International Journal of Medical Laboratory Research (IJMLR)

BASICS OF HUMAN LEUKOCYTE ANTIGENS (HLA) SYSTEM AND ITS APPLICATION IN CLINICAL SPECIALTIES

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Anand Bodade, Ragini Bodade

 

ABSTRACT: Human leukocyte antigen (HLA) is complex immune system with many applications in transfusion and transplant medicine. A lot of clinical challenges such as febrile non-hemolytic transfusion reactions, transfusion-related acute lung injury, and graft-versus-host-disease are caused by HLA antibodies. Histocompatibility in transplant scenario is not the only function of HLA antigens but the main role is to present peptides to immune system and regulate cellular and humoral immunity for the fate of graft. HLA Class I (A, B, and C) and HLA Class II (DR, DQ, and DP) antigens are different in structure and function. Their typing methods have progressed from serology-based techniques to sequence-based typing to next-generation sequencing. Cross-matching techniques have also changed from complement-dependent cytotoxicity to microbead‑based assay to flow cytometry. Finally, HLA and its disease association has long been established, particularly so in cases of autoimmune disorders. The article will be helpful for beginners to get introduced about this unique system and principles in transplant immunology.

 

KEY WORDS: Human Leukocyte Antigen, Major Histocompatibility Complex, Transfusion, Transplantation

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REFERENCES:

1. Gorer PA. The detection of antigenic differences in mouse erythrocytes by the employment of immune sera. British journal of experimental pathology. 1936 Feb; 17,1:42.

2. Dausset, H: Leukoagglutinins: Leukoagglutinins and blood transfusion. J Vox Sang 1954; 4:190.

3. Dausset, J: Iso-leuco-anticorps. ActaHaematol 1958; 20:156.

4. Payne, R: The association of febrile transfusion reactions with leukoagglutinins. J Vox Sang 1957; 2:233.

5. Terasaki, PI, and McClelland, JP: Microdroplet assay of human serum cytotoxins. Nature 1964; 204:998.

6. Terasaki PI, Bernoco D, Park MS, Ozturk G, Iwaki Y.

7. Microdroplet testing for HLA-A,-B,-C, and-D antigens: the Philip Levine Award Lecture. American Journal of Clinical Pathology. 1978 ; 69,2:103-20.

8. Van Rood JJ, Van Leeuwen A. Leukocyte grouping. A method and its application. The Journal of clinical investigation. 1963;42,9:1382-90.

9. World Health Organization: Nomenclature for factors of the HL-A system. Bull WHO 39:483, 1968.

10. Dausset J, Colombani J, Legrand L, Feingold N. Le deuxième sub-locus du système HL-A. Nouv. Rev. Franc. Haematol. 1968; 8: 861.

11. Singal DP, Mickey MR, Mittal KK, Terasaki PI. Serotyping for homotransplantation XVII. Preliminary studies of HL-A subunits and alleles. Transplantation. 1968 ; 6,8:904-12.

12. Sandberg L, Thorsby E, Kissmeyer-Nielsen F, Lindholm A. Evidence of a third sublocus within the HL-A chromosomal region. Histocompatibility testing. 1970;1970:165-9.

13. Bach, FH, and Hirschhorn, K: Lymphocyte interaction: A potential histocompatibility test in vitro. Science 1964; 143:813.

14. Bain, B, and Lowenstein, L: Genetic studies on the mixed leukocyte reaction. Science 1964; 145:1315.

15. Bach, FH, and Amos, DB: Hu-1: Major histocompatibility locus in man.Science 1967; 156:1506.

16. WHO-IUIS TERMINOLOGY COMMITTEE REPORT (1978) Nomenclature for factors of the HLA system 1977. In: Histocompatibility Testing 7977 (Ed. by W.F.Bodmer, J.R.Batchelor, J.G.Bodmer, H.Festenstein and P.J.Morris), p. 14. Munksgaard, Copenhagen.

17. AABB Technical Manual. American Association of Blood Banks.17th edition

18. Orr HT, Lopez de Castro JA, Lancet D, Strominger JL. Complete amino acid sequence of a papain-solubilized human histocompatibility antigen, HLA-B7. 2. Sequence determination and search for homologies. Biochemistry. 1979; 18,25:5711-20.

19. Kaufman, JF, and Strominger, JL: Both chains of HLA-DR bind to the membrane with a penultimate hydrophobic region, and the heavy chain is phosphorylated at its hydrophilic carboxy terminus. Proc Natl AcadSci USA 1979; 76:6304.

