Chondrichthyes: The Immune System of Cartilaginous Fishes

  • Helen DooleyEmail author


The cartilaginous fishes (sharks, skates, rays, and chimaeras) hold a key evolutionary position, being the most distant group to mammals that possesses a “mammalian-like” adaptive immune system based on immunoglobulins (Ig) and T cell receptors (TCRs), which are somatically rearranged by recombination-activating gene (RAG) proteins, as well as polymorphic/polygenic major histocompatibility complex (MHC) molecules. Cartilaginous fishes are therefore an important research model to investigate the evolution of adaptive immunity and its interplay with the innate system. Despite this, cartilaginous fishes have historically been understudied; while early functional studies revealed sharks were able to produce a humoral response following immune stimulation, subsequent progress was hampered by bottlenecks in immune gene sequencing and a paucity of research tools (such as cell lines and monoclonal antibodies) for use in functional studies.

Recent advances in high-throughput sequencing technologies have allowed us to address at least one of these limitations. With the recent publication of draft genomes for the elephant shark, little skate, and whale shark, in addition to a rapidly increasing number of transcriptomes from various elasmobranch species, we are beginning to fill the gaps in our knowledge of the immune molecules present, thereby gaining a more comprehensive understanding of immune functioning in this key vertebrate group.



Many thanks to my PhD students Rita Pettinello, Anthony Redmond, and Hanover Matz for their helpful comments during the drafting of this chapter. Also to Rita, Anthony, and Kirsty Macleod for allowing me to share their unpublished data.


  1. Anandhakumar C et al (2012) Expression profile of toll-like receptor 2 mRNA in selected tissues of shark (Chiloscyllium sp.). Fish Shellfish Immunol 33(5):1174–1182Google Scholar
  2. Aybar L, Shin DH, Smith SL (2009) Molecular characterization of the alpha subunit of complement component C8 (GcC8alpha) in the nurse shark (Ginglymostoma cirratum). Fish Shellfish Immunol 27(3):397–406PubMedCentralPubMedGoogle Scholar
  3. Bandukwala HS et al (2011) Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells. Immunity 34(4):479–491PubMedCentralPubMedGoogle Scholar
  4. Bartl S, Nonaka M (2014) MHC molecules of cartilaginous fishes. In: Smith SL, Sim RB, Flajnik M (eds) Immunobiology of the shark. CRC press, Boca Raton, pp 173–198Google Scholar
  5. Bartl S, Weissman IL (1994) Isolation and characterization of major histocompatibility complex class IIB genes from the nurse shark. Proc Natl Acad Sci U S A 91(1):262–266PubMedCentralPubMedGoogle Scholar
  6. Bartl S et al (1997) Identification of class I genes in cartilaginous fish, the most ancient group of vertebrates displaying an adaptive immune response. J Immunol 159(12):6097–6104Google Scholar
  7. Bird S et al (2002) The first cytokine sequence within cartilaginous fish: IL-1 beta in the small spotted catshark (Scyliorhinus canicula). J Immunol 168(7):3329–3340Google Scholar
  8. Bubeck D (2014) The making of a macromolecular machine: assembly of the membrane attack complex. Biochemistry 53(12):1908–1915Google Scholar
  9. Castro CD et al (2013) Noncoordinate expression of J-chain and Blimp-1 define nurse shark plasma cell populations during ontogeny. Eur J Immunol 43(11):3061–3075PubMedCentralPubMedGoogle Scholar
  10. Chen H et al (2009) Characterization of arrangement and expression of the T cell receptor gamma locus in the sandbar shark. Proc Natl Acad Sci U S A 106(21):8591–8596PubMedCentralPubMedGoogle Scholar
