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Variable Lymphocyte Receptors: A Current Overview

Chapter
Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 57)

Abstract

Jawless vertebrates represented by lampreys and hagfish mount antigen-specific immune responses using variable lymphocyte receptors. These receptors generate diversity comparable to that of T-cell and B-cell receptors by assembling multiple leucine-rich repeat modules with highly variable sequences. Although it is true that jawed and jawless vertebrates have structurally unrelated antigen receptors, their adaptive immune systems have much in common. Most notable is the conservation of lymphocyte lineages. It appears that specialized lymphocyte lineages emerged in a common vertebrate ancestor and that jawed and jawless vertebrates co-opted different antigen receptors within the context of such lymphocyte lineages.

Keywords

Antigen receptor Cytidine deaminase Hagfish Jawless vertebrate Lamprey Leucine-rich repeat Lymphocyte lineage Thymoid Variable lymphocyte receptor 
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Notes

Acknowledgements

Experimental work in my laboratory has been supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan. I thank Dr. Yoichi Sutoh for his kind help with the preparation of figures.

References

  1. Acton RT, Weinheimer PF, Hildemann WH, Evans EE (1969) Induced bactericidal response in the hagfish. J Bacteriol 99:626–628PubMedCentralPubMedGoogle Scholar
  2. Alder MN, Rogozin IB, Iyer LM, Glazko GV, Cooper MD, Pancer Z (2005) Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310:1970–1973CrossRefPubMedGoogle Scholar
  3. Alder MN, Herrin BR, Sadlonova A, Stockard CR, Grizzle WE, Gartland LA, Gartland GL, Boydston JA, Turnbough CL Jr, Cooper MD (2008) Antibody responses of variable lymphocyte receptors in the lamprey. Nat Immunol 9:319–327CrossRefPubMedGoogle Scholar
  4. Anderson MK, Sun X, Miracle AL, Litman GW, Rothenberg EV (2001) Evolution of hematopoiesis: Three members of the PU.1 transcription factor family in a cartilaginous fish, Raja eglanteria. Proc Natl Acad Sci USA 98:553–558PubMedCentralCrossRefPubMedGoogle Scholar
  5. Ardavin CF, Zapata A (1987) Ultrastructure and changes during metamorphosis of the lympho-hemopoietic tissue of the larval anadromous sea lamprey Petromyzon marinus. Dev Comp Immunol 11:79–93CrossRefPubMedGoogle Scholar
  6. Bajoghli B, Aghaallaei N, Hess I, Rode I, Netuschil N, Tay BH, Venkatesh B, Yu JK, Kaltenbach SL, Holland ND, Diekhoff D, Happe C, Schorpp M, Boehm T (2009) Evolution of genetic networks underlying the emergence of thymopoiesis in vertebrates. Cell 138:186–197CrossRefPubMedGoogle Scholar
  7. Bajoghli B, Guo P, Aghaallaei N, Hirano M, Strohmeier C, McCurley N, Bockman DE, Schorpp M, Cooper MD, Boehm T (2011) A thymus candidate in lampreys. Nature 470:90–94CrossRefPubMedGoogle Scholar
  8. Boehm T (2011) Design principles of adaptive immune systems. Nat Rev Immunol 11:307–317CrossRefPubMedGoogle Scholar
  9. Boehm T, Iwanami N, Hess I (2012a) Evolution of the immune system in the lower vertebrates. Annu Rev Genomics Hum Genet 13:127–149CrossRefPubMedGoogle Scholar
  10. Boehm T, McCurley N, Sutoh Y, Schorpp M, Kasahara M, Cooper MD (2012b) VLR-based adaptive immunity. Annu Rev Immunol 30:203–220PubMedCentralCrossRefPubMedGoogle Scholar
