Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H.
Nephritogenic lambda light chain dimer: a unique human miniautoantibody against complement factor H.
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发表时间：
1999-10
影响因子：
4.4
通讯作者：
T. Jokiranta;A. Solomon;M. K. Pangburn;P. Zipfel;S. Meri
中科院分区：
文献类型：
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作者：
T. Jokiranta;A. Solomon;M. K. Pangburn;P. Zipfel;S. Meri
从1例低补体膜增生性肾小球肾炎患者的血清和尿液中分离到一种独特的单抗Ig-lambda轻链二聚体(蛋白LOI)。在体外，Lambda轻链二聚体有效地激活了补体的替代途径(AP)。当加入到正常人血清中时，LOI可以暂时增强AP的溶血活性，但在长时间的孵育过程中，溶血活性会耗尽。蛋白质LOI被发现与AP的主要调节分子H因子结合。通过与因子H的短一致重复结构域3结合，二聚体LOI阻断了H和C3b之间的三个相互作用位点之一，从而抑制了H的活性，并诱导了AP的失控激活。结构分析表明，LOI属于Lambda轻链的Vlambda3a亚基。LOI的可变区(V)与Vlambda3胚系基因Iglv3s2的预测产物关系最密切，尽管它包含几个独特的残基，在三级同源模型结构中，这些残基在推测的Ag结合部位的疏水凹槽周围形成一个不寻常的带电残基环。这个位点与因子H结构域3分子模型中的一个假定结合位点非常吻合，该分子模型包含一个疏水区域周围的带电氨基酸的倒数环。显然，抗体片段样的lambda轻链二聚体对H因子的功能性阻断启动了一种严重的膜增生性肾小球肾炎的发展。因此，Lambda轻链二聚体LOI代表了人类疾病中第一个被描述的致病性微型自身抗体。
A unique monoclonal Ig lambda light chain dimer (protein LOI) was isolated from the serum and urine of a patient with hypocomplementemic membranoproliferative glomerulonephritis. In vitro the lambda light chain dimer efficiently activated the alternative pathway of complement (AP). When added to normal human serum, LOI temporarily enhanced AP hemolytic activity, but during a prolonged incubation the hemolytic activity was depleted. Protein LOI was found to bind to factor H, the main regulator molecule of AP. By binding to the short consensus repeat domain 3 of factor H, the dimer LOI blocked one of three interaction sites between H and C3b and thus inhibited the activity of H and induced an uncontrolled activation of the AP. Structural analysis showed that LOI belonged to the Vlambda3a subgroup of lambda light chains. The variable (V) region of LOI was most closely related to the predicted product of the Vlambda3 germline gene Iglv3s2, although it contained several unique residues that in a tertiary homology model structure form an unusual ring of charged residues around a hydrophobic groove in the putative Ag binding site. This site fitted considerably well with a putative binding site in the molecular model of domain 3 of factor H containing a reciprocal ring of charged amino acids around a hydrophobic area. Apparently, functional blocking of factor H by the Ab fragment-like lambda light chain dimer had initiated the development of a severe form of membranoproliferative glomerulonephritis. Thus, the lambda light chain dimer LOI represents the first described pathogenic miniautoantibody in human disease.