Yazawa Norihito, Fujimoto Manabu, Sato Shinichi, Miyake Kensuke, Asano Noriko, Nagai Yoshinori, Takeuchi Osamu, Takeda Kiyoshi, Okochi Hitoshi, Akira Shizuo, Tedder Thomas F, Tamaki Kunihiko
Department of Regenerative Medicine, Research Institute, International Medical Center of Japan, Tokyo.
Blood. 2003 Aug 15;102(4):1374-80. doi: 10.1182/blood-2002-11-3573. Epub 2003 Apr 24.
Lipopolysaccharide (LPS) is a major gram-negative bacterial component that stimulates innate immune response and also induces B-lymphocyte activation. Recent studies have revealed that common molecular patterns of microorganisms such as LPS are recognized by toll-like receptors (TLRs). B cells have 2 known TLRs that mediate LPS signaling, TLR4 and RP105 (CD180). While TLR4 is expressed on immune cells of various types, RP105 is preferentially expressed on mature B cells. Here we demonstrate that CD19 plays a major role in regulating signal transduction through RP105. Anti-RP105 ligation induced normal proliferation of B cells from mice deficient for MyD88, an adaptor protein that mediates most TLR pathways. By contrast, the loss of CD19 resulted in modest B-cell proliferation against anti-RP105 stimulation as well as LPS stimulation. LPS induced tyrosine phosphorylation of CD19, which was RP105-dependent but TLR4-independent. CD19 formed a complex with Lyn and Vav following RP105 ligation, and CD19 expression was required for optimal Lyn activation and Vav phosphorylation. Consistently, B cells deficient for CD19 exhibited specific defect in the activation of c-Jun N-terminal kinases following RP105 ligation and LPS stimulation. In contrast, CD19 and phosphatidylinositol 3-kinase independently regulated intracellular calcium mobilization induced by anti-RP105 stimulation. Thus, signaling through the B-cell-specific LPS receptor RP105 is uniquely regulated by the B-cell-specific signaling component, Lyn/CD19/Vav complex.
脂多糖（LPS）是革兰氏阴性菌的主要成分，可刺激先天免疫反应并诱导B淋巴细胞活化。最近的研究表明，诸如LPS之类的微生物常见分子模式可被Toll样受体（TLR）识别。B细胞有2种已知的介导LPS信号传导的TLR，即TLR4和RP105（CD180）。虽然TLR4在各种类型的免疫细胞上表达，但RP105优先在成熟B细胞上表达。在这里，我们证明CD19在调节通过RP105的信号转导中起主要作用。抗RP105连接可诱导来自MyD88缺陷小鼠的B细胞正常增殖，MyD88是一种介导大多数TLR途径的衔接蛋白。相比之下，CD19的缺失导致针对抗RP105刺激以及LPS刺激的B细胞增殖适度减少。LPS诱导CD19的酪氨酸磷酸化，这是RP105依赖性的，但不是TLR4依赖性的。RP105连接后，CD19与Lyn和Vav形成复合物，并且最佳的Lyn活化和Vav磷酸化需要CD19表达。一致地，CD19缺陷的B细胞在RP105连接和LPS刺激后c-Jun N末端激酶的活化中表现出特异性缺陷。相反，CD19和磷脂酰肌醇3激酶独立调节抗RP105刺激诱导的细胞内钙动员。因此，通过B细胞特异性LPS受体RP105的信号传导由B细胞特异性信号成分Lyn / CD19 / Vav复合物独特调节。