  11. Cerenius L, Kawabata S, Lee BL, Nonaka M, Soderhall K (2010) Proteolytic cascades and their involvement in invertebrate immunity. Trends Biochem Sci 35:575–583CrossRefPubMedGoogle Scholar
  12. Cooper MD, Alder MN (2006) The evolution of adaptive immune systems. Cell 124:815–822CrossRefPubMedGoogle Scholar
  13. Cruikshank WW, Kornfeld H, Center DM (2000) Interleukin-16. J Leukoc Biol 67:757–766PubMedGoogle Scholar
  14. Dehal P, Boore JL (2005) Two rounds of whole genome duplication in the ancestral vertebrate. PLoS Biol 3, e314PubMedCentralCrossRefPubMedGoogle Scholar
  15. Deng L, Velikovsky CA, Xu G, Iyer LM, Tasumi S, Kerzic MC, Flajnik MF, Aravind L, Pancer Z, Mariuzza RA (2010) A structural basis for antigen recognition by the T cell-like lymphocytes of sea lamprey. Proc Natl Acad Sci USA 107:13408–13413PubMedCentralCrossRefPubMedGoogle Scholar
  16. Deng L, Luo M, Velikovsky A, Mariuzza RA (2013) Structural insights into the evolution of the adaptive immune system. Annu Rev Biophys 42:191–215CrossRefPubMedGoogle Scholar
  17. Du Pasquier L (2000) The phylogenetic origin of antigen-specific receptors. Curr Top Microbiol Immunol 248:160–185PubMedGoogle Scholar
  18. Du Pasquier L, Zucchetti I, De Santis R (2004) Immunoglobulin superfamily receptors in protochordates: before RAG time. Immunol Rev 198:233–248CrossRefPubMedGoogle Scholar
  19. Finstad J, Good RA (1964) The evolution of the immune response. III. Immunologic responses in the lamprey. J Exp Med 120:1151–1168PubMedCentralCrossRefPubMedGoogle Scholar
  20. Flajnik MF (2002) Comparative analyses of immunoglobulin genes: surprises and portents. Nat Rev Immunol 2:688–698CrossRefPubMedGoogle Scholar
  21. Flajnik MF (2014) Re-evaluation of the immunological big bang. Curr Biol 24:R1060–R1065PubMedCentralCrossRefPubMedGoogle Scholar
  22. Flajnik MF, Kasahara M (2001) Comparative genomics of the MHC: glimpses into the evolution of the adaptive immune system. Immunity 15:351–362CrossRefPubMedGoogle Scholar
  23. Flajnik MF, Kasahara M (2010) Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat Rev Genet 11:47–59PubMedCentralCrossRefPubMedGoogle Scholar
  24. Fried C, Prohaska SJ, Stadler PF (2003) Independent Hox-cluster duplications in lampreys. J Exp Zool B Mol Dev Evol 299:18–25CrossRefPubMedGoogle Scholar
  25. Fugmann SD (2010) The origins of the Rag genes—from transposition to V(D)J recombination. Semin Immunol 22:10–16PubMedCentralCrossRefPubMedGoogle Scholar
  26. Fujii T, Nakagawa H, Murakawa S (1979) Immunity in lamprey. I. Production of haemolytic and haemagglutinating antibody to sheep red blood cells in Japanese lampreys. Dev Comp Immunol 3:441–451CrossRefPubMedGoogle Scholar
  27. Fujita T (2002) Evolution of the lectin-complement pathway and its role in innate immunity. Nat Rev Immunol 2:346–353CrossRefPubMedGoogle Scholar
  28. Furlong RF, Holland PW (2002) Were vertebrates octoploid? Philos Trans R Soc Lond B Biol Sci 357:531–544PubMedCentralCrossRefPubMedGoogle Scholar
  29. Girardi M (2006) Immunosurveillance and immunoregulation by γδ T cells. J Invest Dermatol 126:25–31CrossRefPubMedGoogle Scholar
