Pathogenic antiphospholipid antibody: an antigen-selected needle in a haystack.
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.
Lieby
Patricia
P
Laboratoire d'Immunopathologie, Institut de la Santé et de la Recherche Medicale, Equipe Mixte Inserum 0222, Institut d'Immunohématologie, Hôpital central, Hôpitaux Universitaires de Strasbourg, 67091, France.
Poindron
Vincent
V
Roussi
Stamatiki
S
Klein
Cyril
C
Knapp
Anne-Marie
AM
Garaud
Jean-Claude
JC
Cerutti
Martine
M
Martin
Thierry
T
Pasquali
Jean-Louis
JL
D000328:Adult; D000818:Animals; D017302:Annexins / Q000378:metabolism; D017152:Antibodies, Antiphospholipid / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000633:toxicity*; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000633:toxicity; D000941:Antigens / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D001323:Autoantibodies / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000633:toxicity*; D001483:Base Sequence; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005313:Fetal Death / Q000139:chemically induced / Q000276:immunology; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011247:Pregnancy; D017434:Protein Structure, Tertiary
D017302:Annexins; D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D000941:Antigens; D001323:Autoantibodies