Rapid evolutionary emergence of the combinatorial recognition repertoire

Although the capacity of cells to respond to environmental challengessuch as oxidative damage are ancient evolutionary developmentsthat have been carried through to modern higher vertebratesas "innate" immunity, the characteristic immune response ofvertebrates is a relatively recent evolutionary developmentthat is present only in jawed vertebrates. The vertebrate "combinatorial"response is defined by the presence of lymphocytes as specificantigen recognition cells and by the complete panel of antibodies,T cell receptors, and major histocompatibility complex moleculesall of which are members of the immunoglobulin family. Its emergencein evolution was an extremely rapid event (approximately 10million years) that was catalyzed by the horizontal transferof recombinase activator genes (RAG) from microbes to an ancestraljawed vertebrate. RAGs occur in jawed vertebrates, but havenot been found in invertebrates and other intermediate species.We propose that antigen recognition capacity contributed bythis novel combinatorial mechanism gave jawed vertebrates theability to recognize the entire range of potential antigenicmolecular structures, including self components and moleculesof infectious microbes not shared with vertebrates. The contrastwithin the vertebrates is striking because the most ancientextant jawed vertebrates, sharks and their kin, have the completepanoply of T-cell receptors, antibodies, MHC products and RAGgenes, whereas agnathans possess cells resembling lymphocytesbut ostensibly lack all of the molecules definitive of combinatorialimmunity. Another vertebrate innovation may have been the utilizationof nuclear receptor superfamily, in the regulation of lymphocytesand other cells of the immune lineage. Unlike, RAG, however,this superfamily occurs in all metazoans with the exceptionof sponges.