Immunoglobulin Evolution Of

John J Marchalonis, Department of Microbiology and Immunology, College of Medicine, University of Arizona, Arizona, USA

Copyright © 1998 Elsevier Ltd. All Rights Reserved.

The first studies of antibody production in lower vertebrates were carried out between 1897 and 1903 by Mechnikoff, and Widal and Sicard in Europe and Noguchi in the USA. Mechnikoff emphasized the importance of comparative studies, showing that alligators produced antitoxins. Widal and Sicard showed that frogs made antibodies in response to inoculation with living typhus bacteria. Noguchi reported that turtles produced antibodies following challenge with whole blood from frogs, fish or other turtles. Studies of lower animals were carried out sporadically during the next 50 years, but there was a burst of interest in evolutionary studies in the 1960s. Good and his collaborators studied antibody production in nonmammalian vertebrate species ranging from cyclostomes to birds. In 1965, Marchalonis and Edelman first isolated and partially characterized immunoglobulins of a primitive vertebrate, the dogfish shark. They found that shark antibodies resembled mammalian immunoglobulins in possessing light and heavy polypeptide chains expressing charge diversity. Shark immunoglobulin most closely resembled mammalian IgM. Similar results were obtained for another shark, the lemon shark, by Clem and Small in 1967.

Although the fundamental similarities between immunoglobulin chains of lower vertebrates and their homologs in mammals was strongly indicated by the studies carried out in the late 1960s and early 1970s, definitive characterization of these molecules only became possible more recently. Initial strides in studies of immunoglobulins and their genes in human and mouse were facilitated by the fact that these mammalian species are subject to multiple myeloma, a cancer of the lymphoid system that results in the elaboration of monoclonal lymphocytes or plasma cells that secrete monoclonal immunoglobulins. No comparable monoclonal gammopath-ies occurred in primitive vertebrates. Therefore, the application of recombinant DNA technology which allowed genes to be cloned, sequenced and analyzed for their arrangements catalyzed a breakthrough in this area. Litman and his associates found that a murine VH probe (SI07) could be used to screen genomic libraries of elasmobranchs and reptiles with the detection and subsequent characterization of VH genes showing greater than 60% identity to the mammalian prototype. In other instances, as in the case of light chains of sharks, heterologous mammalian probes did not allow isolation of homologous genes and it was necessary to use the approach of isolating the shark immunoglobulins, making potent antiserum to them, and using these to screen cDNA libraries packaged in expression vectors. This approach was successfully used by Shamblott and Litman and Schluter and colleagues to obtain sequences of light chains of horned shark and sandbar shark respectively. Overall, there has been an explosion of knowledge regarding sequences and arrangements of immunoglobulin genes of lower vertebrates. Exciting work characterizing heavy chain genes of amphibians, teleosts and elasmobranchs by the above workers and others including Steiner, Du Pasquier, Schwager, Warr and Cuchens is currently being reported with increasing frequency. A fascinating development that emerged is that, despite the clear and strong homology in comparison among the corresponding chains of lower vertebrates and mammals, gene arrangements can vary considerably when the system specifying the homologous molecules are compared among sharks, chickens and mammals.

Immunoglobulin classes of vertebrates

All vertebrates can make antibodies that exhibit classic immunoglobulin structure consisting of two types of polypeptide chains that are polydisperse in charge and are usually linked covalently by disulfide bonds. Gene and protein sequence data are now available for immunoglobulins of all classes of vertebrates derived from the primitive jawed fish, the placoderms. These include elasmobranchs (e.g. sharks and rays), the ancestors of which diverged from those of mammals more than 400 million years ago, as well as teleost fish (e.g. goldfish), amphibians (e.g. bullfrogs and Xenopus), reptiles (e.g. the caiman), and birds (e.g. chickens). Based upon general structural properties, all placoderm-derived vertebrates possess antibodies comparable to the IgM (immune macroglobulin) isotype of mammals. The heavy chains are the same size as mammalian p chains (70 kDa) and serological cross-reactions between the mammalian and shark chains have been found. The antibody molecules of sharks occur in two forms in serum: a 7S 'monomer' consisting of two light and two heavy chains of the form (I.p), and a pentamer of the form (Lp),0 comparable to the predominant form of human IgM. The intact IgM molecules of bony fish teleosts occur in serum as tetramers instead of the pentamers found in other vertebrates.

Table 1 compares sequence alignments of the p chains of horned shark, clawed toad, chicken and human. Overall, the sequence identity in the constant region domains is approximately 30%. The identity in the framework sequences of the variable regions ranges from 40 to 75%, illustrating strong evolutionary conservation of this portion of the molecule.

Other classes of immunoglobulin characterized by distinct heavy chains are present in lungfish (Dipnoi), amphibians, reptiles and birds. These resemble y chains in consisting of multiple C-region domains, but are distinct from IgG immunoglobulins. All mammals, eutherians, marsupials and monotremes have 7S antibodies (apparent mass 150000) having heavy chains of mass 50000 that are serologically cross-reactive with human IgG. The distinct immunoglobulin monomers of amphibians, reptiles and birds have larger heavy chains than the mammalian y chain and most probably represent the

Human X

Pig X

Sheep X

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