  30. Guo P, Hirano M, Herrin BR, Li J, Yu C, Sadlonova A, Cooper MD (2009) Dual nature of the adaptive immune system in lampreys. Nature 459:796–802PubMedCentralCrossRefPubMedGoogle Scholar
  31. Haire RN, Miracle AL, Rast JP, Litman GW (2000) Members of the Ikaros gene family are present in early representative vertebrates. J Immunol 165:306–312CrossRefPubMedGoogle Scholar
  32. Haruta C, Suzuki T, Kasahara M (2006) Variable domains in hagfish: NICIR is a polymorphic multigene family expressed preferentially in leukocytes and is related to lamprey TCR-like. Immunogenetics 58:216–225CrossRefPubMedGoogle Scholar
  33. Hayday AC (2000) γδ cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975–1026CrossRefPubMedGoogle Scholar
  34. Herrin BR, Alder MN, Roux KH, Sina C, Ehrhardt GR, Boydston JA, Turnbough CL Jr, Cooper MD (2008) Structure and specificity of lamprey monoclonal antibodies. Proc Natl Acad Sci USA 105:2040–2045PubMedCentralCrossRefPubMedGoogle Scholar
  35. Hildemann WH, Thoenes GH (1969) Immunological responses of Pacific hagfish. I. Skin transplantation immunity. Transplantation 7:506–521CrossRefPubMedGoogle Scholar
  36. Hirano M, Das S, Guo P, Cooper MD (2011) The evolution of adaptive immunity in vertebrates. Adv Immunol 109:125–157CrossRefPubMedGoogle Scholar
  37. Hirano M, Guo P, McCurley N, Schorpp M, Das S, Boehm T, Cooper MD (2013) Evolutionary implications of a third lymphocyte lineage in lampreys. Nature 501:435–438PubMedCentralCrossRefPubMedGoogle Scholar
  38. Holland PWH, Garcia-Fernandez J, Williams NA, Sidow A (1994) Gene duplications and the origins of vertebrate development. Development 1994(Suppl):125–133Google Scholar
  39. Holland SJ, Gao M, Hirano M, Iyer LM, Luo M, Schorpp M, Cooper MD, Aravind L, Mariuzza RA, Boehm T (2014) Selection of the lamprey VLRC antigen receptor repertoire. Proc Natl Acad Sci USA 111:14834–14839PubMedCentralCrossRefPubMedGoogle Scholar
  40. Honjo T, Muramatsu M, Fagarasan S (2004) AID: How does it aid antibody diversity? Immunity 20:659–668CrossRefPubMedGoogle Scholar
  41. Hsu E (2011) The invention of lymphocytes. Curr Opin Immunol 23:156–162PubMedCentralCrossRefPubMedGoogle Scholar
  42. Janvier P (2006) Palaeontology: modern look for ancient lamprey. Nature 443:921–924CrossRefPubMedGoogle Scholar
  43. Kanda R, Sutoh Y, Kasamatsu J, Maenaka K, Kasahara M, Ose T (2014) Crystal structure of the lamprey variable lymphocyte receptor C reveals an unusual feature in its N-terminal capping module. PLoS One 9, e85875PubMedCentralCrossRefPubMedGoogle Scholar
  44. Kapitonov VV, Jurka J (2005) RAG1 core and V(D)J recombination signal sequences were derived from Transib transposons. PLoS Biol 3, e181PubMedCentralCrossRefPubMedGoogle Scholar
  45. Kasahara M (2007) The 2R hypothesis: an update. Curr Opin Immunol 19:547–552CrossRefPubMedGoogle Scholar
  46. Kasahara M (2010) Genome duplication and T cell immunity. Prog Mol Biol Transl Sci 92:7–36CrossRefPubMedGoogle Scholar
  47. Kasahara M (2013a) Deja vu: the identity of a third lineage of lymphocytes in lampreys. Immunol Cell Biol 91:599–600CrossRefPubMedGoogle Scholar
  48. Kasahara M (2013b) Impact of whole-genome duplication on vertebrate development and evolution. Semin Cell Dev Biol 24:81–82CrossRefPubMedGoogle Scholar
  49. Kasahara M, Sutoh Y (2014) Two forms of adaptive immunity in vertebrates: similarities and differences. Adv Immunol 122:59–90CrossRefPubMedGoogle Scholar
