Diversity of KIR Genes, Alleles and Haplotypes

  • D. MiddletonEmail author
  • F. Gonzalez-Galarza
  • A. Meenagh
  • P. A. Gourraud


In this chapter, we discuss the vast polymorphism of the killer cell immunoglobulin-like receptors (KIR), of the natural killer (NK) cell, which rivals that of the HLA complex. There are several aspects of this polymorphism. Initially, there is the presence/absence of individual KIR genes, with four of these genes termed framework genes, being omnipresent, with very few exceptions, in all individuals tested to date. Within each gene, alleles are present at different frequencies. We show how these frequencies vary in different world-wide populations.

Another concept of the KIR complex is the division of an individual genotype into A and/or B haplotypes, the former having a more inhibitory role and the latter, a more activating role on the function of the NK cell. Family studies have been used to ascertain the make-up of these haplotypes, inclusion of allele typing enabling determination of whether one or two copies of a particular gene is present.

The KIR gene complex is rapidly evolving not only at the genetic level but additionally at the functional level with different alleles having different protein expression levels and different avidity with their HLA ligand.

We provide details of a new website, which enables convenient searching for data on KIR gene, allele and genotype frequencies in different populations. Finally, we expand on our original algorithms, using additional family data, to give details on mathematical methods for estimation of haplotypes from genotype data.


Natural Killer Cell Human Leukocyte Antigen Sequence Specific Oligonucleotide Probe Human Leukocyte Antigen Ligand International Histocompatibility Workshop 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are very grateful to Dr. P. Norman, Stanford and Dr. R. Rajalingam, Los Angeles for their very diligent, constructive and critical reading of the manuscript.


