Autoantibody-mediated arthritis in the absence of C3 and activating Fcγ receptors: C5 is activated by the coagulation cascade.
Autoantibody-mediated arthritis in the absence of C3 and activating Fcγ receptors: C5 is activated by the coagulation cascade.
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DOI：
10.1186/ar4117
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发表时间：
2012-12-13
影响因子：
4.9
通讯作者：
Binstadt BA
中科院分区：
文献类型：
--
作者：
Auger JL;Haasken S;Binstadt BA
免疫球蛋白G（IgG）的效应子功能由其Fc区与Fc受体（Fcγ R）和/或补体系统的相互作用介导。补体激活的三个主要途径在C3会聚。然而，C3非依赖性途径可以在IgG引发的炎症反应期间激活C5和其他下游补体成分。这些C5激活的C3非依赖性途径在某些系统中通过激活Fcγ R触发，或可通过凝血级联因子（如凝血酶）激活。在此，我们研究了C3、C5和活化Fcγ R在自发性自身抗体驱动的关节炎模型中的相互作用。我们利用关节炎的K/BxN TCR转基因小鼠模型。我们饲养了在编码补体成分C3、C5和FcRγ（活化Fcγ R共享的细胞质信号传导链）的一个或多个基因中携带靶向或天然突变的K/BxN小鼠。我们测量了关节炎的发展，致关节炎自身抗体的产生，T细胞活化状态和细胞因子的合成。此外，我们用抗C5单克隆抗体或凝血酶抑制剂阿加曲班治疗小鼠。我们以前已经表明，C5基因缺陷保护K/BxN小鼠免受关节炎的发展。我们发现，C3缺乏的K/BxN小鼠患关节炎的严重程度与C3充足的动物相当。关节炎在缺乏C3和FcRγ的K/BxN小鼠中也正常发生，但在这些动物中可以通过抗C5单克隆抗体治疗或阿加曲班治疗得到改善。C3、C5和/或FcRγ的缺失不影响致关节炎自身抗体的产生、T细胞活化和T细胞细胞因子的产生。在K/BxN小鼠中，C5依赖性自身抗体驱动的关节炎可在补体C3和活化Fcγ R基因缺失的情况下发生。我们的研究结果表明，在这种情况下，凝血酶激活C5引起关节炎。
The effector functions of immunoglobulin G (IgG) are mediated by interaction of its Fc region with Fc receptors (FcγRs) and/or the complement system. The three main pathways of complement activation converge at C3. However, C3-independent pathways can activate C5 and other downstream complement components during IgG-initiated inflammatory responses. These C3-independent pathways of C5 activation are triggered by activating FcγRs in some systems or can be activated by factors of the coagulation cascade such as thrombin. Here we studied the interplay of C3, C5, and activating FcγRs in a model of spontaneous autoantibody-driven arthritis. We utilized the K/BxN TCR transgenic mouse model of arthritis. We bred K/BxN mice bearing targeted or naturally-occurring mutations in one or more of the genes encoding complement components C3, C5, and FcRγ, the cytoplasmic signaling chain shared by the activating FcγRs. We measured arthritis development, the production of arthritogenic autoantibodies, T cell activation status and cytokine synthesis. In addition, we treated mice with anti-C5 monoclonal antibodies or with the thrombin inhibitor argatroban. We have previously shown that genetic deficiency of C5 protects K/BxN mice from the development of arthritis. We found here that C3-deficient K/BxN mice developed arthritis equivalent in severity to C3-sufficient animals. Arthritis also developed normally in K/BxN mice lacking both C3 and FcRγ, but could be ameliorated in these animals by treatment with anti-C5 monoclonal antibody or by treatment with argatroban. Production of arthritogenic autoantibodies, T cell activation, and T cell cytokine production were not affected by the absence of C3, C5, and/or FcRγ. In K/BxN mice, C5-dependent autoantibody-driven arthritis can occur in the genetic absence of both complement C3 and activating FcγRs. Our findings suggest that in this setting, thrombin activates C5 to provoke arthritis.
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影响因子：
4.4
作者：
Corr, M;Crain, B
通讯作者：
Crain, B
DOI：
10.1111/j.1600-0897.2007.00543.x
发表时间：
2007-12-01
影响因子：
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作者：
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通讯作者：
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DOI：
10.4049/jimmunol.0903678
发表时间：
2010-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
Fischetti, Fabio;Durigutto, Paolo;Tedesco, Francesco
通讯作者：
Tedesco, Francesco
影响因子：
64.5
作者：
TAKAI, T;LI, M;RAVETCH, JV
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RAVETCH, JV