  11. Chen H et al (2010) Characterization of arrangement and expression of the beta-2 microglobulin locus in the sandbar and nurse shark. Dev Comp Immunol 34(2):189–195Google Scholar
  12. Chen H et al (2012) Somatic hypermutation of TCR gamma V genes in the sandbar shark. Dev Comp Immunol 37(1):176–183Google Scholar
  13. Clem LW, Small PA Jr (1967) Phylogeny of immunoglobulin structure and function. I. Immunoglobulins of the lemon shark. J Exp Med 125(5):893–920PubMedCentralPubMedGoogle Scholar
  14. Clem IW, De BF, Sigel MM (1967) Phylogeny of immunoglobulin structure and function. II. Immunoglobulins of the nurse shark. J Immunol 99(6):1226–1235Google Scholar
  15. Conticello SG et al (2005) Evolution of the AID/APOBEC family of polynucleotide (Deoxy)cytidine deaminases. Mol Biol Evol 22:367–377Google Scholar
  16. Criscitiello MF (2014) Shark T cell receptors. In: Smith SL, Sim RB, Flajnik M (eds) Immunobiology of the shark. CRC Press, Boca Raton, pp 237–248Google Scholar
  17. Criscitiello MF, Saltis M, Flajnik MF (2006) An evolutionarily mobile antigen receptor variable region gene: doubly rearranging NAR-TcR genes in sharks. Proc Natl Acad Sci U S A 103(13):5036–5041PubMedCentralPubMedGoogle Scholar
  18. Criscitiello MF et al (2010) Evolutionarily conserved TCR binding sites, identification of T cells in primary lymphoid tissues, and surprising trans-rearrangements in nurse shark. J Immunol 184(12):6950–6960PubMedCentralPubMedGoogle Scholar
  19. Criscitiello MF et al (2012) Shark class II invariant chain reveals ancient conserved relationships with cathepsins and MHC class II. Dev Comp Immunol 36(3):521–533Google Scholar
  20. Crouch K et al (2013) Humoral immune response of the small-spotted catshark, Scyliorhinus canicula. Fish Shellfish Immunol 34(5):1158–1169Google Scholar
  21. Culbreath L, Smith SL, Obenauf SD (1991) Alternative complement pathway activity in nurse shark serum. Am Zool 31(5):A131–A131Google Scholar
  22. Das S et al (2016) Characterization of lamprey BAFF-like gene: evolutionary implications. J Immunol 197(7):2695–2703PubMedCentralPubMedGoogle Scholar
  23. Day NK et al (1970) Complement and complement-like activity in lower vertebrates and invertebrates. J Exp Med 132(5):941–950PubMedCentralPubMedGoogle Scholar
  24. Diaz M, Greenberg AS, Flajnik MF (1998) Somatic hypermutation of the new antigen receptor gene (NAR) in the nurse shark does not generate the repertoire: possible role in antigen-driven reactions in the absence of germinal centers. Proc Natl Acad Sci U S A 95(24):14343–14348PubMedCentralPubMedGoogle Scholar
  25. Diaz M et al (1999) Mutational pattern of the nurse shark antigen receptor gene (NAR) is similar to that of mammalian Ig genes and to spontaneous mutations in evolution: the translesion synthesis model of somatic hypermutation. Int Immunol 11(5):825–833Google Scholar
  26. Diaz M et al (2002) Structural analysis, selection, and ontogeny of the shark new antigen receptor (IgNAR): identification of a new locus preferentially expressed in early development. Immunogenetics 54(7):501–512Google Scholar
  27. Dijkstra JM (2014) TH2 and Treg candidate genes in elephant shark. Nature 511(7508):E7–E9Google Scholar
  28. Dijkstra JM et al (2013) Comprehensive analysis of MHC class II genes in teleost fish genomes reveals dispensability of the peptide-loading DM system in a large part of vertebrates. BMC Evol Biol 13:260PubMedCentralPubMedGoogle Scholar
  29. Dodds AW et al (1998) Isolation and initial characterisation of complement components C3 and C4 of the nurse shark and the channel catfish. Dev Comp Immunol 22(2):207–216Google Scholar
  30. Dooley H, Flajnik MF (2005) Shark immunity bites back: affinity maturation and memory response in the nurse shark, Ginglymostoma cirratum. Eur J Immunol 35(3):936–945PubMedGoogle Scholar
