Does impaired adipose tissue B cell function lead to loss of natural antibody secretion and increase susceptibility to infection in obesity?

肥胖影响了英国近30%的成年人。肥胖对心血管疾病、糖尿病和癌症风险增加的影响是众所周知的。肥胖还影响免疫系统，导致对感染的易感性增加。这一点在COVID-19中变得尤为明显;肥胖是COVID-19住院和死亡的主要风险因素之一。肥胖也会增加肺炎和术后感染的风险，给医院带来重要的临床挑战。抗体是对抗感染的关键工具。它们是由一种称为B细胞的白色血细胞产生的。在细菌或病毒感染期间，产生对细菌或病毒特异性的抗体，从而消除感染。这些是疫苗接种诱导的抗体类型。然而，这些抗体的产生可能需要长达3周。另一种类型的抗体称为天然抗体。这些识别在所有微生物上发现的通用成分。它们不断产生，在感染期间产量增加，在感染开始时提供全面保护。动物研究表明，天然抗体是感染早期保护的关键。在肥胖和老年人中发现较低水平的天然抗体，这可以部分解释他们对感染的易感性增加。因此，能够使B细胞产生更多的天然抗体以增加对感染的抵抗力可能是非常有帮助的。或者我们可以制造一种天然抗体产品来治疗严重感染的病人。为了开发这样的治疗方法，我们需要更好地了解人体内产生天然抗体的B细胞，我们已经发现，包围我们内脏的脂肪是产生天然抗体的重要场所。B细胞存在于腹部脂肪（称为网膜）和心脏周围的脂肪组织（称为心包）中。我们发现肥胖患者的B细胞产生的天然抗体比非肥胖患者的少得多，并且它们在感染期间不能增加天然抗体的产生。在这个项目中，我们将与进行腹部手术和心脏手术的外科医生合作，从同意的患者的网膜和心包中获得脂肪样本。我们将确切地研究出这些脂肪组织中的B细胞是如何制造天然抗体的，以及为什么它们在肥胖人群中失去了这样做的能力。我们想要确定可以增强这些B细胞保护功能的分子或药物，以恢复天然抗体的产生，并增加肥胖人群对感染的抵抗力。利用在脂肪活检中发现的B细胞的基因序列，我们希望产生一种具有高度抗菌特性的天然抗体。然后将在动物感染模型中测试这种天然抗体的功效。

Obesity affects nearly 30% of adults in the UK. The effect of obesity on increased risk of cardiovascular diseases, diabetes and cancer is well recognised. Obesity also affects the immune system leading to increased susceptibility to infections. This has become dramatically apparent with COVID-19; obesity is one of the main risk factors of hospitalisation and death with COVID-19. Obesity also increases the risk of pneumonia and post-operative infections, raising important clinical challenges in hospitals.Antibodies are a critical tool in the fight against infections. They are produced by a type of white blood cell called B cells. During infection with bacteria or a virus, antibodies specific to the bacteria or virus are produced leading to the elimination of the infection. These are the type of antibodies induced by vaccination. However, the production of these antibodies can take up to 3 weeks. Another type of antibody exists called natural antibodies. These recognise generic components found on all microbes. They are constantly made and their production increases during infection, providing blanket protection at the beginning of infections. Animal studies show that natural antibodies are key for protection early during infection. Lower levels of natural antibodies are found in obese and old individuals, which could partly explain their increased susceptibility to infections. Thus, it could be very helpful to be able to make B cell produce more natural antibodies to increase resistance to infection. Or we could manufacture a natural antibody product to treat patients with bad infections. To develop such treatments, we need to better understand the B cells that produce natural antibodies in human.We have discovered that the fat that surrounds our internal organs is an important place for the production of natural antibodies. B cells are found in our abdominal fat (known as the omentum) and in the fat tissue that surrounds the heart (known as the pericardium). We found that B cells from obese patients produce far fewer natural antibodies than those from non-obese patients and they fail to increase production of natural antibodies during infection. In this project, we will work with surgeons performing abdominal surgery and heart operations to obtain fat samples from omentum and pericardium from consenting patients. We will work out exactly how B cells within these fat tissues are making natural antibodies and why they lose the ability to do so in obese people. We want to identify molecules or drugs that can boost the protective function of these B cells to restore natural antibody production and increase resistance to infection in obese people. Using the genetic sequence of the B cells found in the fat biopsies, we want to produce a natural antibody with high anti-microbial properties. The efficacy of this natural antibody will then be test in animal models of infection.