, Volume 61, Issue 3, pp 209–230 | Cite as

Porcine IgG: structure, genetics, and evolution

  • J. E. Butler
  • Nancy Wertz
  • Nicholas Deschacht
  • Imre Kacskovics
Original Paper


Eleven genomic porcine Cγ gene sequences are described that represent six putative subclasses that appear to have originated by gene duplication and exon shuffle. The genes previously described as encoding porcine IgG1 and IgG3 were shown to be the IgG1a and IgG1b allelic variants of the IGHG1 gene, IgG2a and IgG2b are allelic variants of the IGHG2 gene, while “new” IgG3 is monomorphic, has an extended hinge, is structurally unique, and appears to encode the most evolutionarily conserved porcine IgG. IgG5b differs most from its putative allele, and its CH1 domain shares sequence homology with the CH1 of IgG3. Four animals were identified that lacked either IgG4 or IgG6. Alternative splice variants were also recovered, some lacking the CH1 domain and potentially encoding heavy chain only antibodies. Potentially, swine can transcribe >20 different Cγ chains. A comparison of mammalian Cγ gene sequences revealed that IgG diversified into subclasses after speciation. Thus, the effector functions for the IgG subclasses of each species should not be extrapolated from “same name subclasses” in other species. Sequence analysis identified motifs likely to interact with Fcγ receptors, FcRn, protein A, protein G, and C1q. These revealed IgG3 to be most likely to activate complement and bind FcγRs. All except IgG5a and IgG6a should bind to FcγRs, while all except IgG6a and the putative IgG5 subclass proteins should bind well to porcine FcRn, protein A, and protein G.


IgG subclasses Evolution Genetics Fc receptors Comparative immunology 



This research supported by Cooperative Agreement IOWR 2003-02669 with the USDA-ARS, The University of Iowa Carver Trust and Grants 05-015 and 06-043 from the National Porkboard and grant OTKA T049015 from the Hungarian Academy of Sciences.


  1. Auchincloss H Jr, Sachs DH (1998) Xenogeneic transplantation. Annu Rev Immunol 16:433–470PubMedCrossRefGoogle Scholar
  2. Bianchi ATJ, Schotten JW, Jongenelen IMCA, Koch G (1990) The use of monoclonal antibodies in an enzyme immunospot assay to detect isotype-specific antibody secreting cells in pigs and chickens. Vet Immunol Immunopathol 24:125–134PubMedCrossRefGoogle Scholar
  3. Birshstein BK, Campbell R, Greenberg ML (1980) A γ2b–γ2a hybrid immunoglobulin heavy chain produced by a variant of the MPC11 mouse myeloma cell line. Biochem 19:1730–1737CrossRefGoogle Scholar
  4. Brambell FWR (1971) The transmission of passive immunity from mother to young. Frontiers of Biology Series. North Holland, AmsterdamGoogle Scholar
  5. Brown WR, Kacskovics I, Amendt B, Shinde R, Blackmore N, Rothschild M, Butler JE (1995) The hinge deletion variant of porcine IgA results from a mutation at the splice acceptor site in the first Cα intron. J Immunol 154:3836–3842PubMedGoogle Scholar
  6. Burnett RC, Hanly WC, Zhai S-K, Knight KL (1989) The IgA heavy chain gene family in rabbit: cloning and sequence analyses of 13 Cα genes. EMBO J 8:4041–4047PubMedGoogle Scholar
  7. Burton DR, Boyd J, Brampton AD, Easterbrook-Smith SB, Emanuel J, Novotny EJ, Rademacher TW, van Schravendijk MR, Sternberg MJ, Dwek RA (1980) The Clq receptor site on immunoglobulin G. Nature 288:338–344PubMedCrossRefGoogle Scholar
  8. Butler JE (1969) Bovine immunoglobulins. J Dairy Sci 52:1895–1909CrossRefGoogle Scholar
  9. Butler JE (1974) Immunoglobulins of the mammary secretions. In: Larson BL, Smith V (eds) Lactation, a comprehensive treatise. Academic Press, New York Vol. III, Chapter V:217–55Google Scholar
  10. Butler JE (1983) Bovine immunoglobulins: An augmented review. Vet Immunol Immunopathol 4:43–152PubMedCrossRefGoogle Scholar
