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Examining the non-linear relationship between monoclonal antiphospholipid antibody sequence, structure and function

Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK; Centre for Rheumatology Research, Division of Medicine, University College London, London, UK i.giles{at}ich.ucl.ac.uk

A Lambrianides

Medical Molecular Biology Unit, Institute of Child Health, University College London, London, UK

A Rahman

Centre for Rheumatology Research, Division of Medicine, University College London, London, UK

In the antiphospholipid syndrome (APS), pathogenic antiphospholipid antibodies (aPL) that cause thrombosis or pregnancy morbidity are characterized by binding to anionic phospholipids (PL) and β2-glycoprotein I (β₂GPI). Sequence analysis of human monoclonal aPL has shown that high affinity for these antigens is associated with the presence of three particular amino acids: arginine (Arg), asparagine and lysine in the complementarity determining regions (CDRs) of their heavy and light chains. In vitro expression systems have been used to create variants of the antibodies in which these amino acids have been altered. In general, removal of Arg residues reduces affinity for anionic PL and β₂GPI. Arg at different positions in the sequence, however, have different effects on binding affinity and effects on binding are not always mirrored by effects on pathogenicity. This review will focus upon the sequence motifs that have been found to distinguish pathogenic from non-pathogenic aPL, and whether these or other properties may help to identify distinct pathogenic subsets of aPL. In particular, we will focus on our recent work in which we are trying to develop a better understanding of the molecular mechanisms involved in activation of target cells by pathogenic aPL. These studies, together with molecular models of antigen/antibody complexes, help us to understand exactly how pathogenic antibodies interact with antigens. Ultimately, this understanding may aid the design of more powerful diagnostic/prognostic assays and targeted therapeutic agents to block the pathogenic effects of these antibodies.

Key Words: antiphospholipid antibodies • antiphospholipid syndrome • function • sequence

Lupus, Vol. 17, No. 10, 895-903 (2008)
DOI: 10.1177/0961203308091541


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