation, we can use VEXAS syndrome to understand these relationships in more detail and develop new laboratory tests to track disease evolution and identify therapeutic options. The knowledge we will gain by studying VEXAS syndrome will help improve our overall understanding of inflammageing and how this process contributes to the development of other common chronic age-related disorders.