Major histocompatibility complex class 1 chain-related genes (MIC) are part of the non-classical MHC genes located on the short arm of chromosome 6. MICA comprises of approximately 11 kb DNA and encodes polypeptide of 383 amino acids. The expression of MICA is limited to the surface of the epithelial cells, fibroblasts, keratinocytes and monocytes, but not on the surface of CD4+, CD8+ and CD19+ lymphocytes. It manifests its role by binding with the NK cell receptor NKG2D. There are 84 different alleles for MICA due to discovered polymorphisms in the exons 2 to 5. The aim of this review is to present the data known so far about the association of MICA with different diseases and the role of anti-MICA antibodies in organ and stem cell transplantation. The frequency of different MICA alleles and their association with different HLAB alleles, as well as the association of MICA with different inflammatory diseases, infection diseases and tumors was determined. Post- and pre-transplant anti-MICA antibodies are associated with antibody-mediated rejection in kidney and heart transplantation. Patients with hematopoietic stem cell transplantation, which have MICA mismatch, have higher frequency of graft versus host disease episodes. In spite of lack of conclusive data about the role of anti- MICA antibodies in organ and stem cell transplantation, there is still clinical relevance for investigation of the polymorphisms of the MICA gene and anti-MICA antibodies.
1. Bahram S, Bresnahan M, Geraghty DE, Spies T. A second lineage of mammalian major histocompatibility complex class I genes. Proceedings of the National Academy of Sciences of the United States of America . 1994;91(14):6259-63.
2. Leelayuwat C, Townend DC, Degli-Esposti MA, Abraham LJ, Dawkins RL. A new polymorphic and multicopy MHC gene family related to nonmammalian class I. Immunogenetics. 1994;40(5):339-51.
3. Shiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue antigens. 2004;64(6):631-49.
4. Shiina T, Hosomichi K, Inoko H, Kulski JK. The HLA genomic loci map: expression, interaction, diversity and disease. Journal of human genetics. 2009;54(1):15-39.
5. MIC Genes [M.Tevfik DORAK].
6. Groh V, Bahram S, Bauer S, Herman a, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(22):12445-50.
7. Bauer S. Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA. Science. 1999;285(5428):727-9.
8. Zwirner NW, Dole K, Stastny P. Differential surface expression of MICA by endothelial cells, fibroblasts, keratinocytes, and monocytes. Human Immunology. 1999;60(4):323-30.
9. Zwirner NW, Fernández-Viña MA, Stastny P. MICA, a new polymorphic HLA-related antigen, is expressed mainly by keratinocytes, endothelial cells, and monocytes. Immunogenetics. 1998;47(2):139-48.
10. Schrambach S, Ardizzone M, Leymarie V, Sibilia J, Bahram S. In vivo expression pattern of MICA and MICB and its relevance to auto-immunity and cancer. PloS one. 2007;2(6):e518.
11. Pende D, Cantoni C, Rivera P, Vitale M, Castriconi R, Marcenaro S, et al. Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin. European journal of immunology. 2001;31(4):1076-86.
12. Zwirner N, Fuertes M. Immunobiology of the human MHC class I chain-related gene A (MICA): from transplantation immunology to tumor immune escape. Immunologia. 2006;25(1):25-38.
13. Tian W, Boggs D a, Ding WZ, Chen DF, Fraser P a. MICA genetic polymorphism and linkage disequilibrium with HLA-B in 29 African-American families. Immunogenetics. 2001;53(9):724-8.
14. Fodil N, Pellet P, Laloux L, Hauptmann G, Theodorou I, Bahram S. MICA haplotypic diversity. Immunogenetics. 1999;49(6):557-60.
15. Rees MT, Downing J, Darke C. A typing system for the major histocompatibility complex class I chain related genes A and B using polymerase chain reaction with sequence-specific primers. Genetic testing. 2005;9(2):93-110.
16. Mameli a, Cauli a, Taccari E, Scarpa R, Punzi L, Lapadula G, et al. Association of MICA alleles with psoriatic arthritis and its clinical forms. A multicenter Italian study. Clinical and experimental rheumatology. 2008;26(4):649-52.