  1. 1.
    Caligiuri MA (2008) Blood 112:461CrossRefPubMedGoogle Scholar
  2. 2.
    Ljunggren HG, Karre K (1990) Immunol Today 11:237CrossRefPubMedGoogle Scholar
  3. 3.
    Liu WR, Kim J, Nwankwo C, Ashworth LK, Arm JP (2000) Immunogenetics 51:659CrossRefPubMedGoogle Scholar
  4. 4.
    Trowsdale J, Barten R, Haude A, et al. (2001) Immunol Rev 181:2Google Scholar
  5. 5.
    Wende H, Colonna M, Ziegler A, Volz A (1999) Mamm Genome 10:154CrossRefPubMedGoogle Scholar
  6. 6.
    Biron CA, Nguyen KB, Pien GC, Salazar-Mather TP (1999) Annu Rev Immunol 17:189CrossRefPubMedGoogle Scholar
  7. 7.
    Baxter AG, Smyth MJ (2002) Autoimmunity 35:1CrossRefPubMedGoogle Scholar
  8. 8.
    Shi F, Ljunggren H, Sarvetnick N (2001) Trends Immunol 22:97CrossRefPubMedGoogle Scholar
  9. 9.
    Williams F, Meenagh A, Sleator C et al (2005) Hum Immunol 66:836CrossRefPubMedGoogle Scholar
  10. 10.
    Hiby SE, Walker JJ, O’Shaughnessy KM et al (2004) J Exp Med 200:957CrossRefPubMedGoogle Scholar
  11. 11.
    Ruggeri L, Capanni M, Mancusi A, et al. (2004) Bailliere’s Best Pract Res Clin Haematol 17:427Google Scholar
  12. 12.
    Cooley S, Trachtenberg E, Bergmann TL, et al. (2009) Blood 113:726Google Scholar
  13. 13.
    Moretta L, Biassoni R, Bottino C, Mingari MC, Moratta A (2000) Immunol Today 9:20Google Scholar
  14. 14.
    Vilches C, Parham P (2002) Annu Rev Immunol 20:217CrossRefPubMedGoogle Scholar
  15. 15.
    Martin AM, Freitas EM, Witt CS, Christiansen FT (2000) Immunogenetics 5l:268Google Scholar
  16. 16.
    Wilson MJ, Torkar M, Haude A et al (2000) Proc Natl Acad Sci USA 97:4778CrossRefPubMedGoogle Scholar
  17. 17.
    Norman PJ, Stephens HA, Verity DH, Chandanyingyong D, Vaughan RW (2001) Immunogenetics 52:195CrossRefPubMedGoogle Scholar
  18. 18.
    Middleton D, Curran M, Maxwell L (2002) Transplant Immunol 10:147CrossRefGoogle Scholar
  19. 19.
    Marsh SGE, Parham P, Dupont B et al (2003) Hum Immunol 64:648PubMedGoogle Scholar
  20. 20.
    Gomez-Lozano N, Gardiner CM, Parham P, Vilches C (2002) Immunogenetics 54:314Google Scholar
  21. 21.
    Rajagopalan S, Fu J, Long EO (2001) J Immunol 167:1877PubMedGoogle Scholar
  22. 22.
    Moesta AK, Norman PJ, Yawata M et al (2008) J Immunol 180:3969PubMedGoogle Scholar
  23. 23.
    Norman PJ, Abi-Rached L, Gendzekhadze K, et al (2007) Nat Genet 39:1092Google Scholar
  24. 24.
    Uhrberg M, Valiante NM, Shum BP et al (1997) Immunity 7:753CrossRefPubMedGoogle Scholar
  25. 25.
    Robinson J, Waller MJ, Stoehr P, Marsh SGE (2005) Nucl Acids Res 331:D523Google Scholar
  26. 26.
    Horton R, Coggill P, Miretti MM et al (2006) Tissue Antigens 68:450CrossRefPubMedGoogle Scholar
  27. 27.
    Vilches C, Castano J, Gomez-Lozano N, Estefania E (2007) Tissue Antigens 70:415CrossRefPubMedGoogle Scholar
  28. 28.
    Gomez-Lozano N, Vilches C (2002) Tissue Antigens 59:184CrossRefPubMedGoogle Scholar
  29. 29.
    Norman PJ, Cook MA, Carey BS et al (2004) Immunogenetics 56:225CrossRefPubMedGoogle Scholar
  30. 30.
    Middleton D, Williams F, Halfpenny IA (2005) Transplant Immunol 14:135CrossRefGoogle Scholar
  31. 31.
    De Santis D, Witt C, Gomez-Lozano N, et al (2006) In Hansen JA (ed) Immunobiology of the Human MHC. IHWG, Seattle, p 1233Google Scholar
  32. 32.
    Cook MA, Norman PJ, Curran MD et al (2003) Hum Immunol 64:567CrossRefPubMedGoogle Scholar
  33. 33.
  34. 34.
