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Antigen Valence: Evolution and Organization of the Immune Response

Explore the degeneracy in B cell activation pathways and the evolution of immune response strategies to maximize protection coverage. Investigate optimal schemes for antibody coverage using Artificial Universe of Surfaces (AUS) and explore the relationship between binding strength, affinity, and free energy.

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Antigen Valence: Evolution and Organization of the Immune Response

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  1. Antigen valence and the evolution and organization of the immune response Subtitle: The importance of degeneracy in understanding B cell activation pathways Phil Hodgkin

  2. V • Evolutionarily logical or vestigial?

  3. Hypothesis • That it is due to evolution of strategies for minimizing “time to protection” while maximizing the ‘coverage’ of the universe of possible antigens

  4. Test • Create an artificial universe of surfaces for antibody and antigens and rules for interaction in solution (not exact, but indicative of large number matching probability problem) • Investigate optimal schemes for covering universe of possibilities with ‘antibodies’ • [Avoiding the self tolerance question]

  5. Creating an Artificial Universe of Surfaces (AUS)

  6. Creating an Artificial Universe of Surfaces (AUS) Variants of the Universe N50 S9 gives numbers p can be assigned

  7. Probability of a randomly chosen receptor having a designated complementarity Log scale and #

  8. ‘Coverage’ of all possible surfaces is degenerate at lower levels of complementarity For N50 S9

  9. Number of epitopes per ‘antigen’ increases likelihood of a higher value reached

  10. Converting binding strength to affinity • Binding strength (affinity) related to free energy loss • Two components of free energy - enthalpy and entropy • Contribution of each bond to loss of free energy is additive • Free energy is exponentially related to affinity

  11. Calibration Calibrated by Eisen et al. DNP-lysine myeloma proteins

  12. -1 -5 -10 -15 10 10 10 10 47 epitopes “Covering” 5 x 10 50 47 10 5 x 10 Size of the repertoire needed is dramatically affected by necessary affinity 28 30 10 5 x 10 Number of receptors 15 9 x 10 10 6 10 7 x 10 21 -20 10 Affinity Kd (M)

  13. 16 10 14 10 10 12 10 10 10 10 8 10 6 10 4 10 2 10 0 10 -2 10 -4 10 -6 10 -8 10 -1 -5 10 10 Precursor frequency and affinity The pF is dramatically affected by the required affinity 10-fold increase in affinity = 100 fold decrease in pF So what is reqd affinity? Receptor # Number of precursors -10 -15 -20 10 10 10

  14. 4 2 10 1 10 100 75 50 (M) Kd 25 0 -5 -7 -6 10 10 10 Antibody concentration (M) Affinity, concentration and precursor frequency Number of precursors % sites bound

  15. -10 10 M Multivalence enhancement Monovalent binding -5 10 M -10 10 M Three site binding Two site binding

  16. Putting everything together

  17. How are these logical constraints reflected in B cell behaviour ?

  18. Natural antibodies • A priori antibodies • Constitutive • Predominantly IgM • “Agglutinins” • Bind autoantigens • B-1 lineage • Limited V diversity

  19. Activation of B cell by T-I Ags • Conventional B cells • “Cross-linking” of surface Ig • Limited isotypes - usually IgM • Low affinity • Weak memory and little somatic hypermutation

  20. T-dependent antibodies Secretion Switch Division

  21. T-dependent antibodies • Persistence of antigen drives • Development of high affinity • Isotype switching

  22. T-dependent antibodies • IgM, IgG, IgA, IgE • High affinity • Memory

  23. Summary of features • Natural Abs have limited repertoire of specificity, secrete IgM • TI Abs have restricted isotype, weak memory, weak SHM • TD Abs have range of isotypes and induce SHM and memory

  24. Layering of antibody sources Logic Logic • All “bugs” built from subunits • Almost all highly multivalent antigens can be “covered immediately by small repertoire • very early production • very restricted repertoire • All IgM • No adaptation Natural Support

  25. Layering of antibody sources Logic • Detects multivalent Ags missed by “Natural” system • Low affinity high avidity means high pF and fast response • High pF - no advantage in memory • High avidity means no need of SHM • Fast, low affinity • Mainly IgM - IgG3 • Activation requires cross linking • Little memory or SHM Support T-independent

  26. Logic • Most monovalent antigens cannot be covered at high affinity • Most ignored! • Protein indicates “life” and attempted from low affinity start • Must mutate to achieve hi affinity • effective increase in repertoire must be huge • Slow response • Antigen signal not required • Presentation converts monovalent protein into array • Switch from IgM division related • Extensive proliferation for SHM Support T-dependent

  27. Antigen valence and time to protection

  28. Antigen valence and time to protection High affinity costs time

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