414/514 Immunology Principles 415/515 Immunology Principles and Practice

Antigen Interactions

Antigen-Antibody Interactions

• Antigen-antibody interactions involve reversible formation of multiple noncovalent bonds between epitope and paratope
  • The spatial complementarity required is based upon the electron cloud shapes of both epitope and paratope<>
  • Overall epitope and paratope configuration, which determines the availability of electrons for interaction, is more important than the nature of the atoms involved (e.g., note the cross-reactivity of benzoate, phenylarsonate and benzenesulfonate with antibodies prepared against benzenesulfonate)<>
  • The lock and key relationship between epitope and paratope is enhanced by induced fit (~1 angstrom at the peptide backbone level, and more at the side chain level) due to their mutually deformable conformations
• Intermolecular interactions between side chains of epitope subunits and those of the paratope include these noncovalent interactions
  • Hydrogen-bonding
    • reversible hydrogen bridges between hydrophilic (hydroxyl, amino and carboxyl) groups<>
    • relatively weak, essentially electrostatic interactions that are enhanced by displacement of water molecules
  • Electrostatic interactions
    • oppositely charged ionic groups, such as carboxyl and amino groups, attract each other<>
    • force of these interactions is inversely proportional to the square of the distance between the charges
      • mutual attractiveness between them increases exponentially as the charged groups come closer together<>
      • displacement of water molecules, with their high dielectric constant, increases the force of these interactions
  • Van der Waal's forces
    • depend upon interaction between external electron clouds that lead to induced dipole interactions<>
    • force of these interactions is inversely proportional to the 7th power of the distance between the electron clouds
  • Hydrophobic interactions
    • nonpolar groups associate with one another in an aqueous environment<>
    • association of water molecules with one another as they are displaced from the nonpolar groups provides the driving force for these interactions
• Conformational complexity is crucial for close interaction of epitope and paratope
  • Allows the molecules to come very close together, which allows multiple weak interactions to form<>
  • The closer they get to one another, the stronger the interaction between them
• Specificity is not absolute
  • Cross-reactivity between epitopes with similar, but not identical, structures is based on structural complementarity<>
  • Homologus antigen (the inducing antigen) gives better reactivity with antibody than heterologous antigen
• Affinity vs. Avidity
  • Affinity - strength of binding between a single epitope and paratope ... this is a function of how many noncovalent bonds are formed, and how strong each of them is ... find out much more about affinity!<>
  • Avidity
    • Functional affinity - strength of the interaction of antigen molecules with multiple epitopes with antibodies with more than one paratope<>

    n Ab + m Ag = Abn Agn

    • Multiple epitope-paratope interactions are involved, so the factors contributing to avidity are complicated (consider the extreme case of a bacterium with multiple non-identical epitopes interacting with an IgM antibody with ten paratopes)<>
    • Multivalency of antigen and antibody lead to a "bonus" effect due to cooperative interactivity of the molecules in AgAb complexes
      • the probability that all AgAb interactions will dissociate simultaneously is exceedingly small<>
      • therefore, if one interaction is dissociated, the others will remain associated, thus enhancing the probability that those dissociated will reassociate

TCR Interactions with MHC-Antigen Fragment Complexes

• MHC class I interactions govern interactions of CTL TCRs with antigen
  • Doherty and Zinkernagel (1974) showed this in experiments in which CTL were shown to lyse virus-infected cells only when those cells also possessed the same MHC-I molecules as the CTL
• MHC class II interactions govern interactions of T helper cell TCRs with antigen
  • Shevach and Rosenthal (1978) showed this in experiments in which Th cells were activated by APCs only when the Th cells and APCs possessed the same MHC-II molecules
• Ternary nature of TCR-MHC-Ag Complex
  • APCs process antigens and present short linear fragments (peptides) of antigen on their surfaces in association with MHC-I and MHC-II molecules<>
  • T cells are activated as a result of simultaneously binding both the antigenic peptides and MHC molecules via their TCRs
    • TCR Valpha CDR3 binds the N-terminus of the antigenic peptide, whereas TCR Vbeta CDR3 binds the C-terminus of the antigenic peptide<>
    • Only those amino acid sidechains not involved in binding the MHC molecule are available for binding to TCR contact residues, so binding of TCR with the antigen fragment itself is rather weak . . . however<>
    • Binding of TCR (Valpha CDR1/CDR2 and Vbeta CDR1/CDR2) to MHC alpha-helical regions (alpha1 and alpha2 domains in MHC-I; alpha1 and beta1 domains in MHC-II) contributes to the total affinity of the TCR-MHC-Ag interaction<>
    • The dimeric nature of both TCR and MHC-Ag complexes contributes to the avidity of these interactions<>
    • Other surface molecules contribute further to both the general specificity (CD4, CD8) and overall avidity (ICAM, LFA, CD2, etc.) of these interactions<>
    • Multiple noncovalent interactions mediate TCR interactions with MHC-Ag peptide . . . just as was seen for antigen-antibody interactions