  11. Butler JE (1997) Immunoglobulin gene organization and the mechanism of repertoire development. Scand J Immunol 45:455–462PubMedCrossRefGoogle Scholar
  12. Butler JE (2006) Preface: Why I agreed to do this. In: Butler JE, guest ed. Antibody repertoire development. Dev Comp Immunol 30:1–17Google Scholar
  13. Butler JE, Wertz N (2006) Antibody repertoire development in fetal and neonatal pigs. XVII. IgG subclass transcription in newborns revisited with emphasis on new IgG3. J Immunol 177:5480–5489PubMedGoogle Scholar
  14. Butler JE, Sun J, Weber P, Francis D (2000) Antibody repertoire development in fetal and neonatal piglets. III. Colonization of the gastrointestinal tracts results in preferential diversification of the pre-immune mucosal B-cell repertoire. Immunol Br 100:119–130CrossRefGoogle Scholar
  15. Butler JE, Sun J, Weber P, Ford SP, Rehakova Z, Sinkora J, Lager KM (2001) Antibody repertoire development in fetal and neonatal piglets. IV. Switch recombination, primary in fetal thymus occurs independent of environmental antigen and is only weakly associated with repertoire diversification. J Immunol 167:3239–3249PubMedGoogle Scholar
  16. Butler JE, Weber P, Sinkora M, Baker D, Schoenherr A, Mayer B, Francis D (2002) Antibody repertoire development in fetal and neonatal piglets. VIII. Colonization is required for newborn piglets to make serum antibodies to T-dependent and type 2 T-independent antigens. J Immunol 169:6822–6830PubMedGoogle Scholar
  17. Butler JE, Francis D, Freeling J, Weber P, Sun J, Krieg AM (2005) Antibody repertoire development in fetal and neonatal piglets. IX. Three PAMPs act synergistically to allow germfree piglets to respond to TI-2 and TD antigens. J Immunol 175:6772–6785PubMedGoogle Scholar
  18. Butler JE, Lemke CD, Weber P, Sinkora M, Lager KM (2007) Antibody repertoire development in fetal and neonatal piglets. XIX. Undiversified B cells with hydrophobic HCDR3s preferentially proliferate in PRRS. J Immunol 178:6320–6331PubMedGoogle Scholar
  19. Butler JE, Weber P, Wertz N, Lager KM (2008a) Porcine reproductive and respiratory syndrome virus (PRRSV) subverts development of adaptive immunity by proliferation of germline-encoded B cells with hydrophobic HCDR3s. J Immunol 180:2347–2356PubMedGoogle Scholar
  20. Butler JE, Lager KM, Splichal I, Francis D, Kacskovics I, Sinkora M, Wertz N, Sun J, Zhao Y, Brown WR, DeWald R, Dierks S, Muyldermanns S, Lunney JK, McCray PB, Rogers CS, Welsh MJ, Navarro P, Klobasa F, Habe F, Ramsoondar J (2008b) The piglet as a model for B cell and immune system development. Vet Immunol Immunopathol (in press).Google Scholar
  21. Clark MR (1997) IgG effector mechanisms. Chem Immunol 65:88–110PubMedGoogle Scholar
  22. Colle JH, Perret R, Truffa-Bachi P (1987) Hybrid polypeptide heavy chains produced by two hybridoma lines. Mol Immunol 24:39–46PubMedCrossRefGoogle Scholar
  23. Crawley A, Wilkie BN (2003) Porcine Ig isotypes: function and molecular characteristics. Vaccine 21:2911–2922PubMedCrossRefGoogle Scholar
  24. Dall’Acqua WF, Cook KE, Damschroder MD, Woos RM, Wu H (2006) Modulation of the effector functions of a human IgG1 through engineering of its hinge. J Immunol 177:1129–1138PubMedGoogle Scholar
  25. Deisenhofer J (1981) Crystallographic refinement and atomic models of a human Fc fragment and its complex with fragment B of protein A from Staphylococcus aureus at 2.9- and 2.8-A resolution. Biochem 20:2361–2370CrossRefGoogle Scholar
  26. Duncan AR, Winter G (1988) The binding site for C1q on IgG. Nature 332:738–740PubMedCrossRefGoogle Scholar
  27. Emanuel EJ, Brampton AD, Burton DR, Dwek RA (1982) Formation of complement subcomponent C1q–immunoglobulin G complex. Thermodynamic and chemical-modification studies. Biochem J 205:361–372PubMedGoogle Scholar