20. Kaufman, JF, and Strominger, JL: The extracellular region of light chains from human and murine MHC class II antigens consists of two domains. J Immunol 130:808, 1983.

21. Figueroa, F, and Klein, J: The evolution of class II genes. Immunol Today 7:78, 1986.

22. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. Nature. 1987; 329,6139:506-512.

23. Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature. 1987; 329,6139:512-518.

24. McQueen KL, Parham P. Variable receptors

25. controlling activation and inhibition of NK cells.Current opinion in immunology. 2002 ;14,5:615-621.

26. Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annual review of immunology. 2002; 20,1:217-251.

27. Tait B. The role of HLA matching and recipient sensitization in organ allograft outcome.The HLA Complex in Biology and Medicine: A Resource Book.1st ed. 2010. p. 491-509.

28. Bodmer JG, Marsh SG, Albert ED, Bodmer WF, Bontrop RE, Charron D, Dupont B, Erlich HA, Fauchet R, Mach B, Mayr WR. Nomenclature for factors of the HLA system, 1996. Human immunology. 1997; 53,1:98-128.

29.  Google search: http:// www.imgt.org

30.  Harmening DM. The HLA system.Modern Blood Banking and Transfusion Practices.6th edition.

31. Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O. Hyperacute rejection of kidney allografts, associated with pre-existing humoral antibodies against donor cells. The Lancet. 1966; 288,7465:662-5.

32. Lee, CC: Population Genetics. University of Chicago Press, Chicago, 1955.

33. Dausset J, Colombani J, Colombani M, Legrand L, Feingold N. Un nouvel antigène du système HL-A (Hu-1): l'antigène 15, allèle possible des antigènes 1, 11, 12. Nouv Rev Fr Hematol. 1968; 8,3:398-406.

34. Kissmeyer-Nielsen, F, Svejgaard, A, and Hange, M: Genetics of the HL-A transplantation system. Nature 1968; 291:1116.

35. Svejgaard, A, and Kissmeyer-Nielsen, F: Crossreactive human HL-Aisoantibodies. Nature 1968; 219:868.

36. Legrand, L, and Dausset, J: Histocompatibility Testing 1972. Munksgaard, Copenhagen, 1972, p 441.

37. Rodey G, Fuller T. Preliminary report of the American Society for Histocompatibility and Immunogenetics phase I workshop on HLA class I public epitopes. In Transplantation proceedings 1987 ; 19,1: 872.

38. Colombani, J, Colombani, M, and Dausset, J: Cross-reactions in the HL-A system with special reference to Da 6 cross-reacting group. In Terasaki, PI (ed): Histocompatibility Testing 1970. Munksgaard, Copenhagen, 1970, p 79.

39. Rodey, GE, and Fuller, TC: Public epitopes and the antigenic structure of HLA molecules. Crit Rev Immunol 1987; 7:229.

40. Kohler, G, and Milstein, C: Derivation of specific antibody producing tissue culture and tumor lines by cell fusion. Eur J Immunol 1976;  6:611.

41. Harmening DM. The HLA system.Modern Blood Banking and Transfusion Practices.3rd ed., Ch. 23. F A Davis Co: 1998. p. 445-64.

42. hla.alleles.org from IPD-IMGT/HLA Database web site

43. Mehra NK. Defining genetic architecture of the populations in the Indian subcontinent: Impact of human leukocyte antigen diversity studies. Indian J Hum Genet 2010; 16:105-7.

44. Thomas J. Kindt; Richard A. Goldsby; Barbara Anne Osborne; Janis Kuby (2007). Kuby immunology.Macmillan. ISBN 978-1-4292-0211-4. Retrieved 28 November 2010.

45. Aderem A, Underhill DM (1999). "Mechanisms of phagocytosis in macrophages".  Annual Review of Immunology. 17: 593–623. 

46. Claas F, Castelli Visser R, Schreuder I, Rood J. Allo-antibodies to an antigenic determinant shared by HLA‐A2 and B17. Tissue Antigens. 1982; 19,5:388-91.

47. Troup, CM, and Walford, RL: Cytotoxicity test for the typing of human lymphocytes. Am J ClinPathol 1969; 51:529.

48. Eisen, SA, Wedner, HJ, and Parker, CW: Isolation of pure human peripheral blood T-lymphocytes using nylon wool columns. ImmunolCommun 1972; 1:571.

49. Lowry RJ, Goguen J, Carpenter CB, Strom TB, Garovoy MR. Improved B Cell Typing for HLA—DR Using Nylon Wool Column Enriched B Lymphocyte Preparations. Tissue Antigens. 1979; 14,4:325-30.

