Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system

The primordial combinatorial immune recognition repertoire arose in the evolution of jawed vertebrates approximately 450 million years ago as a rapid genetic process independent of antigenic selection. We propose that it encompassed the entire repertoire of innate immunity involving molecules that had evolved over billions of years. The 'antigen-driven' compartment involving invasive pathogens operates in 'real time' showing inducibility and increases in affinity. Individuals within a species differ in their repertoires because of distinct antigenic challenges, genetics, or local environmental effects. The 'homeostatic' compartment that recognizes invariant cell and serum components should be conserved in all individuals of a species. The potential to recapitulate the entire recognition spectrum must be regenerated during the formation of new species. Evidence for the capacity of the combinatorial response to encompass the entire preexisting repertoire was obtained in studies of natural human IgG antibodies present in intravenous immunoglobulin. Since essential cellular recognition and regulatory elements are conserved throughout evolution, we propose that the natural antibodies of sharks, the most anciently emerged vertebrates to possess the combinatorial immune response, will resemble those of mammals in showing specificity for the conserved recognition/regulatory molecules. If verified, this hypothesis will establish the fundamental importance of natural antibodies not only in defense, but in regulation and functional homeostasis of the individual.