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Invertebrate Immunity and Adaptive Immunity

Invertebrates do not possess an adaptive immune system, as evidenced by a lack of antibodies and the absence of clonal selection or accelerated secondary responses. Since both vertebrates and invertebrates possess variations of an innate immune system, the fact that defects in adaptive immunity can lead to pathological consequences in vertebrates indicates that it has evolved to play an essential role despite its absence in invertebrates. There are many possible explanations for how these two separate branches of life have so radically diverged so as to rely on largely different but connected systems of immunity, and these explanations are closely tied to the functions of the organisms themselves

Invertebrate Immunity

A basic explanation for this phenomena is that the adaptive immune expansion was evolutionarily favored, incurring a smaller net fitness cost which thus led to an increased reliance on adaptive immunity and a correspondent decrease in innate immune expansion. This selection would be particularly favored in hosts which are frequently exposed to the same microbes, as an adaptive response would allow for reduced energy expenditure during subsequent encounters with a given microbe. It may be that vertebrates were able to utilize a memory-based immune response to efficiently manage increasingly complex interactions with microbes composing a “commensal” microbiome. When faced with prolonged colonization by myriad species it is likely that the specificity of the adaptive immune response would offer an energetically favorable means of maintaining the microbiome, allowing for the secretion of significant levels of relatively benign IgA to prevent microbe/toxin entry rather than constitutive engagement of caustic innate responses which can harm host tissues. Vertebrates do constitutively secrete anti-microbial compounds into the gut, however the ability to generate clonal populations of lymphocytes was likely selected for in lieu of the expansion of innate antimicrobial responses such that a defect in adaptive immunity renders the extant innate mechanisms insufficient to manage certain forms of host-microbe interaction.

Many invertebrate species have developed expanded innate immune repertoires which allow them to better anticipate and eliminate virulent microbes without the need for the development of immunological memory. For example, the constitutively produced, alternatively spliced Ig-like Dscam protein of Drosophila allows for the opsonization of a broad range of pathogens (1). Because adaptive immune mechanisms take weeks to fully develop and play a larger role in secondary than in primary acute infections it is unsurprising that rapid innate responses are favored in this short-lived invertebrate species. Adaptive responses are likely evolutionarily most favored in species which take longer to reach sexual maturity such that immunological memory provides a reproductive advantage by reducing recurrent risks. Accordingly, the expansion of an adaptive immune system may have been strongly selected for such that there was reduced selective pressure on the innate immune repertoire. It is true that innate responses are engaged prior to adaptive responses in vertebrates and as such there would still be selective pressure to develop innate mechanisms to prevent unnecessary engagement of potentially pathological adaptive mechanisms, however the reproductive advantages conveyed by the adaptive immune system likely reduce these pressures.

While the reasons for vertebrate reliance on adaptive immunity are difficult to ascertain with certainty, it is very probable that effective adaptive immune responses provided a significant fitness advantage to early vertebrates, allowing them to better survive to sexual maturity and to better manage complex interactions with environmental/commensal microorganisms. There would have thus been less selective pressure to promote the energetically expensive constitutive production of a wide range of innate antimicrobial compounds such as Dscam splice variants. When adaptive immune responses are impaired, the lack of such compounds renders vertebrate innate immune responses insufficient to deal with certain microorganisms, leading to debilitating immunodeficiencies. In summary, the survival advantages conveyed upon vertebrates by adaptive immunity likely resulted in reduced selection for innate immune diversity such that innate immunity is no longer sufficient to manage complex host-microbe interactions.

Adaptive Immunity - V(D)J Recombination

In animals with an adaptive immune system, their immune B cells express antibodies which are randomly generated as the cell matures in the bone marrow or Bursa environments. These antibodies are formed through a process known as V(D)J recombination wherein random segments of DNA are combined together in a random fashion to generate any of billions of possible antibody structures. In addition to normal V(D)J recombination, certain animals such as chickens and other birds have a complementary process called gene conversion. Though the process functions through distinct mechanisms, it has the same end result of generating an increased set of random antibody structures on the surfaces of B cells. This assortment of random antibodies is essential to the function of B cells and the adaptive immune system as a whole, as the immune system will only work in there is a large cohort of B cells available to recognize and target invading pathogens for destruction.

One potential advantage which may be conferred by the limited diversity generated by V(D)J recombination in chickens is that it can bias the antibody repertoire to some extent. This could be valuable if chickens had historically been frequently faced with a particular pathogen against which they were more likely to generate functional antibodies due to limited V(D)J arrangements. Prior to gene conversion B cells would express nearly identical Ig molecules, and variations on these initial Igs may be more likely to act against these pathogens; indeed a similar advantage has been speculated to explain the existence of preformed VDJ cassettes in cartilaginous fishes. Additionally, having all B cells initially express nearly identical Ig receptors provides an ideal system for monitoring the generation of antibody diversity by only allowing for bursal exit when the resultant Ig is sufficiently distinct from the initial sequence. While this may prove advantageous against specific pathogens it may come at a cost to truly broad antibody diversity, potentially limiting the production of antibodies against specific epitopes based on initial VDJ and pseudogene sequences, although this weakness would likely be limited. Another disadvantage to gene conversion is that it can be eliminated by an inactivation of AID. In species which generate combinatorial diversity such an inactivation leads to a dangerous hyper-IgM syndrome but in chickens it would lead to a complete abrogation of antibody diversity, ensuring the death of these animals.

