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Related Experiment Videos

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

Patricia Lieby1, Vincent Poindron, Stamatiki Roussi

  • 1Laboratoire 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.

Blood
|May 29, 2004
PubMed
Summary

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Pathogenic antiphospholipid antibodies causing fetal loss in mice were studied. Mutations acquired during B cell maturation, not germline sequences, were crucial for pathogenicity, highlighting antigen-driven selection in autoimmune disease.

Area of Science:

  • Immunology
  • Autoimmunity
  • Molecular Biology

Background:

  • Antiphospholipid antibodies (aPLs) are autoantibodies targeting phospholipids, often associated with antiphospholipid syndrome (APS), increasing risks of thrombosis and fetal loss.
  • The specific mechanisms driving pathogenicity in aPLs, particularly the role of somatic mutations during B cell maturation, remain incompletely understood.

Purpose of the Study:

  • To investigate the role of specific mutations within the variable regions of a pathogenic antiphospholipid antibody in its ability to induce fetal loss.
  • To determine whether germline antibody configurations are inherently pathogenic or if acquired mutations are essential for disease manifestation.

Main Methods:

  • Selection of five monoclonal antiphospholipid antibodies from a single patient with antiphospholipid syndrome.

Related Experiment Videos

  • Passive transfer of a pathogenic antibody into pregnant mice to assess fetal loss induction.
  • In vitro reversion of key mutations in the pathogenic antibody's variable regions to a germline configuration.
  • Comparison of antigen binding (phospholipids, annexin A5) and pathogenicity between the original and germline-reverted antibodies.

    • Main Results:

    • Only one of the five tested monoclonal antiphospholipid antibodies induced fetal loss upon passive transfer.
    • The pathogenic antibody's activity was dependent on annexin A5, and its variable regions contained three key replacement mutations.
    • The germline-reverted antibody showed reduced reactivity to phospholipids, lost annexin A5 dependence, and was no longer pathogenic, though it reacted with other self-antigens.

    Conclusions:

    • Acquired somatic mutations during in vivo B cell maturation are critical for the pathogenicity of this specific antiphospholipid antibody.
    • The antigen-driven maturation process of natural autoreactive B cells can lead to pathogenic autoantibodies responsible for adverse clinical outcomes like fetal loss.