  31. Dooley H et al (2006) First molecular and biochemical analysis of in vivo affinity maturation in an ectothermic vertebrate. Proc Natl Acad Sci U S A 103(6):1846–1851PubMedCentralPubMedGoogle Scholar
  32. Dulvy NK et al (2014) Extinction risk and conservation of the world's sharks and rays. elife 3:e00590PubMedCentralPubMedGoogle Scholar
  33. Eason DD et al (2004) Expression of individual immunoglobulin genes occurs in an unusual system consisting of multiple independent loci. Eur J Immunol 34(9):2551–2558PubMedGoogle Scholar
  34. Endo Y et al (1998) Two lineages of mannose-binding lectin-associated serine protease (MASP) in vertebrates. J Immunol 161(9):4924–4930PubMedGoogle Scholar
  35. Endo Y et al (2003) Origin of mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 involved in the lectin complement pathway traced back to the invertebrate, amphioxus. J Immunol 170(9):4701–4707PubMedCentralPubMedGoogle Scholar
  36. Fidler JE, Clem LW, Small PA Jr (1969) Immunoglobulin synthesis in neonatal nurse sharks (Ginglymostoma cirratum). Comp Biochem Physiol 31(2):365–371PubMedGoogle Scholar
  37. Flajnik MF (2014) Re-evaluation of the immunological Big Bang. Curr Biol 24(21):R1060–R1065PubMedCentralPubMedGoogle Scholar
  38. Glenney GW, Wiens GD (2007) Early diversification of the TNF superfamily in teleosts: genomic characterization and expression analysis. J Immunol 178(12):7955–7973PubMedGoogle Scholar
  39. Goshima M et al (2016) The complement system of elasmobranches revealed by liver transcriptome analysis of a hammerhead shark, Sphyrna zygaena. Dev Comp Immunol 61:13–24PubMedGoogle Scholar
  40. Graham M, Shin DH, Smith SL (2009) Molecular and expression analysis of complement component C5 in the nurse shark (Ginglymostoma cirratum) and its predicted functional role. Fish Shellfish Immunol 27(1):40–49PubMedCentralPubMedGoogle Scholar
  41. Granja AG et al (2017) Characterization of BAFF and APRIL subfamily receptors in rainbow trout (Oncorhynchus mykiss). Potential role of the BAFF / APRIL axis in the pathogenesis of proliferative kidney disease. PLoS One 12(3):e0174249PubMedCentralPubMedGoogle Scholar
  42. Greenberg AS et al (1995) A new antigen receptor gene family that undergoes rearrangement and extensive somatic diversification in sharks. Nature 374(6518):168–173PubMedGoogle Scholar
  43. Grimes DJ et al (1985) Vibrios as autochthonous flora of neritic sharks. Syst Appl Microbiol 6(2):221–226Google Scholar
  44. He X et al (2005) The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 433(7028):826–833PubMedGoogle Scholar
  45. Hinds KR, Litman GW (1986) Major reorganization of immunoglobulin VH segmental elements during vertebrate evolution. Nature 320(6062):546–549PubMedGoogle Scholar
  46. Hsu E (2014) Considering V(D)J recombination in the shark. In: Smith SL, Sim RB, Flajnik M (eds) Immunobiology of the shark. CRC press, Boca Raton, pp 199–220Google Scholar
  47. Hsu E et al (2006) The plasticity of immunoglobulin gene systems in evolution. Immunol Rev 210:8–26PubMedCentralPubMedGoogle Scholar
  48. Inoue JG et al (2010) Evolutionary origin and phylogeny of the modern holocephalans (Chondrichthyes: Chimaeriformes): a mitogenomic perspective. Mol Biol Evol 27(11):2576–2586PubMedGoogle Scholar
  49. Jensen JA et al (1981) The complement system of the nurse shark: hemolytic and comparative characteristics. Science 214(4520):566–569PubMedGoogle Scholar
  50. Kasahara M et al (1993) The evolutionary origin of the major histocompatibility complex: polymorphism of class II alpha chain genes in the cartilaginous fish. Eur J Immunol 23(9):2160–2165Google Scholar
  51. Kasamatsu J et al (2010) Phylogenetic and expression analysis of lamprey toll-like receptors. Dev Comp Immunol 34(8):855–865Google Scholar
