Paradoxes of Immunity: Alternative Forms of Adaptive Immunity Discovered by Evolutionary Genomics

The fundamental discoveries in immunology in the 20th century initially focused on humans and other mammals, and then they extended to other vertebrates, including birds and fishes. Significant parallels in immune system architecture and mechanisms were revealed. In all organisms, from humans to zebrafish, antibodies and B cells, CD8⁺ and CD4⁺ T cells that recognize MHC I and MHC II, respectively, were identified, along with a set of major cytokines. Advances in DNA sequencing technologies and the development of bioinformatics for genome and transcriptome analysis allowed researchers to identify unique features in immune systems in some fishes and cyclostomes in the early 21st century. Such features stood in contradiction with established concepts based on studies of the mammalian immune system. The loss of several key genes encoding critical molecular mediators of adaptive immunity (MHC II, CD4, and others) was uncovered in anglerfish, codfish, and pipefish. Simultaneously, a unique type of adaptive immune system was discovered in lampreys and hagfish which utilizes different structural scaffolds (based on LRR-rich domains) to generate adaptive immune receptors (VLRs), as well as antibodies. Moreover, most species that could be classified as immunodeficient based on the studies of the vertebrate immune system proved to retain protective functions, suggesting the existence of compensatory mechanisms.