  50. Kasahara M, Suzuki T, DuPasquier L (2004) On the origins of the adaptive immune system: novel insights from invertebrates and cold-blooded vertebrates. Trends Immunol 25:105–111CrossRefPubMedGoogle Scholar
  51. Kasahara M, Kasamatsu J, Sutoh Y (2008) Two types of antigen receptor systems in vertebrates. Zool Sci 25:969–975CrossRefPubMedGoogle Scholar
  52. Kasamatsu J, Suzuki T, Ishijima J, Matsuda Y, Kasahara M (2007) Two variable lymphocyte receptor genes of the inshore hagfish are located far apart on the same chromosome. Immunogenetics 59:329–331CrossRefPubMedGoogle Scholar
  53. Kasamatsu J, Sutoh Y, Fugo K, Otsuka N, Iwabuchi K, Kasahara M (2010) Identification of a third variable lymphocyte receptor in the lamprey. Proc Natl Acad Sci USA 107:14304–14308PubMedCentralCrossRefPubMedGoogle Scholar
  54. Kato L, Stanlie A, Begum NA, Kobayashi M, Aida M, Honjo T (2012) An evolutionary view of the mechanism for immune and genome diversity. J Immunol 188:3559–3566CrossRefPubMedGoogle Scholar
  55. Kishishita N, Matsuno T, Takahashi Y, Takaba H, Nishizumi H, Nagawa F (2010) Regulation of antigen-receptor gene assembly in hagfish. EMBO Rep 11:126–132PubMedCentralCrossRefPubMedGoogle Scholar
  56. Klein J, Sato A, Mayer WE (2000) Jaws and AIS. In: Kasahara M (ed) Major histocompatibility complex: evolution, structure, and function. Springer, Tokyo, pp 3–26CrossRefGoogle Scholar
  57. Kuraku S (2013) Impact of asymmetric gene repertoire between cyclostomes and gnathostomes. Semin Cell Dev Biol 24:119–127CrossRefPubMedGoogle Scholar
  58. Kuraku S, Meyer A, Kuratani S (2009) Timing of genome duplications relative to the origin of the vertebrates: did cyclostomes diverge before or after? Mol Biol Evol 26:47–59CrossRefPubMedGoogle Scholar
  59. Li J, Das S, Herrin BR, Hirano M, Cooper MD (2013) Definition of a third VLR gene in hagfish. Proc Natl Acad Sci USA 110:15013–15018PubMedCentralCrossRefPubMedGoogle Scholar
  60. Linthicum DS, Hildemann WH (1970) Immunologic responses of Pacific hagfish. III. Serum antibodies to cellular antigens. J Immunol 105:912–918PubMedGoogle Scholar
  61. Litman GW, Finstad FJ, Howell J, Pollara BW, Good RA (1970) The evolution of the immune response. III. Structural studies of the lamprey immunoglobulin. J Immunol 105:1278–1285PubMedGoogle Scholar
  62. Litman GW, Anderson MK, Rast JP (1999) Evolution of antigen binding receptors. Annu Rev Immunol 17:109–147CrossRefPubMedGoogle Scholar
  63. Marchalonis JJ, Edelman GM (1968) Phylogenetic origins of antibody structure. III. Antibodies in the primary immune response of the sea lamprey, Petromyzon marinus. J Exp Med 127:891–914PubMedCentralCrossRefPubMedGoogle Scholar
  64. Matsushita M, Matsushita A, Endo Y, Nakata M, Kojima N, Mizuochi T, Fujita T (2004) Origin of the classical complement pathway: lamprey orthologue of mammalian C1q acts as a lectin. Proc Natl Acad Sci USA 101:10127–10131PubMedCentralCrossRefPubMedGoogle Scholar
  65. Mayer WE, O’hUigin C, Tichy H, Terzic J, Saraga-Babic M (2002) Identification of two Ikaros-like transcription factors in lamprey. Scand J Immunol 55:162–170CrossRefPubMedGoogle Scholar
