title: A systematic analysis of sequences of human antiphospholipid and anti-beta2-glycoprotein I antibodies: the importance of somatic mutations and certain sequence motifs.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Centre for Rheumatology, University College London, London, England.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Giles
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Haley
authors.forename: Sylvia
authors.initials: S
authors.lastname: Nagl
authors.forename: David A
authors.initials: DA
authors.lastname: Isenberg
authors.forename: David S
authors.initials: DS
authors.lastname: Latchman
authors.forename: Anisur
authors.initials: A
authors.lastname: Rahman
mesh_terms: D000595:Amino Acid Sequence; D017152:Antibodies, Antiphospholipid / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology; D053482:beta 2-Glycoprotein I
chemical_list: D017152:Antibodies, Antiphospholipid; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I