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首页> 外文期刊>Clinical and Experimental Immunology: An Official Journal of the British Society for Immunology >A peptide mimic blocks the cross-reaction of anti-DNA antibodies with glomerular antigens
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A peptide mimic blocks the cross-reaction of anti-DNA antibodies with glomerular antigens

机译：肽模拟物可阻止抗DNA抗体与肾小球抗原的交叉反应

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摘要

Anti-DNA antibodies play a pivotal role in the pathogenesis of lupus nephritis by cross-reacting with renal antigens. Previously, we demonstrated that the binding affinity of anti-DNA antibodies to self-antigens is isotype-dependent. Furthermore, significant variability in renal pathogenicity was seen among a panel of anti-DNA isotypes [derived from a single murine immunoglobulin (Ig)G3 monoclonal antibody, PL9-11] that share identical variable regions. In this study, we sought to select peptide mimics that effectively inhibit the binding of all murine and human anti-DNA IgG isotypes to glomerular antigens. The PL9-11 panel of IgG anti-DNA antibodies (IgG1, IgG2a, IgG2b and IgG3) was used for screening a 12-mer phage display library. Binding affinity was determined by surface plasmon resonance. Enzyme-linked immunosorbent assay (ELISA), flow cytometry and glomerular binding assays were used for the assessment of peptide inhibition of antibody binding to nuclear and kidney antigens. We identified a 12 amino acid peptide (ALWPPNLHAWVP, or ALW') which binds to all PL9-11 IgG isotypes. Preincubation with the ALW peptide reduced the binding of the PL9-11 anti-DNA antibodies to DNA, laminin, mesangial cells and isolated glomeruli significantly. Furthermore, we confirmed the specificity of the amino acid sequence in the binding of ALW to anti-DNA antibodies by alanine scanning. Finally, ALW inhibited the binding of murine and human lupus sera to dsDNA and glomeruli significantly. In conclusion, by inhibiting the binding of polyclonal anti-DNA antibodies to autoantigens in vivo, the ALW peptide (or its derivatives) may potentially be a useful approach to block anti-DNA antibody binding to renal tissue.
机译：抗DNA抗体通过与肾脏抗原发生交叉反应，在狼疮性肾炎的发病机理中发挥关键作用。以前，我们证明了抗DNA抗体对自身抗原的结合亲和力是同种型依赖性的。此外，在一组具有相同可变区的抗DNA同种型[源自单一鼠类免疫球蛋白（Ig）G3单克隆抗体PL9-11]中，发现肾脏致病性存在显着差异。在这项研究中，我们试图选择能有效抑制所有鼠类和人类抗DNA IgG同种型与肾小球抗原结合的肽模拟物。 IgG抗DNA抗体（IgG1，IgG2a，IgG2b和IgG3）的PL9-11组用于筛选12-mer噬菌体展示文库。结合亲和力由表面等离子体共振确定。酶联免疫吸附测定（ELISA），流式细胞术和肾小球结合测定用于评估抗体与核抗原和肾抗原结合的肽抑制作用。我们鉴定了一个12个氨基酸的肽（ALWPPNLHAWVP或ALW'），它与所有PL9-11 IgG同种型结合。用ALW肽预孵育可显着降低PL9-11抗DNA抗体与DNA，层粘连蛋白，肾小球系膜细胞和分离的肾小球的结合。此外，我们通过丙氨酸扫描证实了氨基酸序列在ALW与抗DNA抗体结合中的特异性。最后，ALW显着抑制了鼠和人狼疮血清与dsDNA和肾小球的结合。总之，通过在体内抑制多克隆抗DNA抗体与自身抗原的结合，ALW肽（或其衍生物）可能是阻止抗DNA抗体与肾脏组织结合的有用方法。

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