Reconstructing immune phylogeny: new perspectives

Abstract

Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.The evolutionary development of the METAZOANS was associated with the diversification of a wide range of specialized cell-surface molecules that mediate key metabolic processes, as well as provide crucial contact interfaces and carry out a broad range of other essential functions. It is not unexpected that some of these molecules also came to function as barriers to pathogenic invasion and, in doing so, began to carry out dedicated innate immune protective functions. Whereas the simplest form of protection, barrier formation, is essentially mechanical in nature, relentless pressure from genetic variation in pathogens probably drove the evolution of such innate immune protective molecules towards diversification and, in parallel, towards integration of signalling pathways to regulate cellular responses to external stimulation. However, despite the sophistication that such innate immune mediators achieved over time, their biological complexity, by definition, would be limited by genome space, so with increasing complexity of body plan and/or increasing pathogen sophistication, they could be overwhelmed. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMore than 500 million years ago, a TRANSPOSITION event, probably involving a recombinationactivating gene (RAG)-bearing element, might have given rise to the predecessors of the rearranging antigen-binding receptors of the jawed vertebrates, which encompass the vertebrate radiations that extend from the cartilaginous fish through to humans. This is considered the defining point in the emergence of RAG-mediated (conventional) adaptive immunity 1,2 , which has evolved to create a mechanism for deriving almost limitless variation from very few genes. Studies in traditional and non-traditional animal models, such as sharks, bony fish and birds, have brought this event and its ramifications for host defence into sharper focus. We can now predict much about how these rearranging antigenbinding receptors probably arose, what alternative pathways of immune-receptor gene evolution have occurred, what relationships exist between B-and T-cell-mediated immunity and natural killer (NK)-cell function, how complex immune ...

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“…Moreover, it has been found that diversification of FREPs is generated through gene conversion and point mutation [18]. Diversification of innate immune effectors has also been found in other invertebrates, leading to general reconsideration of invertebrate immune capabilities [19][20][21][22][23].…”

Why study the evolution of immunity?

“…Those in all jawed vertebrates, sharks to humans, are based on the rearrangement of segmental elements encoding the immunoglobulin domains in T and B cell receptors and are mediated by recombinase-activating proteins RAG-1 and RAG-2 (ref. 7). In contrast, the random assembly of diverse leucine-rich repeat modules generates the lymphocyte receptor repertoire in jawless vertebrates, lamprey and hagfish in a RAG-independent way 8 .…”

“…Findings not in the text are in refs. 4,7,16. Dscam, Down's syndrome cell adhesion molecule; CDR3, complementarity-determining region 3; FR2, framework region 2; XRCC4, DNA-repair protein; Ku70 and Ku80, DNA-binding proteins; DNA-PK, DNAdependent protein kinase; TCR, T cell antigen receptor; Ig, immunoglobulin; Ψ, pseudo.…”

Darwin and Fisher meet at biotech: On the potential of computational molecular evolution in industry

“…For epidemiology--related problems, these techniques become particularly powerful when combined with classical epidemiologic models SIR or SIS (Kuhnert, Stadler et al 2014, Leventhal, Gunthard et al 2014. Application of evolutionary methods may be also useful for the analyses of somatic hypermutation in antibody sequences during antibody maturation, or to monitor somatic mutations in cancerous tissues (Litman, Cannon et al 2005, Campbell, Pleasance et al 2008, Yates and Campbell 2012, Zhu, Ofek et al 2013. Indeed, applications of phylogenetic methods to cancer and immunology research are now attracting more attention and funding.…”