Pathogenic antiphospholipid antibody: an antigen-selected needle in a haystack

• Published in: Blood Vol. 104; no. 6; pp. 1711 - 1715
• Main Authors: Lieby, Patricia, Poindron, Vincent, Roussi, Stamatiki, Klein, Cyril, Knapp, Anne-Marie, Garaud, Jean-Claude, Cerutti, Martine, Martin, Thierry, Pasquali, Jean-Louis
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.09.2004; The Americain Society of Hematology; American Society of Hematology
• Subjects: Adult; Animals; Annexins - metabolism; Antibodies, Antiphospholipid - chemistry; Antibodies, Antiphospholipid - genetics; Antibodies, Antiphospholipid - immunology; Antibodies, Antiphospholipid - toxicity; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - toxicity; Antigens - immunology; Antiphospholipid Syndrome - immunology; Autoantibodies - chemistry; Autoantibodies - genetics; Autoantibodies - immunology; Autoantibodies - toxicity; Base Sequence; Biological and medical sciences; Cellular Biology; Diseases of mother, fetus and pregnancy; Enzyme-Linked Immunosorbent Assay; Female; Fetal Death - chemically induced; Fetal Death - immunology; General aspects; Germ-Line Mutation - genetics; Gynecology. Andrology. Obstetrics; Humans; Immunopathology; Life Sciences; Medical sciences; Mice; Models, Molecular; Molecular Sequence Data; Pregnancy; Pregnancy. Fetus. Placenta; Protein Structure, Tertiary; Autoimmunity; Pregnancy disorders; Pathogenesis; Phospholipid; Cardiovascular disease; Autoimmune disease; Hemopathy; Abortion; Vascular disease; Genetics; Human; Antiphospholipid antibody syndrome; Antibody; Rodentia; Autoantibody; B-Lymphocyte; Antigen; Vertebrata; Platelet; Mammalia; Autoantigen; Mouse; Animal; Risk factor; Mutation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-02-0462

Antiphospholipid antibodies represent a heterogeneous group of autoantibodies directed against anionic phospholipids (PLs) usually linked to protein cofactors. Their presence during the antiphospholipid syndrome is associated with risks of thrombosis and fetal losses. Among 5 randomly selected monoclonal antiphospholipid antibodies, all originating from a single patient suffering from this autoimmune disease, only 1 induced fetal losses when passively injected into pregnant mice. Its antiphospholipid activity was dependent on annexin A5, and its variable regions contained mainly 3 replacement mutations. To clarify the role of these mutations in the pathogenicity of the antibody, they were in vitro reverted to the germ line configuration. The resulting “germ line” antibody reacted with multiple self-antigens and only partially lost its reactivity against PLs, but it was no more dependent on annexin A5 and, more importantly, was no more pathogenic. This study illustrates that the in vivo antigen-driven maturation process of natural autoreactive B cells can be responsible for pathogenicity. (Blood. 2004;104:1711-1715)