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

脂肪组织 B 细胞功能受损是否会导致天然抗体分泌丧失并增加肥胖感染的易感性？

• 批准号: MR/W018497/1
• 负责人: Cecile Benezech
• 金额: $ 71.23万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW018497%2F1
• 关键词: Does; impaired; adipose; tissue; cell

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.

英国近30%的成年人患有肥胖症。肥胖会增加患心血管疾病、糖尿病和癌症的风险，这是众所周知的。肥胖还会影响免疫系统，导致对感染的易感性增加。这一点在COVID-19中尤为明显；肥胖是COVID-19患者住院和死亡的主要危险因素之一。肥胖还增加了肺炎和术后感染的风险，给医院带来了重要的临床挑战。抗体是对抗感染的关键工具。它们是由一种叫做B细胞的白细胞产生的。在感染细菌或病毒期间，产生针对细菌或病毒的抗体，从而消除感染。这些抗体是由接种疫苗引起的。然而，这些抗体的产生可能需要长达3周的时间。另一种类型的抗体被称为天然抗体。这些识别所有微生物中发现的通用成分。它们在感染期间不断产生并增加产量，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。肥胖和老年人体内的天然抗体水平较低，这可以部分解释他们对感染的易感性增加的原因。因此，能够使B细胞产生更多的天然抗体来增加对感染的抵抗力是非常有帮助的。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。为了开发这种治疗方法，我们需要更好地了解在人体中产生天然抗体的B细胞。我们已经发现，内脏周围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远远少于非肥胖患者的B细胞，并且在感染期间它们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膜中获取脂肪样本。我们将弄清楚这些脂肪组织中的B细胞是如何产生天然抗体的，以及为什么它们在肥胖者身上失去了产生抗体的能力。我们想要确定能够增强这些B细胞保护功能的分子或药物，以恢复自然抗体的产生，并增加肥胖人群对感染的抵抗力。利用在脂肪活组织检查中发现的B细胞的基因序列，我们希望生产一种具有高抗微生物特性的天然抗体。这种天然抗体的功效将在感染动物模型中进行测试。

项目成果

IL-17 signalling is critical for controlling subcutaneous adipose tissue dynamics and parasite burden during chronic murine Trypanosoma brucei infection.

• DOI: 10.1038/s41467-023-42918-8
• 发表时间: 2023-11-03
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Sinton, Matthew C.;Chandrasegaran, Praveena R. G.;Capewell, Paul;Cooper, Anneli;Girard, Alex;Ogunsola, John;Perona-Wright, Georgia;Ngoyi, Dieudonne;Kuispond, Nono;Bucheton, Bruno;Camara, Mamadou;Kajimura, Shingo;Benezech, Cecile;Mabbott, Neil A.;Macleod, Annette;Quintana, Juan F.
• 通讯作者: Quintana, Juan F.

FRC-derived retinoic acid: The key to unlocking milky spots.

• DOI: 10.1084/jem.20230157
• 发表时间: 2023-05-01
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Daley, Alexander D.;Benezech, Cecile
• 通讯作者: Benezech, Cecile