50. van Rood, JJ, van Leeuwen, A, and Ploem, JS: Simultaneous detection of two cell populations by two-color fluorescence and application to the recognition of B cell determinants. Nature 1976; 262:795.

51. Fauchet R, Bodmer JG, Kennedy LJ, Mazzilli MC, Muller C, Raffoux C, et al. HLA–A, B, C monoclonal antibodies. In: Albert ED, Baur MP, Mayr WR, editors. Histocompatibility Testing.Springer-Verlag: Berlin Heidelberg; 1984. p. 211-7.

52. Vartdal F, Gaudernack G, Funderud S, Bratlie A, Lea T, Ugelstad J, Thorsby E. HLA class I and II typing using cells positively selected from blood by immunomagnetic isolation‐a fast and reliable technique. Tissue antigens. 1986; 28,5:301-12.

53. Tiercy, JM, Jannet, M, and Mach, B: A new approach for the analysis of HLA class II polymorphism: HLA oligo typing. Blood Rev 4:9, 1990.

54. Erlich H, Bugawan T, Begovich AB, Scharf S, Griffith R, Saiki R, Higuchi R, Walsh PS. HLA‐DR, DO and DP typing using PCR amplification and immobilized probes. International Journal of Immunogenetics. 1991; 18,1‐2:33-55.

55. Bugawan TL, Begovich AB, Erlich HA. Rapid HLA-DPB typing using enzymatically amplified DNA and nonradioactive sequence‑specific oligonucleotide probes. Immunogenetics 1990; 32:231-41.

56. Bugawan TL, Apple R, Erlich HA. A method for typing polymorphism at the HLA‑A locus using PCR amplification and immobilized oligonucleotide probes. Tissue Antigens 1994; 44:137-47.

57. Newton CR, Graham A, Heptinstall LE, Powell SJ, Summers C, Kalsheker N, Smith JC, Markham AF. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic acids research. 1989 ; 17,7:2503-16.

58. Olerup O, Zetterquist H. HLA‑DR typing by PCR amplification with sequence‑specific primers (PCR‑SSP) in 2 hours: An alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 1992; 39:225-35.

59. Santamaria P, Boyce-Jacino MT, Lindstrom AL, Barbosa JJ, Faras AJ, Rich SS. HLA class II “typing”: direct sequencing of DRB, DQB, and DQA genes. Human immunology. 1992; 33,2:69-81.

60. Spurkland A, Knutsen I, Markussen G, Vartdal F, Egeland T, Thorsby E. HLA matching of unrelated bone marrow transplant pairs: direct sequencing of in vitro amplified HLA‐DRB1 and‐DQB1 genes using magnetic beads as solid support. Tissue Antigens. 1993 ; 41,3:155-64.

61. Knipper AJ, Hinney A, Schuch B, Enczmann J, Uhrberg M, Wernet P. Selection of unrelated bone marrow donors by PCR‐SSP typing and subsequent nonradioactive sequence‐based typing for HLA DRB1/3/4/5, DQB1, and DPB1 alleles. Tissue antigens. 1994 ; 44,5:275-84.

62. Shankarkumar U, Pawar A, Ghosh K. Implications of HLA sequence-based typing in transplantation. J Postgrad Med 2008; 54:41-4.

63. Beck S, Geraghty D, Inoko H, Rowen L, Aguado B, Bahram S. The MHC sequencing consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature 1999; 401:921-3.

64. Hosomichi K, Shiina T, Tajima A, Inoue I. The impact of next-generation sequencing technologies on HLA research. J Hum Genet 2015; 60:665-73

65. Fuller TC, Phelan DO, Gebel HM, Rodey GE. Antigenic specificity of antibody reactive in the antiglobulin-augmented lymphocytotoxicity test. Transplantation. 1982; 34,1:24-9.

66. Fuller, TC, and Rodey, GE: Specificity of alloantibodies against antigens of the HLA complex. In Theoretical Aspects of HLA: A Technical Workshop.American Association of Blood Banks, Arlington, VA, 1982, p 51.

67. Lucas ZJ, Coplon N, Kempson R, Cohn R. Early renal transplant failure associated with subliminal sensitization. Transplantation. 1970; 10,6:522-9..

68. Patel, R, and Briggs, WA: Limitation of the lymphocyte cytotoxicity crossmatch test in recipients of kidney transplants having preformed anti-leukocyte antibodies. N Engl J Med 1971; 284:1016.

