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Arginine Residues Are Important in Determining the Binding of Human Monoclonal Antiphospholipid Antibodies to Clinically Relevant Antigens¹

Ian Giles^2,*,,, Nancy Lambrianides^*,, Nisha Pattni^*,, David Faulkes, David Latchman, Pojen Chen, Silvia Pierangeli, David Isenberg^* and Anisur Rahman^*,

^* Centre for Rheumatology, Department of Medicine, University College, London, United Kingdom; Medical Molecular Biology Unit, Institute of Child Health, University College, London, United Kingdom; Department of Microbiology, Immunology and Biochemistry, Morehouse School of Medicine, Atlanta, GA 30310; and Department of Medicine, Division of Rheumatology, University of California, Los Angeles, CA 90095

In the antiphospholipid syndrome (APS), antiphospholipid Abs (aPL) bind to anionic phospholipids (PL) and various associated proteins, especially ₂-glycoprotein I (2GPI) and prothrombin. In the present study, we show that altering specific Arg residues in the H chain of a human pathogenic 2GPI-dependent aPL, IS4, has major effects on its ability to bind these clinically important Ags. We expressed whole human IgG in vitro by stable transfection of Chinese hamster ovary cells with expression plasmids containing different V_H and V_L sequences. V_H sequences were derived from IS4 by altering the number of Arg residues in CDR3. V_L sequences were those of IS4, B3 (anti-nucleosome Ab), and UK4 (2GPI-independent aPL). Binding of the expressed H/L chain combinations to a range of anionic, neutral, and zwitterionic PL, as well as prothrombin, 2GPI, dsDNA, and chicken OVA, was determined by ELISA. Of four Arg residues in IS4VH CDR3 substituted to Ser, two at positions 100 and 100g, reduced binding to all Ags, while two at positions 96 and 97 reduced binding to 2GPI but increased or decreased binding to different PL. Eleven of 14 H/L chain combinations displayed weak binding to OVA with Arg to Ser replacements of all four Arg residues enhancing binding to this Ag. Only one H/L chain combination bound neutral PL and none bound dsDNA; hence, these effects are particularly relevant to Ags important in antiphospholipid syndrome. We hypothesize that these four Arg residues have developed as a result of somatic mutations driven by an Ag containing both PL and 2GPI.

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