Thus, the characteristic features of the MHC molecules are all present when these molecules are first encountered, and there are no intermediate forms to guide our understanding of their evolution. Although we can trace the evolution of the components of the innate immune system, the mystery of the origin of the adaptive immune system still largely persists. But although we may not have a sure answer to the question of what selective forces led to RAG-dependent elaboration of adaptive immunity, it has never been clearer that, as Charles Darwin remarked about evolution in general, “from so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.”
Summary.
Evolution of RAG-dependent adaptive immunity in jawed vertebrates was once considered a wholly unique and inexplicable ‘immunological Big Bang.’ However, we now understand that adaptive immunity has also evolved independently at least one other time during evolution. Our close vertebrate cousins, the jawless fishes, have evolved an adaptive immune system built on a completely different basis—the diversification of LRR domains rather than immunoglobulin domains—but which otherwise seems to have the essential features of clonal expression of receptors produced through a somatic rearrangement and with a form of immunological memory, all features of an adaptive immune system. We now appreciate that evolution of the RAG-dependent adaptive immune system is probably related to the insertion of a transposon into a member of a primordial immunoglobulin superfamily gene, which must have occurred in a germline cell in an ancestor of the vertebrates. By chance, the transposon terminal sequences, the forerunners of the RSSs, were placed in an appropriate location within this primordial antigen-receptor gene to enable intramolecular somatic recombination, thus paving the way for the full-blown somatic gene rearrangement seen in present-day immunoglobulin and T-cell receptor genes. The MHC molecules that are the ligands for T-cell receptors first appear in the cartilaginous fishes, suggesting coevolution with RAG-dependent adaptive immunity. The transposase genes (the RAG genes) could have already been present and active in some other function in the genome of this ancestor. RAG1 seems to be of very ancient origin, as RAG1related sequences have been found in a wide variety of animal genomes.
Summary to Chapter 5.