69. Bray, RA: Flow cytometry in the transplant laboratory. Ann NY AcadSci 677:138, 1993.

70. Billen EV, Voorter CE, Christiaans MH, van den Berg‑Loonen EM.Luminex donor‑specific crossmatches. Tissue Antigens 2008; 71:507-13.

71. AABB Technical Manual. American Association of Blood Banks. 18th edition

72. Thorsby E. A short history of HLA. Tissue Antigens 2009; 74:101-16.

73. Polesky, HF: New concepts in paternity testing. Diagn Med 1981.

74. Tiwari, JL, and Terasaki, PI: HLA and Disease. New York, Springer-Verlag, 1985.

75. Mourant, AE, Kopec, AC, and Domaniewska-Solczak, K: Blood Groups and Diseases. New York, Oxford University Press, 1978.

76. Malaviya AN, Mehra NK, Adhar GC, Jindal K, Bhargava S, Batta RK, Vaidya MC, Tandon RK, Sankaran B. The clinical spectrum of HLA-B27 related rheumatic diseases in India. The Journal of the Association of Physicians of India. 1979; 27,6:487.

77. Madhavan R, Parthiban M, Rajendran CP, Chandrasekaran AN, Zake L, Sanjeevi CB. HLA class I and class II association with ankylosing spondylitis in a southern Indian population. Annals of the New York Academy of Sciences. 2002; 958,1:403-7.

78. Darrell JT, Dzik WH. Leukocyte reduced blood components: Laboratory and clinical aspects. Editors: Toby L. Simon, Edward L. Snyder, Bjarte G. Solheim, Christopher P. Stowell, Ronald G. Strauss, Marian Petrides .

79. Rossi’s Principles of   Transfusion Medicine.4th ed. Blackwell Publisher; 2000. p. 228-46. 45.

80. Colombani, J: Blood platelets in HL-A serology. Transpl Proc 1971; 3:1078.

81. Svejgaard, A, Kissemeyer-Nielson, F, and Thorsby, E: HL-A typing of platelets. In Terasaki, PI (ed): Histocompatibility Testing 1970. Munksgaard, Copenhagen, 1970, p 160.

82. Leibert, M, and Aster, RH: Expression of HLA-B12 on platelets, on lymphocytes, and in serum: A quantitative study. Tissue Antigens 1977; 9:199.

83. Aster, RH, Szatkowski, N, and Liebert, M: Expression of HLA-B12, HLA-B8, W4, and W6 on platelets.Transpl Proc 1977; 9:1965.

84. Duquesnoy, RJ, Testin, J, and Aster, RH: Variable expression of W4 and W6 on platelets: Possible relevance to platelet transfusion therapy of alloimmunized thrombocytopenic patients. Transpl Proc 1977; 9:1827.

85. Duquesnoy, RJ, Filip, DJ, and Rody, GE: Successful transfusion of platelet “mismatched” for HLA antigens to alloimmunized thrombocytopenic patients. Am J Hematol 1977; 2:219.

86. Brand, A, van Leeuwen, A, and Eernisse, JG: Platelet immunology with special regard to platelet transfusion therapy. ExcerptaMedica International Congress 1978; 415:639.

87. Herzig, RH, Herzig, GP, and Biell, MI: Correction of poor platelet transfusion responses with leukocyte-poor HLA-matched platelet concentrates. Blood 1975; 46:743.

88. Seftel MD, Growe GH, Petraszko T, Benny WB, Le A, Lee CY, Spinelli JJ, Sutherland HJ, Tsang P, Hogge DE. Universal prestorage leukoreduction in Canada decreases platelet alloimmunization and refractoriness. Blood. 2004 ; 103,1:333-9..

89. Popovsky MA, Moore SB. Diagnostic and pathogenetic considerations in transfusion-related acute lung injury.Transfusion 1985; 5:573-7.

90. Petz LD, Calhoun L, Yam P, Cecka M, Schiller G, Faitlowicz AR, Herron R, Sayah D, Wallace RB, Belldegrun A. Transfusion‐associated graft‐versus‐host disease in immunocompetent patients: report of a fatal case associated with transfusion of blood from a second‐degree relative, and a survey of predisposing factors. Transfusion. 1993 ; 33,9:742-50.

91. Davey RJ. Transfusion-associated graft-versus-host disease and the irradiation of blood components.Immunol Invest 1995; 24:431-4.

