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The Primary Antibody Repertoire Represents a Linked Network of Degenerate Antigen Specificities¹

Venkatasamy Manivel^*, Fahri Bayiroglu^*, Zaved Siddiqui^*, Dinakar M. Salunke and Kanury V. S. Rao^2,*

^* Immunology Group, International Center for Genetic Engineering and Biotechnology, and National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India

In this study, germline Abs were used to select clones from a random dodecapeptide phage-display library. This revealed a much greater heterogeneity of binders than could be obtained with mutated daughter Abs that presumably had been selected in vivo by nominal Ag during active immune responses. We demonstrate that the pluripotency of germline Abs can subsequently be optimized by binding interactions that correlate with thermodynamic changes indicative of structural adaptations at the interface. This singular feature confers on each Ab a distinct window of Ag specificities, where the entropic space explored constitutes a thermodynamic signature of that particular Ab. Combining site plasticity may facilitate overlaps in such windows, with independent Abs converging onto common determinants with near identical binding affinities. In addition to providing for an amplified recognition potential, this networking of individual spectra of Ag specificities simultaneously facilitates the rapid recognition of Ag. Importantly, it also ensures that the primary response is composed of Abs with a high degree of "evolvability."

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