  52. Kimura A, Nonaka M (2009) Molecular cloning of the terminal complement components C6 and C8beta of cartilaginous fish. Fish Shellfish Immunol 27(6):768–772Google Scholar
  53. Kimura A, Ikeo K, Nonaka M (2009) Evolutionary origin of the vertebrate blood complement and coagulation systems inferred from liver EST analysis of lamprey. Dev Comp Immunol 33(1):77–87Google Scholar
  54. Knight IT, Grimes DJ, Colwell RR (1988) Bacterial hydrolysis of urea in the tissues of Carcharhinid sharks. Can J Fish Aquat Sci 45(2):357–360Google Scholar
  55. Kohu K et al (2005) Overexpression of the Runx3 transcription factor increases the proportion of mature thymocytes of the CD8 single-positive lineage. J Immunol 174(5):2627–2636Google Scholar
  56. Kokubu F et al (1988) Complete structure and organization of immunoglobulin heavy chain constant region genes in a phylogenetically primitive vertebrate. EMBO J 7(7):1979–1988PubMedCentralPubMedGoogle Scholar
  57. Law SK, Dodds AW, Porter RR (1984) A comparison of the properties of two classes, C4A and C4B, of the human complement component C4. EMBO J 3(8):1819–1823PubMedCentralPubMedGoogle Scholar
  58. Lee SS et al (2000) Rearrangement of immunoglobulin genes in shark germ cells. J Exp Med 191(10):1637–1648PubMedCentralPubMedGoogle Scholar
  59. Lee SS et al (2002) Hypermutation in shark immunoglobulin light chain genes results in contiguous substitutions. Immunity 16(4):571–582Google Scholar
  60. Lee V et al (2008) The evolution of multiple isotypic IgM heavy chain genes in the shark. J Immunol 180(11):7461–7470PubMedCentralPubMedGoogle Scholar
  61. Li R et al (2012) Characterisation and expression analysis of B-cell activating factor (BAFF) in spiny dogfish (Squalus acanthias): cartilaginous fish BAFF has a unique extra exon that may impact receptor binding. Dev Comp Immunol 36(4):707–717Google Scholar
  62. Luer CA et al (1995) The elasmobranch thymus - anatomical, histological, and preliminary functional-characterization. J Exp Zool 273(4):342–354Google Scholar
  63. Luer C, Walsh CJ, Bodine AB (2014) Sites of immune cell production in elasmobranch fishes: lymphomyeloid tissues and organs. In: Smith SL, Sim RB, Flajnik M (eds) Immunobiology of the shark. CRC Press, Boca Raton, pp 79–88Google Scholar
  64. Ma Q et al (2013) Molecular cloning and expression analysis of major histocompatibility complex class IIB gene of the Whitespotted bambooshark (Chiloscyllium plagiosum). Fish Physiol Biochem 39(2):131–142Google Scholar
  65. Malecek K et al (2008) Immunoglobulin heavy chain exclusion in the shark. PLoS Biol 6(6):e157PubMedCentralPubMedGoogle Scholar
  66. Marchalonis J, Edelman GM (1965) Phylogenetic origins of antibody structure. I. Multichain structure of immunoglobulins in the smooth dogfish (Mustelus canis). J Exp Med 122(3):601–618PubMedCentralPubMedGoogle Scholar
  67. Marchalonis J, Edelman GM (1966) Phylogenetic origins of antibody structure. II. Immunoglobulins in the primary immune response of the bullfrog, Rana catesbiana. J Exp Med 124(5):901–913PubMedCentralPubMedGoogle Scholar
  68. Matsumoto M et al (1996) Affinity maturation without germinal centres in lymphotoxin-alpha-deficient mice. Nature 382(6590):462–466Google Scholar
  69. Medzhitov R, Janeway CA Jr (1997) Innate immunity: the virtues of a nonclonal system of recognition. Cell 91(3):295–298Google Scholar
  70. Miracle AL et al (2001) Complex expression patterns of lymphocyte-specific genes during the development of cartilaginous fish implicate unique lymphoid tissues in generating an immune repertoire. Int Immunol 13(4):567–580Google Scholar
  71. Miyahara Y et al (2008) Generation and regulation of human CD4+ IL-17-producing T cells in ovarian cancer. Proc Natl Acad Sci U S A 105(40):15505–15510PubMedCentralPubMedGoogle Scholar