While V(D)J recombination generates little diversity in these B cells, these recombination events ensure that these gene segments are not adjacent in all somatic/germ cells in the chicken. This may be advantageous in that it prevents antibodies from being expressed in non-immune cells, thereby limiting any potentially deleterious effects that might arise from such aberrant expression patterns. Additionally, such recombination still allows for the insertion of random nucleotides to improve the basis for a broad repertoire.

While antibodies primarily serve to respond to surface epitopes on microbes, TcRs need to be able to respond to all antigens. Accordingly, while biasing the antibody repetoire may provide some advantage in allowing for opsonization of a common pathogen, it would be essential for TcRs to be able to recognize all antigens present on a pathogen in order to orchestrate the immune response and as such a less biased TcR repetoire could be valuable against a broad range of pathogens. Although this may be a contributing factor, it is likely that the greatest advantage conferred by diversification via V(D)J recombination is that it allows for better control over which sequences of the TcR are being most highly diversified. Unlike antibodies which can recognize antigens in many environments, functional TcRs must be able to identify their cognate antigens in the context of a relatively invariant MHC molecule. Accordingly, generating significant diversity in the CDR1/2 regions which interact with MHC molecules would often lead to TcR inactivation and cell death. V(D)J recombination ensures that the majority of TcR diversity exists in the CDR3 region (composed of portions of the V, D, and J sequences) which interacts with antigens presented on the MHC. Were gene conversion to be used in the process of TcR diversification it is highly likely that CDR1/2 sequences would often be disrupted, preventing efficacious development of a broad T cell repertoire.

While antibodies primarily serve to respond to surface epitopes on microbes, TcRs need to be able to respond to all antigens. Accordingly, while biasing the antibody repetoire may provide some advantage in allowing for opsonization of a common pathogen, it would be essential for TcRs to be able to recognize all antigens present on a pathogen in order to orchestrate the immune response and as such a less biased TcR repetoire could be valuable against a broad range of pathogens. Although this may be a contributing factor, it is likely that the greatest advantage conferred by diversification via V(D)J recombination is that it allows for better control over which sequences of the TcR are being most highly diversified. Unlike antibodies which can recognize antigens in many environments, functional TcRs must be able to identify their cognate antigens in the context of a relatively invariant MHC molecule. Accordingly, generating significant diversity in the CDR1/2 regions which interact with MHC molecules would often lead to TcR inactivation and cell death. V(D)J recombination ensures that the majority of TcR diversity exists in the CDR3 region (composed of portions of the V, D, and J sequences) which interacts with antigens presented on the MHC. Were gene conversion to be used in the process of TcR diversification it is highly likely that CDR1/2 sequences would often be disrupted, preventing efficacious development of a broad T cell repertoire.

References

  • 1. Sun, J.C. and L.L. Lanier, Natural killer cells remember: an evolutionary bridge between innate and adaptive immunity? European journal of immunology, 2009. 39(8): p. 2059-2064.
  • 2. Flajnik, M.F. and M. Kasahara, Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity, 2001. 15(3): p. 351-362.
  • 3. Medzhitov, R. and C.A. Janeway, Innate immunity: the virtues of a nonclonal system of recognition. cell, 1997. 91(3): p. 295-298.
  • 4. Lee, Y.K. and S.K. Mazmanian, Has the microbiota played a critical role in the evolution of the adaptive immune system? Science, 2010. 330(6012): p. 1768-1773.
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  • 9. Vilches, C. and P. Parham, KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annual review of immunology, 2002. 20(1): p. 217-251.
  • 10. Baskin, C.R., et al., Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus. Proceedings of the National Academy of Sciences, 2009. 106(9): p. 3455-3460.
  • 11. Hanssen, S.A., et al., Costs of immunity: immune responsiveness reduces survival in a vertebrate. Proceedings of the Royal Society of London, Series B: Biological Sciences, 2004. 271(1542): p. 925-930.
  • 12. Ryzhakov, G., K. Blazek, and I.A. Udalova, Evolution of vertebrate immunity: sequence and functional analysis of the SEFIR domain family member Act1. Journal of molecular evolution, 2011. 72(5-6): p. 521-530.
  • 13. Kang, D., et al., A peptidoglycan recognition protein in innate immunity conserved from insects to humans. Proceedings of the National Academy of Sciences, 1998. 95(17): p. 10078-10082.
  • 14. Azumi, K., et al., Genomic analysis of immunity in a Urochordate and the emergence of the vertebrate immune system:“waiting for Godot”. Immunogenetics, 2003. 55(8): p. 570-581.
  • 15. Renshaw, S.A. and N.S. Trede, A model 450 million years in the making: zebrafish and vertebrate immunity. Disease models & mechanisms, 2012. 5(1): p. 38-47.
  • 16. Marchalonis, J. and S. Schluter, A stochastic model for the rapid emergence of specific vertebrate immunity incorporating horizontal transfer of systems enabling duplication and combinatorial diversification. Journal of theoretical biology, 1998. 193(3): p. 429-444.
  • 17. Marchalonis, J.J. and R.E. Cone, The phylogenetic emergence of vertebrate immunity. The Australian journal of experimental biology and medical science, 1973. 51(4): p. 461.

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