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Related Experiment Videos

Can isotype switch modulate antigen-binding affinity and influence clonal selection?

O Pritsch1, C Magnac, G Dumas

  • 1Unité d'Immuno-Hématologie et d'Immunopathologie, Institut Pasteur, Paris, France.

European Journal of Immunology
|November 28, 2000
PubMed
Summary
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Monoclonal antibodies (MIg) targeting tubulin showed varying binding affinities based on their isotype, even with identical variable regions. This suggests antibody isotype influences antigen binding affinity, impacting B-cell development in lymphoma.

Area of Science:

  • Immunology
  • Molecular Biology
  • Oncology

Background:

  • Four distinct monoclonal immunoglobulins (MIg) with anti-tubulin activity were identified in a lymphoma patient's serum.
  • These MIg included IgA1kappa, IgG1kappa, IgG2kappa, and IgG4kappa, all derived from a single patient.
  • Three of the identified MIg shared identical variable heavy (V(H)) and variable light (V(L)) domains, indicating an antigen-driven selection process.

Purpose of the Study:

  • To investigate the influence of immunoglobulin (antibody) isotype on antigen-binding affinity.
  • To explore the role of isotype switching in the context of B-cell malignant transformation.
  • To determine if variable domain homology translates to consistent binding affinity across different isotypes.

Main Methods:

  • Sequencing of V(H) and V(L) domains from patient-derived MIg.

Related Experiment Videos

  • Binding affinity assays using Fab fragments and purified MIg (IgA1kappa, IgG1kappa) against beta-tubulin.
  • Cloning and expression of recombinant IgMkappa and IgG1kappa using IgA1kappa's V(H) and V(L) domains.

    • Main Results:

    • Despite identical variable domains, IgA1kappa and IgG1kappa exhibited significantly different binding affinities to a common beta-tubulin epitope.
    • Recombinant IgMkappa, derived from IgA1kappa variable domains, showed high binding affinity to tubulin.
    • Recombinant IgG1kappa, similarly derived, displayed a substantially lower binding affinity compared to IgMkappa and the original IgA1kappa.

    Conclusions:

    • Immunoglobulin isotype critically affects antigen-binding affinity, independent of variable domain sequence.
    • The findings provide evidence that isotype switching can occur after antigen-driven mutation acquisition.
    • This suggests that malignant transformation in this case likely happened in a germinal center during active mutation and isotype switching.