17. Romphruk A V, Romphruk A, Choonhakarn C, Puapairoj C, Inoko H, Leelayuwat C. Major histocompatibility complex class I chain-related gene A in Thai psoriasis patients: MICA association as a part of human leukocyte antigen-B-Cw haplotypes. Tissue antigens. 2004;63(6):547-54.
18. Pollock R, Chandran V, Barrett J, Eder L, Pellett F, Yao C, et al. Differential major histocompatibility complex class I chainrelated A allele associations with skin and joint manifestations of psoriatic disease. Tissue antigens. 2011;77(6):554-61.
19. Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America . 2003;100(16):9452-7.
20. Kirsten H, Petit-Teixeira E, Scholz M, Hasenclever D, Hantmann H, Heider D, et al. Association of MICA with rheumatoid arthritis independent of known HLA-DRB1 risk alleles in a family-based and a case control study. Arthritis research & therapy. 2009;11(3):R60.
21. Su H, Wang B, Zhang X, Hao J, Xiao Q, Ye D. [Disequilibrium linkage between the polymorphism in exons 2, 3 and 4 of the MICA gene and HLA-B antigen of patient with ankylosing spondylitis]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2006;23(4):446-8.
22. Yabuki K, Ota M, Goto K, Kimura T, Nomura E, Ohno S, et al. Triplet repeat polymorphism in the MICA gene in HLA-B27 positive and negative caucasian patients with ankylosing spondylitis. Human immunology. 1999;60(1):83-6.
23. Goto K, Ota M, Maksymowych WP, Mizuki N, Yabuki K, Katsuyama Y, et al. Association between MICA gene A4 allele and acute anterior uveitis in white patients with and without HLA-B27. American journal of ophthalmology. 1998;126(3):436-41.
24. Hughes EH, Collins RWM, Kondeatis E, Wallace GR, Graham EM, Vaughan RW, et al. Associations of major histocompatibility complex class I chain-related molecule polymorphisms with Behcet’s disease in Caucasian patients. Tissue antigens. 2005; 66(3):195-9.
25. Muñoz-Saá I, Cambra A, Pallarés L, Espinosa G, Juan A, Pujalte F, et al. Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behçet’s disease. Scandinavian journal of immunology. 2006;64(1):77-82.
26. Gladman DD, Urowitz MB, Darlington GA. Disease expression and class II HLA antigens in systemic lupus erythematosus. Lupus. 1999;8(6):466-70.
27. Gambelunghe G, Gerli R, Bocci EB, Del Sindaco P, Ghaderi M, Sanjeevi CB, et al. Contribution of MHC class I chain-related A (MICA) gene polymorphism to genetic susceptibility for systemic lupus erythematosus. Rheumatology (Oxford, England). 2005;44(3):287-92.
28. Yoshida K, Komai K, Shiozawa K, Mashida A, Horiuchi T, Tanaka Y, et al. Role of the MICA polymorphism in systemic lupus erythematosus. Arthritis and rheumatism. 2011;63(10):3058-66.
29. Hüe S, Mention J-J, Monteiro RC, Zhang S, Cellier C, Schmitz J, et al. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity. 2004;21(3):367-77.
30. Bilbao JR, Martín-Pagola A, Vitoria JC, Zubillaga P, Ortiz L, Castaño L. HLA-DRB1 and MHC class 1 chain-related A haplotypes in Basque families with celiac disease. Tissue antigens. 2002;60(1):71-6.
31. Rueda B, Pascual M, López-Nevot MA, Koeleman BPC, Ortega E, Maldonado J, et al. Association of MICA-A5.1 allele with susceptibility to celiac disease in a family study. The American journal of gastroenterology. 2003;98(2):359-62.
32. Bilbao JR, Martín-Pagola A, Pérez De Nanclares G, Calvo B, Vitoria JC, Vázquez F, et al. HLA-DRB1 and MICA in autoimmunity: common associated alleles in autoimmune disorders. Annals of the New York Academy of Sciences. 2003;1005:314-8.
33. Gambelunghe G, Ghaderi M, Tortoioli C, Falorni A, Santeusanio F, Brunetti P, et al. Two distinct MICA gene markers discriminate major autoimmune diabetes types. The Journal of clinical endocrinology and metabolism. 2001;86(8):3754-60.
