Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice.
Role of C3a receptors, C5a receptors, and complement protein C6 deficiency in collagen antibody-induced arthritis in mice.
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DOI：
10.4049/jimmunol.1102310
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Holers VM
中科院分区：
文献类型：
--
作者：
Banda NK;Hyatt S;Antonioli AH;White JT;Glogowska M;Takahashi K;Merkel TJ;Stahl GL;Mueller-Ortiz S;Wetsel R;Arend WP;Holers VM
补体系统，特别是旁路途径（AP）在小鼠胶原抗体诱导性关节炎（CAIA）损伤的诱导中起重要作用。本研究的目的是直接比较C3 a和C5 a受体以及膜攻击复合物（MAC）作为CAIA发病机制中的效应器机制的作用。与WT小鼠相比，C3 aR −/−、C5 aR −/−和C6缺陷（C6-def）小鼠的临床疾病活动（CDA）分别降低了52%、94%和65%。组织病理学损伤以及IgG和C3沉积的减少与CDA无关。在C3 aR −/−、C5 aR −/−和C6-def小鼠中观察到滑膜中性粒细胞百分比降低，在C3 aR −/−和C5 aR −/−小鼠中观察到巨噬细胞减少，但在C6-def小鼠中未观察到。通过激光捕获显微切割获得的滑膜mRNA在C5 aR −/−小鼠中显示出TNF-α的减少，在C5 aR −/−和C6-def小鼠中显示出IL-1β的减少，而C3 aR −/−小鼠显示出两种细胞因子均无变化。我们的研究结果表明，缺乏C3 aR-，C5 aR-或MAC-启动的效应机制，每个降低对CAIA的易感性，临床效果最明显的C5 aR缺陷小鼠。尽管C3 aR、C5 aR或C6的缺失导致效应机制的差异性缺陷，但与WT小鼠相比，所有三种基因型小鼠的近端关节IgG和C3沉积减少是共同的。这些数据表明，在所有三种效应物的下游存在正反馈放大途径，其促进关节中额外的IgG沉积和C3活化。
The complement system, especially the alternative pathway (AP), plays essential roles in the induction of injury in collagen antibody-induced arthritis (CAIA) in mice. The goal of the current study was to directly compare the roles of receptors for C3a and C5a, as well as the membrane attack complex (MAC), as effector mechanisms in the pathogenesis of CAIA. Clinical disease activity (CDA) in C3aR−/−, C5aR−/−, and C6 deficient (C6-def) mice was decreased by 52%, 94%, and 65%, respectively, as compared with WT mice. Decreases in histopathologic injury as well as in IgG and C3 deposition paralleled the CDA. A decrease in the percentage of synovial neutrophils was observed in C3aR−/−, C5aR−/−, and C6-def mice, and a decrease in macrophages was observed in C3aR−/− and C5aR−/−, but not in C6-def, mice. Synovial mRNA obtained by laser capture microdissection exhibited a decrease in TNF-α in C5aR−/− mice and in IL-1β in both C5aR−/− and C6-def mice, while C3aR−/− mice demonstrated no change in either cytokine. Our findings show that absent C3aR-, C5aR- or MAC-initiated effector mechanisms each decreases susceptibility to CAIA, with clinical effects most pronounced in C5aR deficient mice. Although the absence of C3aR, C5aR, or C6 led to differential deficiencies in effector mechanisms, decreased proximal joint IgG and C3 deposition was common to all three genotypes in comparison to WT mice. These data suggest the existence of positive feedback amplification pathways downstream of all three effectors that promote additional IgG deposition and C3 activation in the joint.
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DOI：
10.4049/jimmunol.0901826
发表时间：
2009-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Banda NK;Levitt B;Glogowska MJ;Thurman JM;Takahashi K;Stahl GL;Tomlinson S;Arend WP;Holers VM
通讯作者：
Holers VM
影响因子：
5.4
作者：
CAVAILLON, JM;FITTING, C;HAEFFNERCAVAILLON, N
通讯作者：
HAEFFNERCAVAILLON, N
影响因子：
16.8
作者：
Mastellos, D;Lambris, JD
通讯作者：
Lambris, JD
影响因子：
4.8
作者：
Cain, SA;Monk, PN
通讯作者：
Monk, PN
影响因子：
4.4
作者：
Banda, Nirmal K.;Takahashi, Kazue;Arend, William P.
通讯作者：
Arend, William P.