A systematic analysis of sequences of human antiphospholipid and anti-β2-glycoprotein I antibodies:: The importance of somatic mutations and certain sequence motifs

被引:33
作者
Giles, IP
Haley, JD
Nagl, S
Isenberg, DA
Latchman, DS
Rahman, A
机构
[1] UCL, Dept Med, Ctr Rheumatol, London W1T 4NJ, England
[2] UCL, Med Mol Biol Unit, Inst Child Hlth, London W1T 4NJ, England
[3] UCL, Dept Biochem & Mol Biol, Biotechnol & Biol Serv, Res Council Ctr Struct Biol, London W1T 4NJ, England
关键词
sequence analysis; monoclonal antiphospholipid antibodies;
D O I
10.1053/sarh.2003.49994
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: Previous studies have suggested the importance of somatic mutations and certain residues in the complementarity determining regions (CDRs) of antiphospholipid antibodies (aPL) implicated in the pathogenesis of antiphospholipid antibody syndrome (APS). The authors tested this hypothesis by carrying out a systematic analysis of all published aPL sequences. Methods: Each aPL variable region sequence was aligned to the closest germline counterpart in the VBASE Sequence Directory by using DNAPLOT software, allowing analysis of nucleotide homology and distribution of somatic mutations. The probability that this distribution arose as a result of antigen-driven accumulation of replacement mutations in the CDRs was tested statistically. Results: There was no preferential gene or family use in the 36 aPL sequences identified. Immunoglobulin (Ig) M aPL had few somatic mutations compared with IgG. Of the IgG aPL, 9 of 14 showed evidence of antigen-driven accumulation of replacement mutations in the CDRs. Multinomial analysis allowed a clearer statistical identification of sequences that had been subject to antigen drive. The more specific IgM aPL and some IgG aPL displayed an accumulation of arginine, asparagine, and lysine residues in CDRs. Conclusions: High-specificity binding in IgG aPL, but not in more specific IgM aPL, is conferred by antigen-driven somatic mutation. This may in part be caused by an accumulation of arginine, asparagine, and lysine residues in the CDRs, which are germlines encoded in the more specific IgM aPL, but often arise because of somatic mutation in IgG aPL. Relevance: An understanding of the role of arginine, asparagine, and lysine residues in the binding of pathogenic aPL to phospholipids, and to beta(2)-glycoprotein I, may eventually help in the development of drugs to interfere with those interactions, and thereby improve the treatment of antiphospholipid antibody syndrome. Copyright 2003, Elsevier Science (USA). All rights reserved.
引用
收藏
页码:246 / 265
页数:20
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