The Role of B Cells and B Cell Toll-like Receptors in Glucose Intolerance

描述（由申请人提供）：2型糖尿病（T2D）与主要源自免疫系统细胞的慢性炎症相关。这些细胞被T2D患者体内环境慢性激活，包括血浆游离脂肪酸（FFAs）和内毒素水平升高。游离脂肪酸和内毒素都是toll样受体（TLR）的配体，它们在TLR参与时通常会激活促炎细胞因子的产生。这些细胞因子可能在T2D和其他代谢综合征的慢性全身性炎症中发挥重要作用。多项研究表明，通过阻断TLR功能来控制肥胖小鼠的炎症可以降低胰岛素抵抗的发生率，而胰岛素抵抗是糖尿病的一个标志。虽然许多细胞类型是炎症细胞因子的来源，免疫细胞细胞因子是胰岛素抵抗所必需的。综上所述，这些分析表明，来自免疫系统细胞的tlr激活炎症是促进T2D和其他代谢疾病的关键过程。虽然单核细胞通常被认为是促炎细胞因子产生的最重要的免疫细胞类型，但B细胞也产生显著水平的细胞因子。我们关于T2D患者B细胞的新数据表明，B细胞TLR2和TLR4的激活通常会导致促炎细胞因子的产生。然而，TLR4配体降低了TLR2介导的TNF-1的产生。这种抗炎作用可能被T2D患者的B细胞完全不能分泌IL-10（一种关键的抗炎细胞因子）所平衡。发现T2D患者中tlr4阳性B细胞比例升高，以及这些B细胞对TLR配体的混合炎症反应，导致假设B细胞和B细胞TLR通过调节炎症、胰岛素抵抗和葡萄糖耐量在T2D中发挥重要作用。由于T2D患者普遍的内毒素血症和游离脂肪酸升高提供了无数的TLR配体，我们的初步数据预测B细胞TLR通过体内细胞因子调节影响T2D。尽管对人类B细胞TLR功能的进一步研究可能具有机制和临床意义，但这一研究的下一个关键步骤是明确证明B细胞和B细胞TLR在T2D炎症和发病机制中发挥作用。这些研究将在饮食诱导的肥胖小鼠T2D模型中进行，该模型利用了现有的转基因小鼠。这个项目将测试1的效果。B细胞缺失；2. TLR仅作用于B细胞；和3。B细胞特异性TLR失活对体内高脂饮食炎症和代谢结果的影响。这些研究将确定B细胞在代谢失衡中的作用，并预测使用已批准的B细胞消融疗法作为代谢综合征和T2D的新疗法的可能疗效。

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is associated with chronic inflammation that predominantly originates from immune system cells. These cells are chronically activated by the in vivo milieu of T2D patients, which includes elevated plasma levels of free fatty acids (FFAs) and endotoxin. Both of FFAs and endotoxin are ligands for toll-like receptors (TLRs), and both generally activate pro-inflammatory cytokine production upon TLR engagement. These cytokines likely play important roles in the chronic systemic inflammation characterizing T2D and other metabolic syndromes. Multiple studies show that controlling inflammation in obese mice by blocking TLR function decreases the incidence of insulin resistance, a hallmark of T2D. Although many cell types are sources of inflammatory cytokines, immune cell cytokines are required for insulin resistance. Taken together, these analyses indicate that TLR-activated inflammation from immune system cells is a key process that promotes T2D and other metabolic diseases. Although monocytes are generally considered the most important immune cell type for pro-inflammatory cytokine production, B cells also produce significant levels of cytokines. Our new data on B cells from T2D patients demonstrate that B cell TLR2 and TLR4 activation generally results in production of pro-inflammatory cytokines. However, TLR4 ligand decreases TLR2- mediated production of TNF-1. This anti-inflammatory effect may be balanced by the complete inability of B cells from T2D patients to secrete IL-10, a critical anti-inflammatory cytokine. The discoveries of an elevated percentage of TLR4-positive B cells in T2D patients and the mixed inflammatory responses of these B cells to TLR ligands lead to the hypothesis that B cells and B cell TLRs play important roles in T2D by regulating inflammation thus insulin resistance and glucose tolerance. Because the general endotoxemia and elevated free fatty acids in T2D patients provide innumerable TLR ligands, our preliminary data predict that B cell TLRs influence T2D through cytokine regulation in vivo. Although additional studies on human B cell TLR function are likely to be mechanistically and clinically important, the next critical step in this line of investigation is to unequivocally demonstrate B cells and B cell TLRs play roles in T2D inflammation and pathogenesis. These studies will be undertaken in a diet-induced obesity mouse model of T2D that takes advantage of available genetically altered mice. This project will test the effects of 1. the absence of B cells; 2. TLR function only on B cells; and 3. B cell-specific TLR inactivation on inflammatory and metabolic outcomes of high fat diet in vivo. These studies will define the role of B cells in metabolic imbalance, and predict the likely efficacy of using approved B cell ablation therapies as new treatments for metabolic syndrome and T2D. PUBLIC HEALTH RELEVANCE: Type 2 diabetes (T2D) is increasing at epidemic rates world-wide, and the treatment arsenal for this disease is limited. Inflammation plays an important role in the etiology and complications of T2D. Inflammation stemming from immune cell cytokine production plays a demonstrated role in insulin resistance, one of the key features of T2D. The role of myeloid cell cytokines in T2D is relatively well understood. Our new work in T2D patients demonstrates that B cells may be another major source of cytokines in T2D. However, our human subjects research, by its nature, cannot definitively link B cells to disease pathogenesis. The project proposes to test the role of B cells and their surface receptors in T2D using model organisms. Importantly, this work will determine whether existing B cell ablation therapies can be used as fundamentally new treatments for T2D.