  72. Mulley JF et al (2014) Transcriptomic analysis of the lesser spotted catshark (Scyliorhinus canicula) pancreas, liver and brain reveals molecular level conservation of vertebrate pancreas function. BMC Genomics 15:1074PubMedCentralPubMedGoogle Scholar
  73. Mylniczenko ND et al (2007) Blood culture results from healthy captive and free-ranging elasmobranchs. J Aquat Anim Health 19(3):159–167Google Scholar
  74. Neefjes J et al (2011) Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 11(12):823–836Google Scholar
  75. Neely HR, Flajnik MF (2016) Emergence and evolution of secondary lymphoid organs. Annu Rev Cell Dev Biol 32:693–711PubMedCentralPubMedGoogle Scholar
  76. Nielsen J et al (2016) Eye lens radiocarbon reveals centuries of longevity in the Greenland shark (Somniosus microcephalus). Science 353(6300):702–704Google Scholar
  77. Nish S, Medzhitov R (2011) Host defense pathways: role of redundancy and compensation in infectious disease phenotypes. Immunity 34(5):629–636PubMedCentralPubMedGoogle Scholar
  78. Nonaka M, Smith SL (2000) Complement system of bony and cartilaginous fish. Fish Shellfish Immunol 10(3):215–228Google Scholar
  79. Nonaka MI et al (2017) Evolutionary analysis of two complement C4 genes: ancient duplication and conservation during jawed vertebrate evolution. Dev Comp Immunol 68:1–11Google Scholar
  80. Ohta Y, Flajnik M (2006) IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates. Proc Natl Acad Sci U S A 103(28):10723–10728PubMedCentralPubMedGoogle Scholar
  81. Ohta Y et al (1999) Isolation of transporter associated with antigen processing genes, TAP1 and TAP2, from the horned shark Heterodontus francisci. Immunogenetics 49(11–12):981–986Google Scholar
  82. Ohta Y et al (2002) Proteasome, transporter associated with antigen processing, and class I genes in the nurse shark Ginglymostoma cirratum: evidence for a stable class I region and MHC haplotype lineages. J Immunol 168(2):771–781Google Scholar
  83. Ohta Y et al (2011) Primordial linkage of beta2-microglobulin to the MHC. J Immunol 186(6):3563–3571PubMedCentralPubMedGoogle Scholar
  84. Okamura K et al (1997) The most primitive vertebrates with jaws possess highly polymorphic MHC class I genes comparable to those of humans. Immunity 7(6):777–790Google Scholar
  85. Ozaki K, Leonard WJ (2002) Cytokine and cytokine receptor pleiotropy and redundancy. J Biol Chem 277(33):29355–29358Google Scholar
  86. Pancer Z et al (2004) Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430(6996):174–180PubMedCentralPubMedGoogle Scholar
  87. Pancer Z et al (2005) Variable lymphocyte receptors in hagfish. Proc Natl Acad Sci U S A 102(26):9224–9229PubMedCentralPubMedGoogle Scholar
  88. Pettinello R, Dooley H (2014) The immunoglobulins of cold-blooded vertebrates. Biomol Ther 4(4):1045–1069Google Scholar
  89. Pettinello R et al (2017) Evolutionary history of the T cell receptor complex as revealed by small-spotted catshark (Scyliorhinus canicula). Dev Comp Immunol 74:125–135Google Scholar
  90. Rast JP et al (1995) Identification and characterization of T-cell antigen receptor-related genes in phylogenetically diverse vertebrate species. Immunogenetics 42(3):204–212Google Scholar
  91. Rast JP et al (1997) Alpha, beta, gamma, and delta T cell antigen receptor genes arose early in vertebrate phylogeny. Immunity 6(1):1–11Google Scholar
  92. Read TD et al (2017) Draft sequencing and assembly of the genome of the world's largest fish, the whale shark: Rhincodon typus smith 1828. BMC Genomics 18(1):532PubMedCentralPubMedGoogle Scholar
  93. Redmond AK, Pettinello R, Dooley H (2017) Outgroup, alignment and modelling improvements indicate that two TNFSF13-like genes existed in the vertebrate ancestor. Immunogenetics 69(3):187–192PubMedCentralPubMedGoogle Scholar