    Middleton D, Menchaca L, Rood H, Komerofsky R (2003) Tissue Antigens 61:403CrossRefPubMedGoogle Scholar
  35. 35.
    Turino C, Scavello G, Ferriola D, Kunkel M, Dapprich J (2006) Hum Immunol 67(Suppl 1):S41CrossRefGoogle Scholar
  36. 36.
    Du Z, Sharma SK, Spellman S, Reed EF, Rajalingham R (2008) Genes Immun 9:470CrossRefPubMedGoogle Scholar
  37. 37.
    Gomez-Lozano N, de Pablo R, Puente S, Vilches C (2003) Eur J Immunol 33:639CrossRefPubMedGoogle Scholar
  38. 38.
    Norman PJ, Carrington CVF, Byng M et al (2002) Genes Immun 3:86CrossRefPubMedGoogle Scholar
  39. 39.
    Middleton D, Meenagh A, Gourrand PA (2007) Immunogenetics 59:145Google Scholar
  40. 40.
    Rajalingam R, Du Z, Meenagh A et al (2008) Immunogenetics 60:207CrossRefPubMedGoogle Scholar
  41. 41.
    Toneva M, Lepage V, Lafay G et al (2001) Tissue Antigens 57:358CrossRefPubMedGoogle Scholar
  42. 42.
    Rajalingam R, Krausa P, Shilling HG et al (2002) Immunogenetics 53:1009CrossRefPubMedGoogle Scholar
  43. 43.
    Parham P (2003) Tissue Antigens 62:194CrossRefPubMedGoogle Scholar
  44. 44.
    Yawata M, Yawata N, McQueen KL et al (2002) Immunogenetics 54:543CrossRefPubMedGoogle Scholar
  45. 45.
    Flores AC, Marcos CY, Paladino N et al (2007) Tissue Antigens 69:568CrossRefPubMedGoogle Scholar
  46. 46.
    Gendzekhadze K, Norman PJ, Abi-Rached L, Layrisse Z, Parham P (2006) Immunogenetics 58:474CrossRefPubMedGoogle Scholar
  47. 47.
    Kulkarni S, Single RM, Martin MP et al (2008) Immunogenetics 60:121CrossRefPubMedGoogle Scholar
  48. 48.
    Gardiner CM, Guethlein LA, Shilling HG et al (2001) J Immunol 166:2992PubMedGoogle Scholar
  49. 49.
    Middleton D, Meenagh A, Moscoso J, Arnaiz-Villena A (2007) Tissue Antigens 71:105CrossRefPubMedGoogle Scholar
  50. 50.
    Middleton D, Meenagh A, Serrano-Vela JI, Moscoso J, Arnaiz-Villena A (2008) Open Immunol J 1:42CrossRefGoogle Scholar
  51. 51.
    Shilling HG, Lienert-Weidenbach K, Valiante NM, Uhrberg M, Parham P (1998) Immunogenetics 48:413CrossRefPubMedGoogle Scholar
  52. 52.
    Rajalingam R, Parham P, Rached L (2004) J Immunol 172:356–369PubMedGoogle Scholar
  53. 53.
    Khakoo SI, Rajalingam R, Shum BP et al (2000) Immunity 12:687CrossRefPubMedGoogle Scholar
  54. 54.
    Kelley J, Walter L, Trowsdale J (2005) Plos Genet 1:129CrossRefPubMedGoogle Scholar
  55. 55.
    Parham P (2005) Nat Rev Immunol 5:201CrossRefPubMedGoogle Scholar
  56. 56.
    Williams F, Maxwell LD, Halfpenny IA et al (2003) Hum Immunol 64:729CrossRefPubMedGoogle Scholar
  57. 57.
    Martin MP, Bashirova A, Traherne J, Trowsdale J, Carrington M (2003) J Immunol 171:2192PubMedGoogle Scholar
  58. 58.
    Gomez-Lozano N, Estefania E, Williams F et al (2004) Eur J Immunol 35:16CrossRefGoogle Scholar
  59. 59.
    Shilling HG, Guethlein LA, Cheng NW et al (2002) J Immunol 168:2307PubMedGoogle Scholar
  60. 60.
    Williams F, Meenagh A, Sleator C, Middleton D (2004) Hum Immunol 65:31CrossRefPubMedGoogle Scholar
  61. 61.
    Maxwell LD, Williams F, Gilmore P, Meenagh A, Middleton D (2004) Hum Immunol 65:613CrossRefPubMedGoogle Scholar
  62. 62.
    Keaney L, Williams F, Meenagh A, Sleator C, Middleton D (2004) Tissue Antigens 64:188CrossRefPubMedGoogle Scholar
  63. 63.
    Halfpenny IA, Middleton D, Barnett YA, Williams F (2004) Hum Immunol 65:602Google Scholar
  64. 64.
    Meenagh A, Williams F, Sleator C, Halfpenny IA, Middleton D (2004) Tissue Antigens 64:226CrossRefPubMedGoogle Scholar