34. Törn C, Gupta M, Nikitina Zake L, Sanjeevi CB, Landin-Olsson M. Heterozygosity for MICA5.0/MICA5.1 and HLA-DR3- DQ2/DR4-DQ8 are independent genetic risk factors for latent autoimmune diabetes in adults. Human immunology. 2003;64(9):902-9.
35. Alizadeh BZ, Eerligh P, Van der Slik AR, Shastry A, Zhernakova A, Valdigem G, et al. MICA marks additional risk factors for Type 1 diabetes on extended HLA haplotypes: an association and meta-analysis. Molecular immunology. 2007;44(11):2806-12.
36. Van Autreve JE, Koeleman BPC, Quartier E, Aminkeng F, Weets I, Gorus FK, et al. MICA is associated with type 1 diabetes in the Belgian population, independent of HLA-DQ. Human immunology. 2006; 67(1-2):94-101.
37. Barker JM. Clinical review: Type 1 diabetes-associated autoimmunity: natural history, genetic associations, and screening. The Journal of clinical endocrinology and metabolism. 2006;91(4):1210-7.
38. Barahmani N, De Andrade M, Slusser JP, Zhang Q, Duvic M. Major histocompatibility complex class I chain-related gene A polymorphisms and extended haplotypes are associated with familial alopecia areata. The Journal of investigative dermatology. 2006;126(1):74-8.
39. Kumar V, Yi Lo PH, Sawai H, Kato N, Takahashi A, Deng Z, et al. Soluble MICA and a MICA variation as possible prognostic biomarkers for HBV-induced hepatocellular carcinoma. PloS one. 2012;7(9):e44743.
40. Li J-J, Pan K, Gu M-F, Chen M-S, Zhao J-J, Wang H, et al. Prognostic value of soluble MICA levels in the serum of patients with advanced hepatocellular carcinoma. Chinese journal of cancer. 2012;32(3):141-8.
41. Jiang X, Zou Y, Huo Z, Yu P. Association of major histocompatibility complex class I chain-related gene A microsatellite polymorphism and hepatocellular carcinoma in South China Han population. Tissue antigens. 2011;78(2):143-7.
42. Luo QZ, Lin L, Gong Z, Mei B, Xu YJ, Huo Z, et al. Positive association of major histocompatibility complex class I chainrelated gene A polymorphism with leukemia susceptibility in the people of Han nationality of Southern China. Tissue antigens. 2011;78(3):178-84.
43. Fuertes MB, Rossi LE, Peralta CM, Cabrera HN, Allevato MA, Zwirner NW. Premalignant quiescent melanocytic nevi do not express the MHC class I chain-related protein A. Medicina. 2011;71(4):357-60.
44. Das H, Groh V, Kuijl C, Sugita M, Morita CT, Spies T, et al. MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function. Immunity. 2001;15(1):83-93.
45. Souza CF, Noguti EN, Visentainer JEL, Cardoso RF, Petzl-Erler ML, Tsuneto LT. HLA and MICA genes in patients with tuberculosis in Brazil. Tissue antigens. 2012;79(1):58-63.
46. Do Sacramento WS, Mazini PS, Franceschi DAS, De Melo FC, Braga MA, Sell AM, et al. Frequencies of MICA alleles in patients from southern Brazil with multibacillary and paucibacillary leprosy. International journal of immunogenetics. 2012;39(3):210-5.
47. Tosh K, Ravikumar M, Bell JT, Meisner S, Hill AVS, Pitchappan R. Variation in MICA and MICB genes and enhanced susceptibility to paucibacillary leprosy in South India. Human molecular genetics. 2006;15(19):2880-7.
48. Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature immunology. 2001;2(3):255-60.
49. Zou Y, Bresnahan W, Taylor RT, Stastny P. Effect of human cytomegalovirus on expression of MHC class I-related chains A. Journal of immunology. 2005;174(5):3098-104.
50. Moenkemeyer M, Heiken H, Schmidt RE, Witte T. Higher risk of cytomegalovirus reactivation in human immunodeficiency virus-1-infected patients homozygous for MICA5.1. Human immunology. 2009;70(3):175-8.
51. Kanto T, Hayashi N. Innate immunity in hepatitis C virus infection: Interplay among dendritic cells, natural killer cells and natural killer T cells. Hepatology research: the official journal of the Japan Society of Hepatology. 2007;37 Suppl 3:S319-26.
