CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10
CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10
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DOI：
10.4049/jimmunol.173.7.4479
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发表时间：
2004-10-01
影响因子：
4.4
通讯作者：
Cerutti, A
中科院分区：
文献类型：
--
作者：
He, B;Qiao, XG;Cerutti, A
TLR是启动先天免疫应答的模式识别受体。TLR 9检测具有低甲基化CpG基序的微生物DNA，并且在人中优先由产生IFN-α的浆细胞样树突细胞和B细胞表达。除了促进IFN-α释放外，TLR 9还发出B细胞活化、增殖和IgM产生的信号。最近的研究结果表明，CpG DNA-TLR 9相互作用在系统性红斑狼疮和类风湿性关节炎中起着关键作用，这两种自身免疫性疾病的特征在于DNA反应性IgG的产生失调。我们发现，CpG DNA通过TLR 9介导的NF-κ B-Rel依赖性先天途径激活B细胞，启动种系C（γ）1、C（γ）2和C（γ）3基因转录，该途径通过STAT蛋白和IFN-应答因子与IL-10合作。该途径被氯喹抑制，氯喹是一种减弱IgG介导的自身免疫性疾病的临床表现的药物。生殖系C-γ基因转录与激活诱导的胞苷脱氨酶（B细胞类别转换诱导机制的关键元件）的上调相关，随后是从C-μ到C（γ）1、C（γ）2和C（γ）3的类别转换DNA重组。随后的IgG产生需要来自BCR和TNF家族的B细胞活化因子（BAFF）的额外信号，所述信号由树突状细胞在暴露于IFN-α时产生。我们的研究结果表明，CpG DNA-TLR 9相互作用可能是重要的启动或放大早期T细胞非依赖性IgG抗病原体的反应。这意味着感染期间释放的CpG DNA可能通过刺激自身反应性B细胞从IgM转变为更具致病性的IgG同种型而加剧自身免疫。
TLRs are pattern recognition receptors that initiate innate immune responses. TLR9 detects microbial DNA with hypomethylated CpG motifs and in humans is preferentially expressed by IFN-alpha-producing plasmacytoid dendritic cells and B cells. In addition to favoring IFN-alpha release, TLR9 signals B cell activation, proliferation, and IgM production. Recent findings suggest that CpG DNA-TLR9 interaction plays a key role in systemic lupus erythematosus and rheumatoid arthritis, two autoimmune disorders characterized by dysregulated production of DNA-reactive IgG. We show that CpG DNA initiates germline C(gamma)1, C(gamma)2, and C(gamma)3 gene transcription by activating B cells through a TLR9-mediated NF-kappaB-Rel-dependent innate pathway that cooperates with IL-10 through STAT proteins and IFN-responsive factors. This pathway is inhibited by chloroquine, a drug that attenuates the clinical manifestations of IgG-mediated autoimmune disorders. Germline C-gamma gene transcription is associated with up-regulation of activation-induced cytidine deaminase, a key element of the B cell class switch-inducing machinery, and is followed by class switch DNA recombination from C-mu to C(gamma)1, C(gamma)2, and C(gamma)3. Subsequent IgG production requires additional signals from BCR and a B cell-activating factor of the TNF family (BAFF), produced by dendritic cells upon exposure to IFN-alpha. Our findings suggest that CpG DNA-TLR9 interaction may be important to initiate or amplify early T cell-independent IgG responses against pathogens. This implies that CpG DNA released during infections may exacerbate autoimmunity by stimulating autoreactive B cells to switch from an IgM to a more pathogenic IgG isotype.