B cell metabolism in activation and autoantibody production

描述（由申请人提供）：免疫学疾病如系统性红斑狼疮（SLE）是由T和B淋巴细胞中的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，包括负责血管炎和肾小球肾炎的免疫复合物形成和沉积，许多治疗SLE的治疗方法都靶向B细胞存活或功能。然而，有效性可能有限，继发性毒性可能严重。一种新的方法可能是干扰淋巴细胞生长和功能所必需的基本代谢过程。我们已经表明，细胞代谢在淋巴细胞活化中受到高度调节，而静息T细胞依赖于氧化代谢，活化导致代谢重编程，大大增加糖酵解。抑制T细胞中的糖酵解可以阻止其效应子功能。可能的是，B细胞也经历代谢重编程，这对于活化和效应子功能是必需的，其可以允许靶向B细胞代谢以抑制自身抗体产生。为了测试这一治疗风湿性疾病的新方向，必须了解B细胞代谢以及代谢变化如何影响B细胞耐受性和自身免疫性。在我们的初步研究中，我们表明B细胞在活化后确实经历代谢重编程以增加糖酵解和乳酸盐的产生，并且抑制这种代谢转变可以防止抗体的产生。重要的是，来自SLE易感BAFF转基因小鼠的B细胞在分离后立即高度糖酵解，表明这种代谢转变在体内与自身抗体产生和疾病同时发生。葡萄糖代谢的关键调节因子是丙酮酸脱氢酶激酶1（PDHK 1），其提供丙酮酸脱氢酶（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PDHK 1可以减少B细胞糖酵解和抗体产生。B细胞代谢尚未成为以往免疫学研究的重点，我们建议评估靶向该过程以抑制SLE中自身抗体产生和疾病的潜力。我们假设高糖酵解速率对于B细胞自身抗体的产生是必不可少的，并且PDHK 1将提供新的代谢靶点来抑制B细胞增殖和自身反应性以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）确定抗体产生是否需要B细胞的代谢重编程以变得高度糖酵解;和（2）检验通过PDHK 1抑制调节葡萄糖代谢是否影响体外和体内B细胞自身反应性。总之，这些研究是第一个直接关注B细胞代谢机制的研究，也是第一个测试PDHK 1的药理学操作靶向代谢和抑制SLE中B细胞自身反应性和自身抗体产生的潜力的研究。

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.