52. Jinushi M, Takehara T, Kanto T, Tatsumi T, Groh V, Spies T, et al. Critical role of MHC class I-related chain A and B expression on IFN-alpha-stimulated dendritic cells in NK cell activation: impairment in chronic hepatitis C virus infection. Journal of immunology (Baltimore, Md.: 1950). 2003;170(3):1249-56.
53. Karacki PS, Gao X, Thio CL, Thomas DL, Goedert JJ, Vlahov D, et al. MICA and recovery from hepatitis C virus and hepatitis B virus infections. Genes and immunity. 2004;5(4):261-6.
54. Zwirner NW, Marcos CY, Mirbaha F, Zou Y, Stastny P. Identification of MICA as a new polymorphic alloantigen recognized by antibodies in sera of organ transplant recipients. Human immunology. 2000;61(9):917-24.
55. Zou Y, Stastny P. Antibodies against major histocompatibility complex class I-related chain A in transplant recipients. Chinese medical journal. 2011;124(5):764-70.
56. Zou Y, Qin Z, Silveus A, Fan Y, Stastny P. Polymorphisms of MICA recognized by human alloantibodies. Immunogenetics. 2009;61(2):91-100.
57. Duquesnoy RJ, Mostecki J, Hariharan J, Balazs I. Structurally based epitope analysis of major histocompatibility complex class I-related chain A (MICA) antibody specificity patterns. Human immunology. 2008;69(12):826-32.
58. Stegall MD, Dean PG, Gloor J. Mechanisms of alloantibody production in sensitized renal allograft recipients. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(5):998-1005.
59. Dragun D, Philippe A, Catar R. Role of non-HLA antibodies in organ transplantation. Current opinion in organ transplantation. 2012;17(4):440-5.
60. Zou Y, Mirbaha F, Lazaro A, Zhang Y, Lavingia B, Stastny P. MICA is a target for complement-dependent cytotoxicity with mouse monoclonal antibodies and human alloantibodies. Human immunology. 2002;63(1):30-9.
61. Alvarez-Márquez A, Aguilera I, Gentil M a, Caro JL, Bernal G, Fernández Alonso J, et al. Donor-specific antibodies against HLA, MICA, and GSTT1 in patients with allograft rejection and C4d deposition in renal biopsies. Transplantation. 2009;87(1):94-9.
62. Mizutani K, Terasaki P, Rosen A, Esquenazi V, Miller J, Shih RNJ, et al. Serial ten-year follow-up of HLA and MICA antibody production prior to kidney graft failure. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2005;5(9):2265-72.
63. Martin L, Guignier F, Mousson C, Rageot D, Justrabo E, Rifle G. Detection of donor-specific anti-HLA antibodies with flow cytometry in eluates and sera from renal transplant recipients with chronic allograft nephropathy. Transplantation. 2003;76(2):395-400.
64. Ozawa M, Rebellato LM, Terasaki PI, Tong A, Briley KP, Catrou P, et al. Longitudinal testing of 266 renal allograft patients for HLA and MICA antibodies: Greenville experience. Clinical transplants. 2006;265-90.
65. Zou Y, Stastny P, Süsal C, Döhler B, Opelz G. Antibodies against MICA antigens and kidney-transplant rejection. The New England journal of medicine. 2007;357(13):1293-300.
66. Terasaki PI, Ozawa M, Castro R. Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2007; (2):408-15.
67. Zhang M, Lu F, Qu L, He J, Yuan X, Gu Y. Serum majorhistocompatibility- complex class I-related chain A antibody detection for the evaluation of graft dysfunction in renal allograft recipients. Chinese medical journal. 2011;124(14):2127-31.
68. Li Z, Luo M, Qiu J, Liu Y, Fan Y, Jahr FM, et al. Detection of antibodies against major histocompatibility complex class Irelated chain A in long-term renal graft recipients. Experimental and clinical transplantation: official journal of the Middle East Society for Organ Transplantation. 2012;10(3):239-42.
69. Lemy A, Andrien M, Lionet A, Labalette M, Noel C, Hiesse C, et al. Posttransplant Major Histocompatibility Complex Class I Chain-Related Gene A Antibodies and Long-Term Graft Outcomes in a Multicenter Cohort of 779 Kidney Transplant Recipients. Transplantation. 2012;9 (12):1258-64.