  94. Ren W et al (2011) The first BAFF gene cloned from the cartilaginous fish. Fish Shellfish Immunol 31(6):1088–1096Google Scholar
  95. Ricklin D et al (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11(9):785–797PubMedCentralPubMedGoogle Scholar
  96. Roach JC et al (2005) The evolution of vertebrate toll-like receptors. Proc Natl Acad Sci U S A 102(27):9577–9582PubMedCentralPubMedGoogle Scholar
  97. Ross GD, Jensen JA (1973) The first component (C1n) of the complement system of the nurse shark (Ginglymostoma cirratum). I. Hemolytic characteristics of partially purified C1n. J Immunol 110(1):175–182Google Scholar
  98. Roux KH et al (1998) Structural analysis of the nurse shark (new) antigen receptor (NAR): molecular convergence of NAR and unusual mammalian immunoglobulins. Proc Natl Acad Sci U S A 95(20):11804–11809PubMedCentralPubMedGoogle Scholar
  99. Ruediger GF, Davis DJ (1907) Phagocytosis and opsonins in the lower animals. J Infect Dis 4(3):3Google Scholar
  100. Rumfelt LL (2014) Shark reproduction, immune system development and maturation: a review. In: Smith SL, Sim RB, Flajnik M (eds) Immunobiology of the shark. CRC press, Boca Raton, pp 51–78Google Scholar
  101. Rumfelt LL et al (2001) A shark antibody heavy chain encoded by a nonsomatically rearranged VDJ is preferentially expressed in early development and is convergent with mammalian IgG. Proc Natl Acad Sci U S A 98(4):1775–1780PubMedCentralPubMedGoogle Scholar
  102. Rumfelt LL et al (2002) The development of primary and secondary lymphoid tissues in the nurse shark Ginglymostoma cirratum: B-cell zones precede dendritic cell immigration and T-cell zone formation during ontogeny of the spleen. Scand J Immunol 56(2):130–148Google Scholar
  103. Rumfelt LL et al (2004) Unprecedented multiplicity of Ig transmembrane and secretory mRNA forms in the cartilaginous fish. J Immunol 173(2):1129–1139Google Scholar
  104. Ryu JK et al (2017) Reconstruction of LPS transfer cascade reveals structural determinants within LBP, CD14, and TLR4-MD2 for efficient LPS recognition and transfer. Immunity 46(1):38–50Google Scholar
  105. Secombes CJ, Zou J (2017) Evolution of interferons and interferon receptors. Front Immunol 8:209PubMedCentralPubMedGoogle Scholar
  106. Secombes CJ, Zou J, Bird S (2014) Cytokines of cartilaginous fish. In: Smith SL, Sim RB, Flajnik M (eds) Immunobiology of the shark. CRC press, Boca Raton, FL, pp 123–142Google Scholar
  107. Shen T et al (2014) Molecular cloning, organization, expression and 3D structural analysis of the MHC class Ia gene in the whitespotted bamboo shark (Chiloscyllium plagiosum). Vet Immunol Immunopathol 157(1–2):111–118Google Scholar
  108. Shin DH et al (2007) Molecular cloning, structural analysis and expression of complement component Bf/C2 genes in the nurse shark, Ginglymostoma cirratum. Dev Comp Immunol 31(11):1168–1182Google Scholar
  109. Small PA Jr, Klapper DG, Clem LW (1970) Half-lives, body distribution and lack of interconversion of serum 19S and 7S IgM of sharks. J Immunol 105(1):29–37Google Scholar
  110. Smith SL (1998) Shark complement: an assessment. Immunol Rev 166:67–78Google Scholar
  111. Smith SL, Nonaka M (2014) Shark complement: genes, protein and function. In: Smith SL, Sim RB, Flajnik M (eds) Immunobiology of the shark. CRC Press, Boca Raton, pp 143–172Google Scholar
  112. Smith LE et al (2012) Characterization of the immunoglobulin repertoire of the spiny dogfish (Squalus acanthias). Dev Comp Immunol 36(4):665–679Google Scholar
  113. Sorenson L, Santini F, Alfaro ME (2014) The effect of habitat on modern shark diversification. J Evol Biol 27(8):1536–1548Google Scholar
