Pathogenic profiles and molecular signatures of antinuclear autoantibodies rescued from NZM2410 lupus mice.
Pathogenic profiles and molecular signatures of antinuclear autoantibodies rescued from NZM2410 lupus mice.
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DOI：
10.1084/jem.20030132
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发表时间：
2004-02-02
期刊：
影响因子：
--
通讯作者：
Mohan C
中科院分区：
文献类型：
--
作者：
Liang Z;Xie C;Chen C;Kreska D;Hsu K;Li L;Zhou XJ;Mohan C
关于狼疮中抗核抗体（ANA）的两个突出问题涉及其致病潜力和分子特征。为了解决这些问题，一组56个抗核和47个非核结合单克隆抗体从4个血清阳性NZM 2410狼疮小鼠被救出。单克隆抗体对核小体、ssDNA、dsDNA和肾小球底物的反应性各不相同。由于结合的DNase-1敏感的核抗原桥，大部分抗体表现出明显的多反应性（对DNA、组蛋白和肾小球抗原）。虽然嗜肾性免疫球蛋白（IG）M和IgG抗体是最致病的，dsDNA结合抗体是适度的，相反，抗核小体抗体显然不是致病性的。与从相同小鼠中获得的非核抗原结合单克隆抗体相比，ANA表现出对VH 5/7183基因和高度阳离子重链（HC）CDR 3区域的利用增加。最有趣的是，ANA的CDR 3区在H96、H98和H100处表现出交替的精氨酸/赖氨酸峰，在H95、H97和H99处具有中性谷。总之，肾小球结合抗dsDNA抗体似乎是狼疮自身抗体中致病性最强的种类。在其HC CDR 3区域中存在交替电荷模式似乎是ANA的突出标志。
Two outstanding questions concerning antinuclear antibodies (ANAs) in lupus involve their pathogenic potential and their molecular signatures. To address these questions, a panel of 56 antinuclear and 47 nonnuclear binding monoclonal antibodies was rescued from four seropositive NZM2410 lupus mice. The monoclonals varied in their reactivity to nucleosomes, ssDNA, dsDNA, and glomerular substrate. A large fraction of the antibodies demonstrated apparent polyreactivity (to DNA, histones, and glomerular antigens) due to bound, DNase-1 sensitive nuclear antigenic bridges. Although nephrophilic immunoglobulin (Ig) M and IgG antibodies were the most pathogenic, the dsDNA-binding antibodies were modestly so; in contrast, antinucleosome antibodies were clearly not pathogenic. Compared with the nonnuclear antigen-binding monoclonal antibodies rescued from the same mice, ANAs exhibited increased utilization of VH5/7183 genes and highly cationic heavy chain (HC) CDR3 regions. Most intriguingly, the CDR3 regions of the ANAs exhibited alternating arginine/lysine peaks at H96, H98, and H100, with neutral troughs at H95, H97, and H99. To summarize, glomerular-binding anti-dsDNA antibodies appear to be the most pathogenic variety of lupus autoantibodies. The presence of an alternating charge pattern in their HC CDR3 regions appears to be a prominent hallmark of ANAs.
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