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The critical role of arginine residues in the binding of human monoclonal antibodies to cardiolipin

Giles, I; Lambrianides, N; Latchman, D; Chen, PJ; Chukwuocha, R; Isenberg, D; Rahman, A; (2005) The critical role of arginine residues in the binding of human monoclonal antibodies to cardiolipin. ARTHRITIS RES THER , 7 (1) R47 - R56. 10.1186/ar1449.

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Abstract

Previously we reported that the variable heavy chain region (V-H) of a human beta(2) glycoprotein I-dependent monoclonal antiphospholipid antibody (IS4) was dominant in conferring the ability to bind cardiolipin ( CL). In contrast, the identity of the paired variable light chain region (V-L) determined the strength of CL binding. In the present study, we examine the importance of specific arginine residues in IS4V(H) and paired V-L in CL binding. The distribution of arginine residues in complementarity determining regions (CDRs) of V-H and V-L sequences was altered by site-directed mutagenesis or by CDR exchange. Ten different 2a2 germline gene- derived V-L sequences were expressed with IS4V(H) and the V-H of an anti-dsDNA antibody, B3. Six variants of IS4V(H), containing different patterns of arginine residues in CDR3, were paired with B3V(L) and IS4V(L). The ability of the 32 expressed heavy chain/light chain combinations to bind CL was determined by ELISA. Of four arginine residues in IS4V(H) CDR3 substituted to serines, two residues at positions 100 and 100 g had a major influence on the strength of CL binding while the two residues at positions 96 and 97 had no effect. In CDR exchange studies, V-L containing B3V(L) CDR1 were associated with elevated CL binding, which was reduced significantly by substitution of a CDR1 arginine residue at position 27a with serine. In contrast, arginine residues in V-L CDR2 or V-L CDR3 did not enhance CL binding, and in one case may have contributed to inhibition of this binding. Subsets of arginine residues at specific locations in the CDRs of heavy chains and light chains of pathogenic antiphospholipid antibodies are important in determining their ability to bind CL.

Type: Article
Title: The critical role of arginine residues in the binding of human monoclonal antibodies to cardiolipin
DOI: 10.1186/ar1449
Keywords: antiphospholipid antibodies, arginine, binding, cardiolipin, ANTI-DNA ANTIBODIES, PRIMARY ANTIPHOSPHOLIPID SYNDROME, SYSTEMIC LUPUS-ERYTHEMATOSUS, ANTICARDIOLIPIN ANTIBODIES, SOMATIC MUTATIONS, AUTOIMMUNE ANTIBODIES, GLYCOPROTEIN-I, LIGHT-CHAIN, MICE, AUTOANTIBODY
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Inflammation
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health > ICH - General Administration > ICH - Directors Office
URI: http://discovery.ucl.ac.uk/id/eprint/54379
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