  66. Mehta TK, Ravi V, Yamasaki S, Lee AP, Lian MM, Tay BH, Tohari S, Yanai S, Tay A, Brenner S, Venkatesh B (2013) Evidence for at least six Hox clusters in the Japanese lamprey (Lethenteron japonicum). Proc Natl Acad Sci USA 110:16044–16049PubMedCentralCrossRefPubMedGoogle Scholar
  67. Nagawa F, Kishishita N, Shimizu K, Hirose S, Miyoshi M, Nezu J, Nishimura T, Nishizumi H, Takahashi Y, Hashimoto S, Takeuchi M, Miyajima A, Takemori T, Otsuka AJ, Sakano H (2007) Antigen-receptor genes of the agnathan lamprey are assembled by a process involving copy choice. Nat Immunol 8:206–213CrossRefPubMedGoogle Scholar
  68. Nonaka M, Kimura A (2006) Genomic view of the evolution of the complement system. Immunogenetics 58:701–713PubMedCentralCrossRefPubMedGoogle Scholar
  69. Ohno S (1970) Evolution by gene duplication. Springer, New YorkCrossRefGoogle Scholar
  70. Ohno S (1999) Gene duplication and the uniqueness of vertebrate genomes circa 1970–1999. Semin Cell Dev Biol 10:517–522CrossRefPubMedGoogle Scholar
  71. Pancer Z, Cooper MD (2006) The evolution of adaptive immunity. Annu Rev Immunol 24:497–518CrossRefPubMedGoogle Scholar
  72. Pancer Z, Amemiya CT, Ehrhardt GR, Ceitlin J, Gartland GL, Cooper MD (2004a) Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430:174–180CrossRefPubMedGoogle Scholar
  73. Pancer Z, Mayer WE, Klein J, Cooper MD (2004b) Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey. Proc Natl Acad Sci USA 101:13273–13278PubMedCentralCrossRefPubMedGoogle Scholar
  74. Pancer Z, Saha NR, Kasamatsu J, Suzuki T, Amemiya CT, Kasahara M, Cooper MD (2005) Variable lymphocyte receptors in hagfish. Proc Natl Acad Sci USA 102:9224–9229PubMedCentralCrossRefPubMedGoogle Scholar
  75. Pollara B, Litman GW, Finstad J, Howell J, Good RA (1970) The evolution of the immune response. VII. Antibody to human “O” cells and properties of the immunoglobulin in lamprey. J Immunol 105:738–745PubMedGoogle Scholar
  76. Putnam NH, Butts T, Ferrier DE, Furlong RF, Hellsten U, Kawashima T, Robinson-Rechavi M, Shoguchi E, Terry A, Yu JK, Benito-Gutierrez EL, Dubchak I, Garcia-Fernandez J, Gibson-Brown JJ, Grigoriev IV, Horton AC, de Jong PJ, Jurka J, Kapitonov VV, Kohara Y, Kuroki Y, Lindquist E, Lucas S, Osoegawa K, Pennacchio LA, Salamov AA, Satou Y, Sauka-Spengler T, Schmutz J, Shin IT, Toyoda A, Bronner-Fraser M, Fujiyama A, Holland LZ, Holland PW, Satoh N, Rokhsar DS (2008) The amphioxus genome and the evolution of the chordate karyotype. Nature 453:1064–1071CrossRefPubMedGoogle Scholar
  77. Rogozin IB, Iyer LM, Liang L, Glazko GV, Liston VG, Pavlov YI, Aravind L, Pancer Z (2007) Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nat Immunol 8:647–656CrossRefPubMedGoogle Scholar
  78. Shimeld SM, Donoghue PC (2012) Evolutionary crossroads in developmental biology: cyclostomes (lamprey and hagfish). Development 139:2091–2099CrossRefPubMedGoogle Scholar
  79. Shintani S, Terzic J, Sato A, Saraga-Babic M, O’hUigin C, Tichy H, Klein J (2000) Do lampreys have lymphocytes? The Spi evidence. Proc Natl Acad Sci USA 97:7417–7422PubMedCentralCrossRefPubMedGoogle Scholar
