Mannose binding lectin is required for alphavirus-induced arthritis/myositis.
Mannose binding lectin is required for alphavirus-induced arthritis/myositis.
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DOI：
10.1371/journal.ppat.1002586
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Heise MT
中科院分区：
文献类型：
--
作者：
Gunn BM;Morrison TE;Whitmore AC;Blevins LK;Hueston L;Fraser RJ;Herrero LJ;Ramirez R;Smith PN;Mahalingam S;Heise MT
蚊媒甲病毒如基孔肯雅病毒和罗斯河病毒（RRV）是能够引起病毒诱导的关节炎和肌炎的大规模流行的新兴病原体。RRV诱导的人类和小鼠疾病的病理学与肌肉和关节内宿主炎症反应的诱导有关，先前的研究已经证明宿主补体系统有助于疾病的发展。在这项研究中，我们使用了小鼠模型的RRV诱导的疾病，以确定和表征哪些补体激活途径介导感染后的疾病进展，我们已经确定了甘露糖结合凝集素（MBL）途径，但不是经典或替代补体激活途径，作为必不可少的发展RRV诱导的疾病。MBL沉积在来自野生型小鼠的RRV感染的肌肉组织中增强，并且与野生型小鼠相比，RRV感染的MBL缺陷小鼠表现出减少的疾病、组织损伤和补体沉积。相比之下，缺乏经典或替代补体激活途径关键组分的小鼠仍发生严重的RRV诱导的疾病。MBL缺陷小鼠的进一步表征表明，与C3−/−小鼠相似，病毒复制和炎性细胞募集与野生型动物相当，表明RRV介导的补体依赖性免疫病理学诱导在很大程度上依赖于MBL。与这些发现一致，诊断患有RRV疾病的人类患者与健康对照相比具有升高的血清MBL水平，并且血清和滑液中的MBL水平与疾病的严重程度相关。这些发现证明了MBL在小鼠和人类中促进RRV诱导的疾病中的作用，并表明补体激活的MBL途径可能是患有RRV诱导的关节炎和肌炎的人的治疗干预的有效靶点。致关节炎甲病毒如罗斯河病毒（RRV）和基孔肯雅病毒通过蚊子传播给人类，并在世界各地引起使人衰弱的传染性关节炎和肌炎的流行。在人类和小鼠中的研究表明，宿主炎症反应对于RRV诱导的关节炎和肌炎的发展至关重要，并且宿主补体系统（宿主炎症反应的组分）通过活化携带补体受体3（CR 3）的炎性细胞在RRV诱导的疾病的发展中起重要作用。在三种主要的补体激活途径中，只有甘露糖结合凝集素（MBL）激活的凝集素途径是RRV诱导的补体激活、组织破坏和疾病所必需的。此外，我们发现MBL水平在患有RRV诱导的多关节炎的人类患者中升高，并且MBL水平与疾病严重程度相关。总之，我们的数据暗示MBL在介导RRV诱导的人类和小鼠疾病中的作用，并表明MBL的治疗靶向可能是人类疾病治疗的有效策略。
Mosquito-borne alphaviruses such as chikungunya virus and Ross River virus (RRV) are emerging pathogens capable of causing large-scale epidemics of virus-induced arthritis and myositis. The pathology of RRV-induced disease in both humans and mice is associated with induction of the host inflammatory response within the muscle and joints, and prior studies have demonstrated that the host complement system contributes to development of disease. In this study, we have used a mouse model of RRV-induced disease to identify and characterize which complement activation pathways mediate disease progression after infection, and we have identified the mannose binding lectin (MBL) pathway, but not the classical or alternative complement activation pathways, as essential for development of RRV-induced disease. MBL deposition was enhanced in RRV infected muscle tissue from wild type mice and RRV infected MBL deficient mice exhibited reduced disease, tissue damage, and complement deposition compared to wild-type mice. In contrast, mice deficient for key components of the classical or alternative complement activation pathways still developed severe RRV-induced disease. Further characterization of MBL deficient mice demonstrated that similar to C3−/− mice, viral replication and inflammatory cell recruitment were equivalent to wild type animals, suggesting that RRV-mediated induction of complement dependent immune pathology is largely MBL dependent. Consistent with these findings, human patients diagnosed with RRV disease had elevated serum MBL levels compared to healthy controls, and MBL levels in the serum and synovial fluid correlated with severity of disease. These findings demonstrate a role for MBL in promoting RRV-induced disease in both mice and humans and suggest that the MBL pathway of complement activation may be an effective target for therapeutic intervention for humans suffering from RRV-induced arthritis and myositis. Arthritogenic alphaviruses such as Ross River virus (RRV) and chikungunya virus are transmitted to humans by mosquitoes and cause epidemics of debilitating infectious arthritis and myositis in various areas around the world. Studies in humans and mice indicate that the host inflammatory response is critical for development of RRV-induced arthritis and myositis, and the host complement system, a component of the host inflammatory response, plays an essential role in the development of RRV-induced disease through activation of complement receptor 3 (CR3)-bearing inflammatory cells. Of the three main complement activation pathways, only the lectin pathway activated by mannose binding lectin (MBL) was essential for RRV-induced complement activation, tissue destruction, and disease. Furthermore, we found that levels of MBL were elevated in human patients suffering from RRV-induced polyarthritis and MBL levels correlated with disease severity. Taken together, our data implicates a role for MBL in mediating RRV-induced disease in both humans and mice, and suggests that therapeutic targeting of MBL may be an effective strategy for disease treatment in humans.
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甘露糖结合凝集素相关的丝氨酸蛋白酶1/3的机理的补体途径激活。
影响因子：
3.6
作者：
Banda NK;Takahashi M;Takahashi K;Stahl GL;Hyatt S;Glogowska M;Wiles TA;Endo Y;Fujita T;Holers VM;Arend WP
通讯作者：
Arend WP
DOI：
10.1111/j.1445-5994.1985.tb04048.x
发表时间：
1985-01-01
期刊：
AUSTRALIAN AND NEW ZEALAND JOURNAL OF MEDICINE
影响因子：
--
作者：
HAZELTON, RA;HUGHES, C;AASKOV, JG
通讯作者：
AASKOV, JG
影响因子：
5.4
作者：
Morrison, TE;Whitmore, AC;Heise, MT
通讯作者：
Heise, MT
影响因子：
37.8
作者：
Jordan, JE;Montalto, MC;Stahl, GL
通讯作者：
Stahl, GL
影响因子：
3.5
作者：
Gupta, B;Agrawal, C;Das, HR
通讯作者：
Das, HR