Blocking of experimental arthritis by cleavage of IgG antibodies in vivo
Blocking of experimental arthritis by cleavage of IgG antibodies in vivo
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DOI：
10.1002/art.22930
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发表时间：
2007-10-01
影响因子：
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通讯作者：
Holmdahl, Rikard
中科院分区：
文献类型：
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作者：
Nandakumar, Kutty Selva;Johansson, Bjorn P.;Holmdahl, Rikard
Objective.研究化脓性链球菌IgG降解酶（IdeS）是否可用于阻断关节炎的发展。纯化重组IdeS并测试针对小鼠IgG的特异性。将IdeS静脉注射到胶原抗体诱导的关节炎（CAIA）、胶原诱导的关节炎（CIA）或复发性CIA小鼠中，并评估其对关节炎发展和严重程度的影响。IdeS在体外有效地切割小鼠IgG 2a/c和IgG 3。即使在低剂量（10 μ g）下，IdeS在体内特异性切割IgG 2a，而没有任何明显的副作用。IdeS处理有效地阻断由IgG 2a抗体诱导的CAIA。当用IgG 2b抗11型胶原抗体诱导关节炎时没有观察到效果;由于IdeS不切割IgG 2b，这表明IgG切割是作用机制。如果在临床关节炎发作后24小时内给药，IdeS治疗可降低关节炎的严重程度，但不能阻断正在进行的严重关节炎。IdeS治疗还显著预防了慢性关节炎小鼠中抗体诱导的复发，并延迟了经典CIA中关节炎的发作并降低了关节炎的严重程度。IdeS在IgG抗体介导的自身免疫性关节炎中具有治疗潜力，代表了阻断致病抗体的新的独特手段。
Objective. To investigate whether IgG-degrading enzyme of Streptococcus pyogenes (IdeS), a bacterial cysteine endopeptidase that cleaves human IgG in the hinge region, can be used for blocking the development of arthritis.Methods. Recombinant IdeS was purified and tested for specificity against mouse IgG. IdeS was injected intravenously into mice with collagen antibody-induced arthritis (CAIA), collagen-induced arthritis (CIA), or relapsing CIA, and its effects on arthritis development and severity were assessed.Results. IdeS efficiently cleaved mouse IgG2a/c and IgG3 in vitro. Even at low dosage (10 mu g), IdeS specifically cleaved IgG2a in vivo without any apparent side effects. IdeS treatment efficiently blocked CAIA induced by IgG2a antibodies. No effect was observed when arthritis was induced with IgG2b anti-type 11 collagen antibodies; since IdeS does not cleave IgG2b, this indicated that IgG cleavage was the mechanism of action. IdeS treatment reduced the severity of arthritis if administered within 24 hours after the onset of clinical arthritis, but did not block ongoing severe arthritis. IdeS treatment also significantly prevented an antibody-induced relapse in mice that had chronic arthritis, and delayed the onset and reduced the severity of arthritis in classic CIA.Conclusion. IdeS has therapeutic potential in IgG antibody-mediated autoimmune arthritis, representing a new and unique means of blocking pathogenic antibodies.