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Antigen valence and the evolution and organization of the immune response. Subtitle: The importance of degeneracy in understanding B cell activation pathways. Phil Hodgkin. V. Evolutionarily logical or vestigial?. Hypothesis.
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Antigen valence and the evolution and organization of the immune response Subtitle: The importance of degeneracy in understanding B cell activation pathways Phil Hodgkin
V • Evolutionarily logical or vestigial?
Hypothesis • That it is due to evolution of strategies for minimizing “time to protection” while maximizing the ‘coverage’ of the universe of possible antigens
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]
Creating an Artificial Universe of Surfaces (AUS) Variants of the Universe N50 S9 gives numbers p can be assigned
Probability of a randomly chosen receptor having a designated complementarity Log scale and #
‘Coverage’ of all possible surfaces is degenerate at lower levels of complementarity For N50 S9
Number of epitopes per ‘antigen’ increases likelihood of a higher value reached
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
Calibration Calibrated by Eisen et al. DNP-lysine myeloma proteins
-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)
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
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
-10 10 M Multivalence enhancement Monovalent binding -5 10 M -10 10 M Three site binding Two site binding
How are these logical constraints reflected in B cell behaviour ?
Natural antibodies • A priori antibodies • Constitutive • Predominantly IgM • “Agglutinins” • Bind autoantigens • B-1 lineage • Limited V diversity
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
T-dependent antibodies Secretion Switch Division
T-dependent antibodies • Persistence of antigen drives • Development of high affinity • Isotype switching
T-dependent antibodies • IgM, IgG, IgA, IgE • High affinity • Memory
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
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
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
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
Antigen valence and time to protection High affinity costs time