The acquired immune system, which has been best-studied in mammals, originated in jawed fish approximately 500 million years ago. Most of the molecules, cells, tissues, and associated mechanisms of this system of defense are found in cartilaginous fishes. Lymphocyte receptors, Ig and TCR, are found in all jawed vertebrates. The most ancient Ig class, IgM, is membrane-bound and then secreted upon stimulation of cartilaginous fish B cells. Another isotype, shark IgW, is related to mammalian IgD. TCRs, both α/β and γ/δ, are found in all animals from gnathostomes to mammals. The organization of gene segments that undergo gene rearrangement differs in cartilaginous fishes, which have a cluster form as compared to the translocon form in bony fish to mammals. Like TCR and Ig, the MHC is found only in jawed vertebrates. Genes involved in antigen processing and presentation, as well as the class I and class II genes, are closely linked within the MHC of almost all studied species.