  80. Smith JJ, Kuraku S, Holt C, Sauka-Spengler T, Jiang N, Campbell MS, Yandell MD, Manousaki T, Meyer A, Bloom OE, Morgan JR, Buxbaum JD, Sachidanandam R, Sims C, Garruss AS, Cook M, Krumlauf R, Wiedemann LM, Sower SA, Decatur WA, Hall JA, Amemiya CT, Saha NR, Buckley KM, Rast JP, Das S, Hirano M, McCurley N, Guo P, Rohner N, Tabin CJ, Piccinelli P, Elgar G, Ruffier M, Aken BL, Searle SM, Muffato M, Pignatelli M, Herrero J, Jones M, Brown CT, Chung-Davidson YW, Nanlohy KG, Libants SV, Yeh CY, McCauley DW, Langeland JA, Pancer Z, Fritzsch B, de Jong PJ, Zhu B, Fulton LL, Theising B, Flicek P, Bronner ME, Warren WC, Clifton SW, Wilson RK, Li W (2013) Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution. Nat Genet 45:415–421PubMedCentralCrossRefPubMedGoogle Scholar
  81. Stadler PF, Fried C, Prohaska SJ, Bailey WJ, Misof BY, Ruddle FH, Wagner GP (2004) Evidence for independent Hox gene duplications in the hagfish lineage: a PCR-based gene inventory of Eptatretus stoutii. Mol Phylogenet Evol 32:686–694CrossRefPubMedGoogle Scholar
  82. Sutoh Y, Kasahara M (2014) Copy number and sequence variation of leucine-rich repeat modules suggests distinct functional constraints operating on variable lymphocyte receptors expressed by agnathan T cell-like and B cell-like lymphocytes. Immunogenetics 66:403–409CrossRefPubMedGoogle Scholar
  83. Suzuki T, Shin IT, Kohara Y, Kasahara M (2004) Transcriptome analysis of hagfish leukocytes: a framework for understanding the immune system of jawless fishes. Dev Comp Immunol 28:993–1003CrossRefPubMedGoogle Scholar
  84. Suzuki T, Shin-I T, Fujiyama A, Kohara Y, Kasahara M (2005) Hagfish leukocytes express a paired receptor family with a variable domain resembling those of antigen receptors. J Immunol 174:2885–2891CrossRefPubMedGoogle Scholar
  85. Takaba H, Imai T, Miki S, Morishita Y, Miyashita A, Ishikawa N, Nishizumi H, Sakano H (2013) A major allogenic leukocyte antigen in the agnathan hagfish. Sci Rep 3:1716PubMedCentralCrossRefPubMedGoogle Scholar
  86. Uinuk-Ool T, Mayer WE, Sato A, Dongak R, Cooper MD, Klein J (2002) Lamprey lymphocyte-like cells express homologs of genes involved in immunologically relevant activities of mammalian lymphocytes. Proc Natl Acad Sci USA 99:14356–14361PubMedCentralCrossRefPubMedGoogle Scholar
  87. Vantourout P, Hayday A (2013) Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol 13:88–100PubMedCentralCrossRefPubMedGoogle Scholar
  88. Venkatesh B, Lee AP, Ravi V, Maurya AK, Lian MM, Swann JB, Ohta Y, Flajnik MF, Sutoh Y, Kasahara M, Hoon S, Gangu V, Roy SW, Irimia M, Korzh V, Kondrychyn I, Lim ZW, Tay BH, Tohari S, Kong KW, Ho S, Lorente-Galdos B, Quilez J, Marques-Bonet T, Raney BJ, Ingham PW, Tay A, Hillier LW, Minx P, Boehm T, Wilson RK, Brenner S, Warren WC (2014) Elephant shark genome provides unique insights into gnathostome evolution. Nature 505:174–179PubMedCentralCrossRefPubMedGoogle Scholar
  89. Wu F, Chen L, Liu X, Wang H, Su P, Han Y, Feng B, Qiao X, Zhao J, Ma N, Liu H, Zheng Z, Li Q (2013) Lamprey variable lymphocyte receptors mediate complement-dependent cytotoxicity. J Immunol 190:922–930CrossRefPubMedGoogle Scholar
  90. Yamaguchi T, Takamune K, Kondo M, Takahashi Y, Kato-Unoki Y, Nakao M, Sano N, Fujii T (2014) Hagfish C1q: Its unique binding property. Dev Comp Immunol 43:47–53CrossRefPubMedGoogle Scholar

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of PathologyHokkaido University Graduate School of MedicineSapporoJapan

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