Lessons from Sequence Analysis of Monoclonal Antiphospholipid Antibodies

From the published sequences of monoclonal aPL there is no evidence that particular human Ig V region genes are used preferentially to encode aPL. Somatic mutations which are antigen driven confer high specificity binding in IgG aPL but do not play a role in the formation of similar binding characteristics in the more specific IgM aPL. We have identified a common factor between these 2 groups of aPL, which is the presence of Arg, Asn, and Lys residues in CDRs and contact sites. These are germline encoded in the more specific IgM aPL but often arise due to somatic mutations in the IgG aPL. Our hypothesis is that the Arg, Asn, and Lys residues increase the affinity of binding via electrostatic interactions and hydrogen bonds with negatively charged epitopes upon PL and domain I of β2-GPI. We have demonstrated the relative importance of certain surface exposed Arg residues at critical positions within the light chain CDR1 and heavy chain CDR3 of different human monoclonal aPL in conferring the ability to bind CL. It is now important to test the effects of sequence changes involving these amino acids on pathogenic functions of these aPL. Such tests may help to define the nature of interactions between aPL, PL, and β2-GPI. This may eventually help in the development of drugs to interfere with those interactions, and thereby improve the treatment of APS.