B cell metabolism in activation and autoantibody production

B 细胞代谢激活和自身抗体产生

• 批准号: 8561193
• 负责人: Jeffrey C. Rathmell
• 金额: $ 7.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8561193
• 关键词: Acetyl Coenzyme A; Activated Lymphocyte; Antibody Formation; Antibody-Producing Cells; Antigen-Antibody Complex; Autoantibodies; Autoimmune Responses; Autoimmunity; B Cell Proliferation; B-Cell Activation; B-Lymphocytes; Cell Respiration; Cell Survival; Cell physiology; Cellular biology; Citric Acid Cycle; Data; Deposition; Disease; Effectiveness; Generations; Glomerulonephritis; Glucose; Glycolysis; Glycolysis Inhibition; Goals; Growth; Immune System Diseases; Immunity; In Vitro; Inflammation; Inflammatory; Lipopolysaccharides; Lymphocyte; Lymphocyte Activation; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Mus; PDH kinase; Pathology; Pathway interactions; Phosphorylation; Play; Process; Production; Pyruvate; Receptors, Antigen, B-Cell; Regulation; Rest; Rheumatism; Role; Supporting Cell; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Toxic effect; Transgenic Mice; Vasculitis; Work; autoreactivity; cell growth; cell growth regulation; cell motility; glucose metabolism; in vivo; novel strategies; novel therapeutic intervention; novel therapeutics; oxidation; prevent; programs; public health relevance; pyruvate dehydrogenase

DESCRIPTION (provided by applicant): Immunological diseases such as Systemic Lupus Erythematosus (SLE) are driven by disruption of regulatory mechanisms in both T and B lymphocytes leading to autoantibody production and inflammation. As autoantibodies promote a variety of SLE-associated pathologies, including immune complex formation and deposition responsible for vasculitis and glomerulonephritis, many therapeutic approaches to treat SLE have targeted B cell survival or function. However, effectiveness can be limited and secondary toxicities can be severe. A new approach may be to interfere with the basic metabolic processes necessary for lymphocyte growth and function. We have shown that cellular metabolism is highly regulated in lymphocyte activation and that while resting T cells rely on an oxidative metabolism, activation leads to a metabolic reprogramming to greatly increase glycolysis. Inhibition of glycolysis in T cells can prevent their effector function. It is likely that B cells lso undergo metabolic reprogramming that is essential for activation and effector function that may allow targeting of B cell metabolism to suppress autoantibody production. To test this new direction for treatment of rheumatic diseases, it is essential to understand B cell metabolism and how changes in metabolism impact B cell tolerance and autoimmunity. In our preliminary studies, we show that B cells do undergo a metabolic reprogramming upon activation to increase glycolysis and lactate production and inhibition of this metabolic transition prevents antibody production. Importantly, B cells from SLE-prone BAFF-transgenic mice were highly glycolytic immediately upon isolation, suggesting that this metabolic transition occurs in vivo coincident with autoantibody production and disease. A key regulator of glucose metabolism is Pyruvate Dehydrogenase Kinase 1 (PDHK1), which provides an inhibitory phosphorylation of Pyruvate Dehydrogenase (PDH) and directs pyruvate conversion into lactate to elevate glycolysis. We show that inhibition of PDHK1 can reduce B cell glycolysis and antibody production. B cell metabolism has not the focus of previous immunological studies and we propose to evaluate the potential of targeting this process to suppress autoantibody production and disease in SLE. We hypothesize that high rates of glycolysis are essential for B cell autoantibody production and that PDHK1 will provide a new metabolic target to suppress B cell proliferation and autoreactivity to treat inflammatory and autoantibody-mediated diseases, such as SLE. To test this hypothesis we will: (1) Establish if metabolic reprogramming of B cells to become highly glycolytic is required for antibody production; and (2) Test if modulation of glucose metabolism by PDHK1 inhibition impacts B cell autoreactivity in vitro and in vivo. Together, these studies are the first to directly focus on mechanisms of B cell metabolism and also to test the potential of pharmacological manipulation of PDHK1 to target metabolism and suppress B cell autoreactivity and autoantibody production in SLE.

描述（由申请人提供）：系统性红斑狼疮 (SLE) 等免疫疾病是由 T 和 B 淋巴细胞调节机制破坏导致自身抗体产生和炎症引起的。由于自身抗体促进多种 SLE 相关病理，包括导致血管炎和肾小球肾炎的免疫复合物形成和沉积，因此许多治疗 SLE 的治疗方法都以 B 细胞存活或功能为目标。然而，效果可能有限，并且二次毒性可能很严重。一种新方法可能是干扰淋巴细胞生长和功能所需的基本代谢过程。我们已经证明，细胞代谢在淋巴细胞激活中受到高度调节，并且虽然静息 T 细胞依赖于氧化代谢，但激活会导致代谢重编程，从而大大增加糖酵解。抑制 T 细胞中的糖酵解可以阻止其效应功能。 B 细胞也可能经历代谢重编程，这对于激活和效应功能至关重要，从而可以靶向 B 细胞代谢来抑制自身抗体的产生。为了测试这一治疗风湿性疾病的新方向，有必要了解 B 细胞代谢以及代谢变化如何影响 B 细胞耐受和自身免疫。在我们的初步研究中，我们表明 B 细胞在激活后确实会经历代谢重编程，以增加糖酵解和乳酸的产生，而抑制这种代谢转变会阻止抗体的产生。重要的是，来自易患 SLE 的 BAFF 转基因小鼠的 B 细胞在分离后立即呈高度糖酵解，这表明这种代谢转变在体内发生与自身抗体的产生和疾病同时发生。葡萄糖代谢的关键调节剂是丙酮酸脱氢酶激酶 1 (PDHK1)，它提供丙酮酸脱氢酶 (PDH) 的抑制性磷酸化，并指导丙酮酸转化为乳酸以提高糖酵解。我们发现抑制 PDHK1 可以减少 B 细胞糖酵解和抗体产生。 B 细胞代谢并不是之前免疫学研究的重点，我们建议评估针对该过程抑制自身抗体产生和 SLE 疾病的潜力。我们假设高糖酵解率对于 B 细胞自身抗体的产生至关重要，并且 PDHK1 将提供新的代谢靶点来抑制 B 细胞增殖和自身反应性，从而治疗炎症和自身抗体介导的疾病，例如 SLE。为了检验这一假设，我们将：(1) 确定 B 细胞的代谢重编程变得高度糖酵解是抗体产生所必需的； (2) 测试通过 PDHK1 抑制调节葡萄糖代谢是否会影响体外和体内 B 细胞自身反应性。总之，这些研究首次直接关注 B 细胞代谢机制，并测试了 PDHK1 药理操作在 SLE 中靶向代谢和抑制 B 细胞自身反应性和自身抗体产生的潜力。