92. Bortin, MM, and Rimm, AA: Increasing utilization of bone marrow transplantation. Transplantation 1986; 42:229.

93. Petersdorf EW, Hansen JA, Martin PJ, Woolfrey A, Malkki M, Gooley T, Storer B, Mickelson E, Smith A, Anasetti C. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation. New England Journal of Medicine. 2001; 345,25:1794-800.

94. Flomenberg N, Baxter-Lowe LA, Confer D, Fernandez-Vina M, Filipovich A, Horowitz M, Hurley C, Kollman C, Anasetti C, Noreen H, Begovich A. Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. Blood. 2004; 104,7:1923-1930.

95. Morishima, RA. For the Japanese Marrow Donor Program. Blood 99:4200, 2002.

96. Siegler, HF. Comparisons of mixed leukocyte skin graft survival in families genotyped for HLA-A.Transpl Proc 1971; 3:115.

97. Hamburger J, Crosnier J, Descamps B, Rowinska D. The value of present methods used for the selection of organ donors. In Transplantation proceedings 1971 Mar (Vol. 3, No. 1, p. 260).

98. Alexander, JW: Impact of transplantation on microbiology and infectious diseases. Transpl Proc 1980; 12:593.

99. Cecka, JM: The UNOS scientific renal transplant registry 2000. ClinTranspl 1, 2001.

100. Sanfilippo, F, Vaughn, WK, and Spees, EKL: The effect of HLA-A, -B matching on cadaver renal allograft rejection comparing public and private specificities. Transplantation 1984; 38:483.

101. Montgomery RA, Zachary AA, Racusen LC, Leffell MS, King KE, Burdick J, Maley WR, Ratner LE. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation. 2000 ; 70,6:887-95.

102. Ross CN, Gaskin GI, Gregor-Macgregor SU, Patel AA, Davey NJ, Lechler RI, Williams GO, Rees AJ, Pusey CD. Renal transplantation following immunoadsorption in highly sensitized recipients. Transplantation. 1993; 55,4:785-9.

103. Hodge EE, Klingman LL, Koo AP, Nally J, Hobbs RE. Pretransplant removal of anti-HLA antibodies by plasmapheresis and continued suppression on cyclosporine-based therapy after heart-kidney transplant. InTransplantation proceedings 1994 (Vol. 26, No. 5, pp. 2750-2751).

104. Kickler T, Braine HG, Piantadosi S, Ness PM, Herman JH, Rothko K. A randomized, placebo-controlled trial of intravenous gammaglobulin in alloimmunized thrombocytopenic patients.

105. Tyan DB, Li VA, Czer LA, Trento AL, Jordan SC. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histoincompatible organ. TRANSPLANTATION-BALTIMORE-. 1994; 57:553.

106. Yacoub M, Festenstein H, Doyle P, Martin M, McCloskey D, Awad J, Gamba A, Khaghani A, Holmes J. The influence of HLA matching in cardiac allograft recipients receiving cyclosporine and azathioprine. InTransplantation proceedings 1987 ; 19, 3: 2487-2489.

107. Karuppan, S, Ericzon, BG, and Moller, E: Relevance of a positive crossmatch in liver transplantation. TransplInt 1991; 4:18.

108. Gugenheim, J, Samuel, D, and Reynes, M: Liver transplantation across ABO blood group barriers. Lancet 1990; 336:519.

109. Mathew JM, Shenoy S, Phelan D, Lowell J, Howard T, Mohanakumar T. Biochemical and immunological evaluation of donor-specific soluble hla in the circulation of liver transplant recipients1. Transplantation. 1996 ; 62,2:217-23.

110. Shaw, LR, Miller, JD, and Slutsky, AS Ethics of lung transplantation with live donors. Lancet 1991; 338:461.

111. Gruessner, AC, and Sutherland, DER: Analysis of United States (US) and non-US pancreas transplants reported to UNOS and the International Pancreas Transplant Registry as of October 2001. ClinTranspl 2001:41, 2002.

112. Shapiro AJ, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. New England Journal of Medicine. 2000; 343,4:230-8.

113. Ayuk F, Bornhäuser M, Stelljes M, Zabelina T, Wagner EM, Schmid C, Christopeit M, Guellstorf M, Kröger N, Bethge W. Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) are associated with poorer outcome after single mismatch unrelated donor stem cell transplantation: a study of the Cooperative Transplant Study Group (KTS) of the German Group for Bone Marrow and Stem Cell Transplantation (DAG-KBT). Transfusion Medicine and Hemotherapy. 2019; 46,5:370-5.