补体抑制在小鼠胶原诱导性关节炎中的作用机制

Mechanisms of effects of complement inhibition in murine collagen-induced arthritis.

作者信息

Banda Nirmal K, Kraus Damian, Vondracek Andrea, Huynh Long H, Bendele Alison, Holers V Michael, Arend William P

机构信息

University of Colorado Health Sciences Center, Denver, CO 80262, USA.

出版信息

Arthritis Rheum. 2002 Nov;46(11):3065-75. doi: 10.1002/art.10591.

DOI:10.1002/art.10591

PMID:12428251

Abstract

OBJECTIVE

To determine the mechanisms of amelioration of collagen-induced arthritis (CIA) in DBA/1J mice by inhibition of complement activation.

METHODS

Mice received 2 intradermal injections of bovine type II collagen (CII), on days 0 and 21. From day 21 (immediately after the second injection of CII) through day 35, mice received intraperitoneal injections of either phosphate buffered saline (PBS), a monoclonal mouse antibody to murine C5 (anti-C5 antibody), or the C3 convertase inhibitor Crry-Ig.

RESULTS

On days 30 and 32, the clinical disease activity score was lower in mice treated with anti-C5 antibody than in those treated with Crry-Ig. Histopathologic evidence of joint damage was 75% lower in the mice treated with anti-C5 antibody than in those treated with either PBS or Crry-Ig. Spleen cells from mice receiving either form of complement inhibition exhibited decreased CII-stimulated proliferation, whereas increased proliferative responses were exhibited by lymph node cells from mice treated with Crry-Ig. Treatment with anti-C5 antibody decreased production of IgG1 anticollagen antibody, while production of IgG2a antibody was inhibited by both complement inhibitory treatments. CII-stimulated spleen cells from anti-C5-treated mice produced lower levels of tumor necrosis factor alpha (TNFalpha) and interleukin-10 (IL-10) compared with those from mice treated with Crry-Ig. Lower steady-state messenger RNA (mRNA) levels for TNFalpha, interferon-gamma (IFNgamma), IL-18, and IL-6 were observed in the joints of anti-C5-treated mice, and for IFNgamma and IL-6 in mice receiving Crry-Ig, all in comparison with PBS-treated mice. However, mRNA levels for IL-1beta and TNFalpha were lower in the joints after treatment with anti-C5 compared with Crry-Ig.

CONCLUSION

These results indicate that inhibition of complement in CIA leads to decreased production of IgG2a antibody and suppressed CII-induced spleen cell proliferation. The greater inhibitory effects on CIA of anti-C5 antibody in comparison with Crry-Ig may be attributable primarily to decreased levels of IL-1beta and TNFalpha mRNA in the joints.

摘要

目的

通过抑制补体激活来确定DBA/1J小鼠胶原诱导性关节炎（CIA）改善的机制。

方法

在第0天和第21天，小鼠接受2次牛II型胶原（CII）皮内注射。从第21天（第二次注射CII后立即）至第35天，小鼠腹腔注射磷酸盐缓冲盐水（PBS）、抗小鼠C5单克隆抗体（抗C5抗体）或C3转化酶抑制剂Crry-Ig。

结果

在第30天和第32天，用抗C5抗体治疗的小鼠临床疾病活动评分低于用Crry-Ig治疗的小鼠。用抗C5抗体治疗的小鼠关节损伤的组织病理学证据比用PBS或Crry-Ig治疗的小鼠低75%。接受任何一种补体抑制形式的小鼠的脾细胞表现出CII刺激的增殖减少，而用Crry-Ig治疗的小鼠的淋巴结细胞表现出增殖反应增加。用抗C5抗体治疗可降低IgG1抗胶原抗体的产生，而两种补体抑制治疗均抑制IgG2a抗体的产生。与用Crry-Ig治疗的小鼠相比，用抗C5治疗的小鼠的CII刺激的脾细胞产生的肿瘤坏死因子α（TNFα）和白细胞介素-1（IL-1）水平较低。与PBS治疗的小鼠相比，在抗C5治疗的小鼠关节中观察到TNFα、干扰素-γ（IFNγ）、IL-18和IL-6的稳态信使核糖核酸（mRNA）水平较低，在接受Crry-Ig治疗的小鼠关节中观察到IFNγ和IL-6的mRNA水平较低。然而，与Crry-Ig相比，抗C5治疗后关节中IL-1β和TNFα的mRNA水平较低。