  28. Franek F, Riha I (1964) Purification and structural characterization of 5 S γ-globulin of newborn pigs. Immunochemistry 1:49–63PubMedCrossRefGoogle Scholar
  29. Franklin EC, Lowenstein J, Bigelow B, Meltzer M (1964) Heavy chain disease—a new disorder of serum γ-globulins. Am J Med 37:332–350PubMedCrossRefGoogle Scholar
  30. Gaboriaud C, Juanhuix J, Gruez A, Lacroix M, Darnault C, Pignol D, Verger D, Fontecilla-Camps JC, Arlaud GJ (2003) The crystal structure of the globular head of complement protein C1q provides a basis for its versatile recognition properties. J Biol Chem 278:46974–46982PubMedCrossRefGoogle Scholar
  31. Grey HM, Abel CA, Jount WJ, Kunkel HG (1968) A subclass of human γA-globulins (γA2) which lacks the disulfide bonds linking heavy and light chains. J Exp Med 128:1223–1236PubMedCrossRefGoogle Scholar
  32. Hamers-Castermann C, Atarhouch T, Muyldermans S, Robinson G, Hamers C, Songa EB, Bendahman N, Hamers R (1993) Naturally occurring antibodies devoid of light chains. Nature 363:446–448CrossRefGoogle Scholar
  33. Hunkapillar T, Hood L (1989) Diversity of the immunoglobulin gene superfamily. Adv Immunol 44:1–63CrossRefGoogle Scholar
  34. Idusogie EE, Presta LG, Gazzano-Santoro H, Totpal K, Wong PY, Ultsch M, Meng YG, Mulkerrin MG (2000) Mapping of the C1q binding site on rituxan, a chimeric antibody with a human IgG1 Fc. J Immunol 164:4178–4184PubMedGoogle Scholar
  35. Janeway CA Jr, Travers P, Walport M, Shlomchik MJ (2005) Immunobiology Garland Press, N.Y. 823 ppGoogle Scholar
  36. Kacskovics I, Sun J, Butler JE (1994) Five subclasses of swine IgG identified from the cDNA sequences of a single animal. J Immunol 153:3566–3573Google Scholar
  37. Kacskovics I, Mayer B, Kis Z, Frenyo LV, Zhao Y, Muyldermans S, Hammarstrom L (2006) Cloning and characterization of the dromedary (Camelus dromedarius) neonatal Fc receptor (drFcRn). Dev Comp Immunol 30:1203–1215PubMedCrossRefGoogle Scholar
  38. Kaltreider HB, Johnson JS (1972) Porcine immunoglobulins. I. Identification of subclasses and preparation of specific antisera. J Immunol 109:992–998PubMedGoogle Scholar
  39. Kehoe JM, Capra JD (1974) Nature and significance of immunoglobulin subclasses. N Y State J Med 74:489–491PubMedGoogle Scholar
  40. Kilian M, Russell MW (2004) Microbial evasion of IgA function. In: Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee JR, Mayer L (eds) Mucosal immunology. Elsevier/Academic, Amsterdam, pp 291–303Google Scholar
  41. Kunkel HG, Natvig JB, Jostin FG (1969) A “lepore” type of hybrid γ globulin. Proc Natl Acad Sci USA 62:144–149PubMedCrossRefGoogle Scholar
  42. Lefranc M-P, Lefranc G (2001) The immunoglobulin facts book. Academic, NYGoogle Scholar
  43. Lefranc M-P, Lefranc G, Rabbitts TH (1982) Inherited deletion of immunoglobulin heavy chain constant region genes in normal individuals. Nature 300:760–762PubMedCrossRefGoogle Scholar
  44. Lemke CD, Haynes JS, Spaete R, Adolphson D, Vorwald A, Lager KM, Butler JE (2004) Lymphoid hyperplasia resulting in immune dysregulation is caused by PRRSV infection in pigs. J Immunol 172:1916–1925PubMedGoogle Scholar
  45. Lopez-Carvalho T, Foote J, Kearney JF (2005) Marginal zone B cells in lymphocyte activation and regulation. Curr Opin Immunol 17:244–250CrossRefGoogle Scholar
  46. Marquart M, Deisenhofer J (1982) The three-dimensional structure of antibodies. Immunol Today 3:160–166CrossRefGoogle Scholar
  47. Martin WL, West AP Jr, Gan L, Bjorkman PJ (2001) Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol Cell 7:867–877PubMedCrossRefGoogle Scholar
  48. McAleer J, Weber P, Sun J, Butler JE (2005) Antibody repertoire development in fetal and neonatal piglets. XI. The thymic B cell repertoire develops independently from that in blood and mesenteric lymph nodes. Immunology 114:171–183PubMedCrossRefGoogle Scholar