  65. 65.
    Meenagh A, Gonzalez A, Sleator C, McQuaid S, Middleton D (2008) Tissue Antigens 72:383CrossRefPubMedGoogle Scholar
  66. 66.
    Gonzalez A, Meenagh A, Sleator C, Middleton D (2008) Tissue Antigens 72:11CrossRefPubMedGoogle Scholar
  67. 67.
    Yawata M, Draghi M, Little AM, Partheniou F, Parham P (2006) J Exp Med 203:633CrossRefPubMedGoogle Scholar
  68. 68.
    Abi-Rached L, Parham P (2005) J Exp Med 201:1319CrossRefPubMedGoogle Scholar
  69. 69.
    Maxwell LD, Wallace A, Middleton D, Curran MD (2002) Tissue Antigens 60:254CrossRefPubMedGoogle Scholar
  70. 70.
    Middleton D, Gonzalez A, Gilmore PM (2007) Hum Immunol 68:128CrossRefPubMedGoogle Scholar
  71. 71.
    Ordonez D, Meenagh A, Gomez-Lozano N et al (2008) Genes Immun 9:431CrossRefPubMedGoogle Scholar
  72. 72.
    Shilling HG, Young N, Guethlein LA et al (2002) J Immunol 169:239PubMedGoogle Scholar
  73. 73.
    Carrington M, Martin MP (2006) Curr Top Microbiol Immunol 298:225CrossRefPubMedGoogle Scholar
  74. 74.
    Single RM, Martin MP, Gao X et al (2007) Nat Genet 39:1114CrossRefPubMedGoogle Scholar
  75. 75.
    Fauriat C, Andersson S, Bjorklund AT et al (2008) J Immunol 181:6010PubMedGoogle Scholar
  76. 76.
    Valiante NM, Uhrberg M, Shilling H et al (1997) Immunity 7:739CrossRefPubMedGoogle Scholar
  77. 77.
    Santourlidis S, Trompeter HI, Weinhold S et al (2002) J Immunol 169:4253PubMedGoogle Scholar
  78. 78.
    Van Bergen J, Stewart CA, van Des Elsen PJ, Trowsdale J (2005) Eur J Immunol 35:2191CrossRefPubMedGoogle Scholar
  79. 79.
    Davies GE, Locke SM, Wright PW et al (2007) Genes Immun 8:245CrossRefPubMedGoogle Scholar
  80. 80.
    Martin MP, Pascal V, Yeager M et al (2007) Immunogenetics 59:823CrossRefPubMedGoogle Scholar
  81. 81.
    Pando MJ, Gardiner CM, Gleimer M, McQueen KL, Parham P (2003) J Immunol 171:6640PubMedGoogle Scholar
  82. 82.
    Martin MP, Qi Y, Gao X et al (2007) Nat Genet 39:733CrossRefPubMedGoogle Scholar
  83. 83.
    Sanjanwala B, Draghi M, Norman PJ, Guethlein LA, Parham P (2008) J Immunol 181:6293PubMedGoogle Scholar
  84. 84.
    Cella M, Longo A, Ferrara GB, Strominger JL, Colonna M (1994) J Exp Med 180:1235CrossRefPubMedGoogle Scholar
  85. 85.
    Foley BA, De Santis D, Van Beelen E et al (2008) Blood 112:435CrossRefPubMedGoogle Scholar
  86. 86.
    Carr WH, Pando MJ, Parham (2005) J Immunol 175:5222Google Scholar
  87. 87.
    Dempster AP (1977) J Roy Stat Soc B 39:921Google Scholar
  88. 88.
    Gourraud PA, Genin E, Cambon-Thomsen A (2004) Eur J Hum Genet 12:805CrossRefPubMedGoogle Scholar
  89. 89.
    Gourraud PA, Gagne K, Bignon JD, et al (2007) Tissue Antigens 69(Suppl 1):96Google Scholar
  90. 90.
    Single RM, Martin MP, Meyer D, Gao X, Carrington M (2008) Immunogenetics 60:711Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • D. Middleton
    • 1
    Email author
  • F. Gonzalez-Galarza
    • 2
  • A. Meenagh
    • 2
  • P. A. Gourraud
    • 3
    • 4
  1. 1.Transplant ImmunologyRoyal Liverpool and Broadgreen University Hospital and School of Infection and Host Defence Liverpool UniversityLiverpoolUK
  2. 2.Northern Ireland Region Histocompatibility and Immunogenetics LaboratoryBelfast City HospitalBelfastUK
  3. 3.INSERM, Unit 558University of ToulouseToulouseFrance
  4. 4.Department of NeurologyUniversity of California at San FranciscoSan FranciscoUSA

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