Structural and functional characterization of a human IgG monoclonal antiphospholipid antibody.
Antiphospholipid antibodies (aPL) are likely involved in the pathogenesis of the antiphospholipid syndrome (APS). This study analyzes the structural and functional characteristics of a human monoclonal aPL (HL7G) from the IgG2 subtype with λ light chains generated from a patient with primary APS and recurrent cerebral microemboli. DNA encoding the variable region of heavy and light chains of the antibody was sequenced, analyzed, and compared to HL5B a previously described monoclonal aPL from the same patient. Both antibodies are derived from the same germline genes. HL7G had similar but more extensive somatic mutations in the CDR1 and 2 regions than HL5B, indicating that both antibodies are closely related and derived by a T cell-dependent antigen driven process. In ELISA assays HL7G bound to cardiolipin and several other phospholipid antigens in the absence of protein cofactors. Different from HL5B this aPL bound to β2-glycoprotein I (β2GPII). This suggests that reactivity of aPL against β2GPI is determined by only few specific amino acid exchanges. HL7G was able to induce tissue factor (TF) as one of the procoagulant effects of aPL. Our data suggest that the binding specificity of aPL is only of limited value to predict the biological effect and the pathophysiological impact of the antibodies.
Prinz
Nadine
N
Institute of Clinical Chemistry and Laboratory Medicine, Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
Häuser
Friederike
F
Lorenz
Mareike
M
Lackner
Karl J
KJ
von Landenberg
Philipp
P
D017152:Antibodies, Antiphospholipid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016736:Antiphospholipid Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D002308:Cardiolipins / Q000276:immunology; D002478:Cells, Cultured; D022801:Complementarity Determining Regions; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D027041:Somatic Hypermutation, Immunoglobulin; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D053482:beta 2-Glycoprotein I / Q000276:immunology
D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D002308:Cardiolipins; D022801:Complementarity Determining Regions; D007074:Immunoglobulin G; D053482:beta 2-Glycoprotein I; D013925:Thromboplastin