  49. McCall MN, Easterbrook-Smith SB (1989) Comparison of the role of tyrosine residues in human IgG and rabbit IgG in binding of complement subcomponent C1q. Biochem J 257:845–851PubMedGoogle Scholar
  50. Mendicino M, Ramsoondar J, Phelps C, Vaught T, Ball S, Dai Y, LeRoith T, Monahan J, Chen S, Dandro A, Boone J, Jobst P, Vance A, Wertz N, Polejaeva I, Butler J, Ayares D, Wells K (2009) Targeted disruption of the porcine immunoglobulin heavy chain locus produces a B cell null phenotype. Nature Biotechnology (pending)Google Scholar
  51. Mestecky J, Moro I, Kerr MA, Woof JM (2004) Mucosal immunoglobulins. In: Mestecky J, Lamm ME, Strober W, Bienenstock J, McGhee JR, Mayers L (eds) Mucosal immunology. Elsevier/Academic, Burlington, MA, pp 153–181Google Scholar
  52. Metzger JJ, Fougereau M (1967) Characterization of two subclasses of γG immunoglobulin in swine. CR Hebd Seances Acad Sci Ser P Sci Nat 265:724–727Google Scholar
  53. Migone N, Oliviero S, de Lange G, Delacroix DL, Boschis D, Altruda F, Silengo L, DeMarchi M, Carbonara AO (1984) Multiple gene deletions within the human immunoglobulin heavy chain cluster. Proc Natl Acad Sci USA 81:5811–5815PubMedCrossRefGoogle Scholar
  54. Mihaesco E, Gendron M-C, Congy N, Frangione B (1988) Protein ROU, a human IgA hybrid. J Immunol 140:1236–1238PubMedGoogle Scholar
  55. Navarro P, Christenson R, Ekhardt G, Lunney JK, Rothschild M, Bosworth B, Lemke J, Butler JE (2000a) Genetic differences in the frequency of the hinge variants of porcine IgA is breed dependent. Vet Immunol Immunopathol 73:287–295PubMedCrossRefGoogle Scholar
  56. Navarro P, Christenson R, Weber P, Rothschild M, Erhardt G, Lemky J, Butler JE (2000b) Porcine IgA allotypes are not equally transcribed or expressed in heterozygous swine. Mol Immunol 37:653–664PubMedCrossRefGoogle Scholar
  57. Nezlin R (1994) Immunoglobulin structure and function. In: van Oss CJ, van Regenmortel MHV (eds) Immunochemistry. Marcel Dekker, New York, pp 3–45Google Scholar
  58. Nezlin R, Ghetie V (2004) Interactions of immunoglobulins outside the antigen-binding site. Adv Immunol 82:155–215PubMedCrossRefGoogle Scholar
  59. Olsson PG, Rabbani H, Hammarstrom L, Smith CIE (1993) Novel human immunoglobulin heavy chain constant region gene deletion haplotypes characterized by pulse-filed electrophoresis. Clin Exp Immunol 94:84–90PubMedGoogle Scholar
  60. Osserman EF, Takatsuki K (1964) Clinical and immunochemical studies of four cases of heavy (Hγ2) chain disease. Am J Med 37:351–373PubMedCrossRefGoogle Scholar
  61. Pan Q, Hammarstrom L (2000) Molecular basis of IgG subclass deficiency. Immunol Rev 178:99–110PubMedCrossRefGoogle Scholar
  62. Plaut AG, Gilbert JV, Artenstern MA, Capra JD (1975) Neisseria gonorrhoeae and Neisseria meningitidis: extracellular enzyme cleaves human immunoglobulin A. Science 193:1103–1105CrossRefGoogle Scholar
  63. Rabbani H, Brown WR, Butler JE, Hammarström L (1997) Polymorphism of the IgHG3 gene in cattle. Immunogenetic 46:326–331CrossRefGoogle Scholar
  64. Radaev S, Sun PD (2001) Recognition of IgG by Fcgamma receptor. The role of Fc glycosylation and the binding of peptide inhibitors. J Biol Chem 276:16478–16483PubMedCrossRefGoogle Scholar
  65. Radaev S, Motyka S, Fridman WH, Sautes-Fridman C, Sun PD (2001) The structure of a human type III Fc gamma receptor in complex with Fc. J Biol Chem 276:16469–16477PubMedCrossRefGoogle Scholar
  66. Rapacz J, Hasler-Rapacz J (1982) Immunogenetic studies on polymorphism, postnatal passive acquisition and development of immunoglobulin gamma (IgG) in swine. In: Proc 2nd Int. Congress Gen and Appl Livestock Production. Vol III. Editoral Garsi, MadridGoogle Scholar
