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Cross reactive renal antigens for pathogenic anti-dsDNA antibodies in lupus nephritis.

机译：狼疮性肾炎中致病性抗dsDNA抗体的交叉反应性肾脏抗原。

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摘要

Auto-antibodies are serological hallmarks of systemic lupus erythematosus (SLE), with anti-ds (double stranded) DNA antibodies being characteristic of lupus nephritis (LN). Anti-dsDNA Abs can be found deposited in the kidney; however the cross-reactive renal target antigens for these antibodies have not been conclusively identified. In identifying the in-vivo renal antigens for anti-dsDNA Abs, we found that pathogenic anti-dsDNA antibodies as well as immunoglobulin eluted from kidneys of nephritic lupus mice cross-react with alpha-actinin. Furthermore, there was enhanced binding to alpha-actinin derived from lupus prone MRL-lpr/lpr mouse mesangial cells (MCs) as compared with non-autoimmune BALB/c MCs due to alpha-actinin 4 being expressed at significantly higher levels in the MRL-lpr/lpr MCs. We also found novel sequence polymorphisms between MRL- lpr/lpr and BALB/c alpha-actinin 4. To determine if antibodies generated against alpha-actinin in vivo can cross-react with nuclear antigens, we immunized BALB/c mice with alpha-actinin. Immunized, but not control mice displayed high titers of anti-nuclear antibodies and IgG anti-chromatin autoantibodies, hypergammaglobulinemia, renal immunoglobulin deposition and proteinuria. The specificity of the anti-chromatin response as determined by Western and proteomic analysis, was a 25 kDa protein doublet, conclusively identified as High Mobility Group Box Proteins (HMGB 1 & 3), and a 70 kDa protein identified as heat shock protein 70 (HSP70), both of which are known antigenic targets in murine lupus. Importantly, a panel of pathogenic monoclonal autoantibodies had significantly higher affinity for alpha-actinin, chromatin, HMGB and HSP70 as compared to non-pathogenic antibodies, suggesting a common motif within these antigens that is targeted by pathogenic antibodies. Our studies indicate that alpha-actinin's differential expression and sequence motifs make it a target of pathogenic autoantibodies. Moreover, Abs to alpha-actinin may be used as a biomarker of active LN.
机译：自身抗体是系统性红斑狼疮（SLE）的血清学标志，抗ds（双链）DNA抗体是狼疮肾炎（LN）的特征。可以发现抗dsDNA Abs沉积在肾脏中。然而，尚未最终鉴定出这些抗体的交叉反应性肾脏靶抗原。在鉴定抗dsDNA Abs的体内肾脏抗原时，我们发现从肾病性狼疮小鼠肾脏洗脱的致病性抗dsDNA抗体以及免疫球蛋白与α-肌动蛋白发生交叉反应。此外，与非自身免疫BALB / c MC相比，与易患狼疮MRL-lpr / lpr小鼠肾小球系膜细胞（MCs）的α-肌动蛋白的结合增强，这是因为α-actinin4在MRL中的表达水平明显较高-lpr / lpr MC。我们还发现了MRL-lpr / lpr和BALB / c alpha-actinin 4之间的新型序列多态性。为了确定体内针对alpha-actinin生成的抗体是否可以与核抗原交叉反应，我们用alpha-actinin免疫了BALB / c小鼠。免疫但非对照的小鼠表现出高滴度的抗核抗体和IgG抗染色质自身抗体，高球蛋白血症，肾免疫球蛋白沉积和蛋白尿。通过Western和蛋白质组学分析确定的抗染色质反应的特异性是25 kDa蛋白质双峰，最终被鉴定为高迁移率族盒蛋白（HMGB 1和3），而70 kDa蛋白质被鉴定为热休克蛋白70（ HSP70），这两者都是鼠科狼疮的已知抗原性靶标。重要的是，与非致病性抗体相比，一组致病性单克隆自身抗体对α-肌动蛋白，染色质，HMGB和HSP70具有显着更高的亲和力，表明这些抗原中有一个共同的基序，是致病性抗体靶向的。我们的研究表明，α-肌动蛋白的差异表达和序列基序使其成为致病性自身抗体的靶标。而且，α-肌动蛋白的Abs可以用作活性LN的生物标记。

著录项

  • 作者

    Deocharan, Bisram.;

  • 作者单位

    Yeshiva University.;

  • 授予单位 Yeshiva University.;
  • 学科 Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 154 p.
  • 总页数 154
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;
  • 关键词

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