B cell responses to a peptide epitope. X. Epitope selection in a primary response is thermodynamically regulated

We examine the etiological basis of hierarchical immunodominance of B cell epitopes on a multideterminant Ag, A model T-dependant immunogen, containin g a single immunodominant B cell epitope, was used, The primary IgM respons e to this peptide included Abs directed against diverse determinants presen ted by the peptide. Interestingly, affinity of individual monomeric IgM Abs segregated around epitope recognized and was independent of their clonal o rigins. Furthermore, affinity of Abs directed against the immunodominant ep itope were markedly higher than that of the alternate specificities, These studies suggested that the affinity of an epitope-specific primary response , and variations therein, may be determined by the chemical composition of epitope, This inference was supported by thermodynamic analyses of monomer IgM binding to Ag, which revealed that this interaction occurs at the expen se of unfavorable entropy changes. Permissible binding required compensatio n by net enthalpic changes. Finally, the correlation between chemical compo sition of an epitope, the resultant affinity of the early primary humoral r esponse, and its eventual influence on relative immunogenicity could be exp erimentally verified. This was achieved by examining the effect of various amino-terminal substitutions on immunogenicity of a, hitherto cryptic, amin o-terminal determinant, Such experiments permitted delineation of a hierarc hy of individual amino acid residues based on their influence; which correl ated well with calculated Gibbs-free energy changes that individual residue side chains were expected to contribute in a binding interaction. Thus, ma turation of a T-dependant humoral response is initiated by a step that is u nder thermodynamic control.