  67. Ratcliffe MJH (2006) Antibodies, immunoglobulin genes and the bursa of Fabricius in chicken B cell development. Dev Comp Immunol 30:101–118PubMedCrossRefGoogle Scholar
  68. Ravetch JV, Kinet J-P (1991) Fc receptors. Annu Rev Immunol 9:457–492PubMedGoogle Scholar
  69. Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaards LS, Rokhlina T, Taft PJ, Rogan MP, Pezuzulo AA, Karp PH, Itani OA, Kabel AC, Wohlford-Lenane CL, Davis GJ, Hanfland RA, Smith TL, Samuel M, Wax D, Murphy CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ (2008) Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 321:1837–1841PubMedCrossRefGoogle Scholar
  70. Roopenian DC, Akilesh S (2007) FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol 7:715–725PubMedCrossRefGoogle Scholar
  71. Sauer-Eriksson AE, Kleywegt GJ, Uhlen M, Jones TA (1995) Crustal structure of the C2 fragment of streptococcal protein G in complex with the Fc domain of human IgG. Structure 3:265–278PubMedCrossRefGoogle Scholar
  72. Sinkora M, Sun J, Butler JE (2000) Antibody repertoire development in fetal and neonatal piglets. V. VDJ gene chimeras resembling gene conversion products are generated at high frequency by PCR in vitro. Mol Immunol 37:1025–1034PubMedCrossRefGoogle Scholar
  73. Spieker-Polet H, Yam P-C, Knight KL (1993) Differential expression of 13 IgA heavy chain genes in rabbit lymphoid tissues. J Immunol 150:5457–5465PubMedGoogle Scholar
  74. Sun J, Butler JE (1996) Molecular characteristics of VDJ transcripts from a newborn piglet. Immunol Br 88:331–339CrossRefGoogle Scholar
  75. Sun J, Hayward C, Shinde R, Christenson R, Ford SP, Butler JE (1998) Antibody repertoire development in fetal and neonatal piglets. I. Four VH genes account for 80% of VH usage during 84 days of fetal life. J Immunol 161:5070–5078PubMedGoogle Scholar
  76. Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) Software Version 4.0. Mol Biol EvolGoogle Scholar
  77. Terada T, Kneko H, Li AL, Kasahara K, Ibe M, Yokota S, Kondo N (2001) Analysis of Ig subclass deficiency: first reported case of IgG2, IgG4 and IgA deficiency caused by deletion of C alpha1, PSI C gamma, C gamma 2, C gamma 4 and C epsilon in a Mongoloid patient. J Allergy Clin Immunol 108:602–606PubMedCrossRefGoogle Scholar
  78. Vincent AL, Lager KM, Ma W, Lekcharoensuk P, Gramer MR, Loiacona C, Richt JA (2006) Evaluation of hemagglutinin subtypes 1 swine influenza viruses from the United States. Vet Microbiol 118:212–222PubMedCrossRefGoogle Scholar
  79. Waltz E (2006) Polyclonal antibodies step out of the shadow. Nat Biotechnol 24:1181PubMedCrossRefGoogle Scholar
  80. Williams AF (1987) A year in the life of the immunoglobulin superfamily. Immunol Today 8:298–303CrossRefGoogle Scholar
  81. Zhao Y, Pan-Hammarstrom Q, Kacskovics I, Hammarstrom L (2003) The porcine Ig δ gene: Unique chimeric splicing of the first constant region domain in its heavy chain transcripts. J Immunol 171:1312–1318PubMedGoogle Scholar
  82. Zhao Y, Pan-Hammarstrom Q, Yu S, Wertz N, Zhang X, Li N, Butler JE, Hammarstrom L (2006) Identification of IgF, a hinge-region containing Ig class and IgD in Xenopus tropicalis. Proc Natl Acad Sci USA 103:12087–12092PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • J. E. Butler
    • 1
  • Nancy Wertz
    • 1
  • Nicholas Deschacht
    • 2
    • 3
  • Imre Kacskovics
    • 4
  1. 1.Department of Microbiology and, Interdisciplinary Immunology ProgramThe University of IowaIowa CityUSA
  2. 2.Laboratory of Cellular and Molecular ImmunologyVrije Universiteit BrusselsBrusselsBelgium
  3. 3.Department of Molecular and Cellular Interactions, VIBBrusselsBelgium
  4. 4.Department of Immunology, Faculty of ScienceEotovos Lorand University and Immunology Research Group of the Hungarian Academy of Sciences at Eotvos Lorand UniversityBudapestHungary

Personalised recommendations