Department of Nephrology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong, China.
Diabetes. 2021 Feb;70(2):504-515. doi: 10.2337/db20-0373. Epub 2020 Nov 5.
Toll-like receptor 9 (TLR9) is highly expressed in B cells, and B cells are important in the pathogenesis of type 1 diabetes (T1D) development. However, the intrinsic effect of TLR9 in B cells on β-cell autoimmunity is not known. To fill this knowledge gap, we generated NOD mice with a B-cell-specific deficiency of TLR9 (TLR9/CD19-Cre+ NOD). The B-cell-specific deletion of TLR9 resulted in near-complete protection from T1D development. Diabetes protection was accompanied by an increased proportion of interleukin-10 (IL-10)-producing B cells. We also found that TLR9-deficient B cells were hyporesponsive to both innate and adaptive immune stimuli. This suggested that TLR9 in B cells modulates T1D susceptibility in NOD mice by changing the frequency and function of IL-10-producing B cells. Molecular analysis revealed a network of TLR9 with matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, and CD40, all of which are interconnected with IL-10. Our study has highlighted an important connection of an innate immune molecule in B cells to the immunopathogenesis of T1D. Thus, targeting the TLR9 pathway, specifically in B cells, may provide a novel therapeutic strategy for T1D treatment.
Toll 样受体 9（TLR9）在 B 细胞中高度表达，B 细胞在 1 型糖尿病（T1D）发病机制中起重要作用。然而，TLR9 在 B 细胞中对β细胞自身免疫的内在影响尚不清楚。为了填补这一知识空白，我们生成了 B 细胞特异性 TLR9 缺陷（TLR9/CD19-Cre+ NOD）的 NOD 小鼠。B 细胞特异性 TLR9 缺失导致 T1D 发展几乎完全得到保护。糖尿病的保护伴随着产生白细胞介素 10（IL-10）的 B 细胞比例增加。我们还发现，TLR9 缺陷的 B 细胞对先天和适应性免疫刺激的反应性降低。这表明 TLR9 在 B 细胞中通过改变产生 IL-10 的 B 细胞的频率和功能来调节 NOD 小鼠的 T1D 易感性。分子分析显示了一个 TLR9 与基质金属蛋白酶、金属蛋白酶组织抑制剂 1 和 CD40 的网络，所有这些都与 IL-10 相互连接。我们的研究强调了先天免疫分子在 B 细胞中的一个重要连接，与 T1D 的免疫发病机制有关。因此，针对 B 细胞中的 TLR9 途径可能为 T1D 的治疗提供一种新的治疗策略。
