胰岛素抵抗是引发2型糖尿病的始动因素，也是代谢综合征的核心特征。脂肪组织的慢性炎症是导致胰岛素抵抗的主要病因。本课题组前期的研究发现B淋巴细胞在调节脂肪组织的慢性炎症和胰岛素抵抗发病过程中至关重要。 B-2淋巴细胞亚群及其产生的病理性IgG抗体能够促进胰岛素抵抗，而B-1细胞亚群则对胰岛素抵抗有保护作用，并且胰岛素抵抗的人群含有特异性的自身抗体特征。基于这些发现，我们推断在胰岛素抵抗发生过程中存在抗原特异性的自身免疫成分。然而，对病理性B细胞所识别的自身抗原以及B细胞调节胰岛素抵抗发生的机制尚不清楚。因此，本项目拟进一步开展1）探索B细胞亚群调节胰岛素抵抗的作用机制；2）鉴定胰岛素抵抗相关的自身抗原靶点；3）评估胰岛素抵抗相关的自身抗体在肥胖人群中的临床意义。本研究结果将有助于深入理解B淋巴细胞在调节胰岛素抵抗中的作用和机制，为发展新型的抗原特异性的2型糖尿病防治手段提供理论依据。

Insulin resistance is a state which precedes type 2 diabetes (T2D) and is a key feature of obesity related metabolic syndrome. Multiple factors contribute to the development of insulin resistance, but inflammation of visceral adipose tissue (VAT) is known to be a major factor. Our previous studies showed that B lymphocytes play a fundamental role in regulating this process. B-2 subset and its pathogenic IgG antibodies drive obesity associated inflammation and insulin resistance, while B-1 subset protects animal from insulin resistance. In a cohort of obese non-diabetic humans,insulin resistance is linked to a specific autoantibody signature. These data suggest that the development of insulin resistance in obesity has a defined autoimmune component. However, it remains unknown about the immunologic targets recognized by pathogenic B cells and the mechanisms contributing to adaptive immune regulation of insulin resistance. Based on these findings, we propose to 1)define the mechanisms of B cell subsets in regulating insulin resistance; 2)identify the immunologic targets that worsen insulin resistance; 3)assess the clinical significance of the autoantibody signature associated with insulin resistance in obese human subjects. The results of these experiments should increase the understanding of the role of B cells in regulating insulin resistance, and may lead to new diagnostic and therapeutic modalities for T2D.

肥胖诱导的脂肪组织慢性炎症是导致胰岛素抵抗的主要病因，炎症状态下的脂肪组织有大量免疫细胞浸润,其中包括B淋巴细胞，然而关于Ｂ细胞在胰岛素抵抗中作用仍不清楚。本课题重点研究了B淋巴细胞参与调节肥胖诱导胰岛素抵抗的作用机制。结果发现B淋巴细胞的两个亚群B-1a和 B-2细胞对胰岛素抵抗的调节呈相反的作用，B-2细胞可以加重胰岛素抵抗，而B-1a细胞可以减轻胰岛素抵抗。进一步研究发现B-1a 细胞对胰岛素抵抗的保护性作用机制是通过其分泌的抗炎性细胞因子IL-10和天然抗体IgM 所介导。能特异去除B2细胞而保留B1细胞的BAFF单克隆抗体治疗可显著改善肥胖小鼠的胰岛素抵抗。基于上述发现，B细胞通过维持B-2 和B-1a亚群功能的平衡来调节脂肪组织炎症和胰岛素抵抗，本课题为靶向Ｂ细胞免疫治疗２型糖尿病等代谢性疾病提供了理论依据和治疗策略。