Somatic mutations to arginine residues affect the binding of human monoclonal antibodies to DNA, histones, SmD and Ro antigen
Somatic mutations to arginine residues affect the binding of human monoclonal antibodies to DNA, histones, SmD and Ro antigen
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DOI：
10.1016/j.molimm.2003.10.018
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发表时间：
2004-01-01
影响因子：
3.6
通讯作者：
Rahman, A
中科院分区：
文献类型：
--
作者：
Haley, J;Mason, LJ;Rahman, A
系统性红斑狼疮（SLE）与多种抗原的自身抗体有关。双链DNA抗体（抗dsDNA）被认为与系统性红斑狼疮的组织损伤和疾病活动特别密切相关。自身抗体的历史，Sm和Ro被发现在SLE患者，但其作用的发病机制是不清楚的。使用瞬时表达系统，我们以前表明，特定的序列基序在轻链的CDR来自人Vgimel，基因2a 2是非常重要的，在确定他们的能力，形成一个DNA结合位点，当配对的人单克隆抗dsDNA抗体B3的重链。这些基序通常是体细胞突变的位点和/或含有精氨酸残基，在本文报道的实验中，使用相同的表达系统来显示这些CDR基序也影响与组蛋白、Ro抗原和Sm抗原的结合，但是这些CDR基序的特定序列的改变以不同的方式影响与不同抗原的结合。重链也在结合这些抗原中起作用。将相同范围的11 2a 2衍生轻链与不同抗DNA抗体33.H11的重链配对，与使用B3重链获得的结果相比，B3重链与DNA结合的能力降低。使用轻链组合来确定在这些抗体的结合位点处重要序列基序所占据的位置，并解释轻链中不同位置的精氨酸残基所产生的不同作用。(C)2003 Elsevier Ltd.保留所有权利。
Autoantibodies to a wide variety of antigens are associated with systemic lupus erythematosus (SLE). Antibodies to double-stranded DNA (anti-dsDNA) are thought to be particularly closely related to tissue damage and disease activity in SLE. Autoantibodies to histories, Sm and Ro are found in patients with SLE, but their role in pathogenesis is unclear.Using a transient expression system, we previously showed that particular sequence motifs in CDRs of light chains derived from the human Vgimel, gene 2a2 are very important in determining their ability to form a DNA-binding site, when paired with the heavy chain of the human monoclonal anti-dsDNA antibody B3. These motifs are often sites of somatic mutation and/or contain arginine residues.In the experiments reported in this paper, the same expression system was used to show that these CDR motifs also affect binding to histones, Ro antigen and Sm antigen, but that binding to different antigens is affected in diverse ways by particular changes in the sequence of the CDRs. The heavy chain also plays a role in binding to these antigens. Pairing of the same range of 11 2a2 derived light chains with the heavy chain of a different anti-DNA antibody, 33.H11, gave reduced ability to bind DNA in comparison with the results obtained using the B3 heavy chain.Computer-generated models of the three-dimensional structures of these heavy/light chain combinations were used to define the positions occupied by the important sequence motifs at the binding sites of these antibodies, and to explain the different effects exerted by arginine residues at different positions in the light chains. (C) 2003 Elsevier Ltd. All rights reserved.