  114. Stanfield RL et al (2004) Crystal structure of a shark single-domain antibody V region in complex with lysozyme. Science 305(5691):1770–1773Google Scholar
  115. Stanfield RL et al (2007) Maturation of shark single-domain (IgNAR) antibodies: evidence for induced-fit binding. J Mol Biol 367(2):358–372Google Scholar
  116. Tanaka K, Kasahara M (1998) The MHC class I ligand-generating system: roles of immunoproteasomes and the interferon-gamma-inducible proteasome activator PA28. Immunol Rev 163:161–176Google Scholar
  117. Tao Z, Bullard SA, Arias CR (2014) Diversity of bacteria cultured from the blood of lesser electric rays caught in the northern Gulf of Mexico. J Aquat Anim Health 26(4):225–232Google Scholar
  118. Terado T et al (2001) Occurrence of structural specialization of the serine protease domain of complement factor B at the emergence of jawed vertebrates and adaptive immunity. Immunogenetics 53(3):250–254Google Scholar
  119. Terado T et al (2003) Molecular cloning of C4 gene and identification of the class III complement region in the shark MHC. J Immunol 171(5):2461–2466Google Scholar
  120. Tsukamoto K et al (2012) Long-lived dichotomous lineages of the proteasome subunit beta type 8 (PSMB8) gene surviving more than 500 million years as alleles or paralogs. Mol Biol Evol 29(10):3071–3079Google Scholar
  121. Venkatesh B et al (2014a) Elephant shark genome provides unique insights into gnathostome evolution. Nature 505(7482):174–179PubMedCentralPubMedGoogle Scholar
  122. Venkatesh B et al (2014b) Venkatesh et al. reply. Nature 511(7508):E9–E10Google Scholar
  123. Wang Y et al (2001) Complementary effects of TNF and lymphotoxin on the formation of germinal center and follicular dendritic cells. J Immunol 166(1):330–337Google Scholar
  124. Wang Q et al (2012) Community annotation and bioinformatics workforce development in concert – Little Skate Genome Annotation Workshops and Jamborees. Database (Oxford) 2012:bar064Google Scholar
  125. Wang Y et al (2013a) Molecular cloning of the alpha subunit of complement component C8 (CpC8alpha) of whitespotted bamboo shark (Chiloscyllium plagiosum). Fish Shellfish Immunol 35(6):1993–2000Google Scholar
  126. Wang Y et al (2013b) Molecular characterization and expression analysis of complement component C9 gene in the whitespotted bambooshark, Chiloscyllium plagiosum. Fish Shellfish Immunol 35(2):599–606Google Scholar
  127. Wyffels J et al (2014) SkateBase, an elasmobranch genome project and collection of molecular resources for chondrichthyan fishes. F1000Res 3:191PubMedCentralPubMedGoogle Scholar
  128. Xie X et al (2015) The regulatory T cell lineage factor Foxp3 regulates gene expression through several distinct mechanisms mostly independent of direct DNA binding. PLoS Genet 11(6):e1005251PubMedCentralPubMedGoogle Scholar
  129. Zapata A, Amemiya CT (2000) Phylogeny of lower vertebrates and their immunological structures. Curr Top Microbiol Immunol 248:67–107Google Scholar
  130. Zhang C, Du Pasquier L, Hsu E (2013) Shark IgW C region diversification through RNA processing and isotype switching. J Immunol 191(6):3410–3418Google Scholar
  131. Zhu C et al (2011) The multiple shark Ig H chain genes rearrange and hypermutate autonomously. J Immunol 187(5):2492–2501PubMedCentralPubMedGoogle Scholar
  132. Zhu C et al (2012) Origin of immunoglobulin isotype switching. Curr Biol 22(10):872–880PubMedCentralPubMedGoogle Scholar
  133. Zou J et al (2015) The CXC chemokine receptors of fish: insights into CXCR evolution in the vertebrates. Gen Comp Endocrinol 215:117–131Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Microbiology & ImmunologyUniversity of Maryland School of Medicine, Institute of Marine & Environmental Technology (IMET)BaltimoreUSA

Personalised recommendations