70. Tait BD, Süsal C, Gebel HM, Nickerson PW, Zachary A a, Claas FHJ, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation. 2013;95(1):19-47.
71. Suárez-Alvarez B, López-Vázquez A, Gonzalez MZ, Fdez- Morera JL, Díaz-Molina B, Blanco-Gelaz MA, et al. The relationship of anti-MICA antibodies and MICA expression with heart allograft rejection. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2007;7(7):1842-8.
72. Kauke T, Kaczmarek I, Dick A, Schmoeckel M, Deutsch M-A, Beiras-Fernandez A, et al. Anti-MICA antibodies are related to adverse outcome in heart transplant recipients. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation. 2009;28(4):305-11.
73. Smith JD, Brunner VM, Jigjidsuren S, Hamour IM, McCormack a M, Banner NR, et al. Lack of effect of MICA antibodies on graft survival following heart transplantation. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009;9(8):1912-9.
74. Tambur AR, Bray RA, Takemoto SK, Mancini M, Costanzo MR, Kobashigawa JA, et al. Flow cytometric detection of HLAspecific antibodies as a predictor of heart allograft rejection. Transplantation. 2000;70(7):1055-9.
75. Parmar S, Del Lima M, Zou Y, Patah P a, Liu P, Cano P, et al. Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease. Blood. 2009;114(14):2884-7.
76. Boukouaci W, Busson M, Peffault de Latour R, Rocha V, Suberbielle C, Bengoufa D, et al. MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graftversus- host disease. Blood. 2009;114(25):5216-24.
77. Cheng L, Zhang SZ, Xiao CY, Hou YP, Li L, Luo HC, et al. The A5.1 allele of the major histocompatibility complex class I chainrelated gene A is associated with psoriasis vulgaris in Chinese. The British journal of dermatology. 2000;143(2):324-9.
78. Gong W, Fan L, Yang J, Xu L, Yao F. [Analysis on polymorphism in exons 2,3 and 4 of the MICA gene in three different Chinese populations]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics. 2002;19(4):336-9.
79. Nikitina-Zake, L; Gupta, M; Gambelunghe, G; Shtauvere, A; Lernmark ASCB. Frequencies of MICA alleles significantly differ between Latvian, Italian and Swedish populations and are associated with type 1 diabetes mellitius. Proceedings of the 13th IHW. 2006;2:379-80.
80. Ota M, Katsuyama Y, Mizuki N, Ando H, Furihata K, Ono S, et al. Trinucleotide repeat polymorphism within exon 5 of the MICA gene (MHC class I chain-related gene A): allele frequency data in the nine population groups Japanese, Northern Han, Hui, Uygur, Kazakhstan, Iranian, Saudi Arabian, Greek and Italian. Tissue antigens. 1997;49(5):448-54.
81. Piancatelli D, Del Beato T, Oumhani K, El Aouad R, Adorno D. MICA polymorphism in a population from north Morocco, Metalsa Berbers, using sequence-based typing. Human immunology. 2005;66(8):931-6.
82. Petersdorf EW, Shuler KB, Longton GM, Spies T, Hansen JA. Population study of allelic diversity in the human MHC class Irelated MIC-A gene. Immunogenetics. 1999;49(7-8):605-12.
83. Tian W, Boggs DA, Uko G, Essiet A, Inyama M, Banjoko B, et al. MICA, HLA-B haplotypic variation in five population groups of sub-Saharan African ancestry. Genes and immunity. 2003;4(7):500-5.
84. Oliveira LA, Ribas F, Bicalho MG, Tsuneto LT, Petzl-Erler ML. High frequencies of alleles MICA*020 and MICA*027 in Amerindians and evidence of positive selection on exon 3. Genes and immunity. 2008;9(8):697-705.
85. Zhang Y, Lazaro AM, Zou Y, Lavingia B, Moraes EM, Moraes RJ, et al. MICA polymorphism in South American Indians. Immunogenetics. 2002;53(10-11):900-6.
86. Glas J, Martin K, Brünnler G, Kopp R, Folwaczny C, Weiss EH, et al. MICA, MICB and C1_4_1 polymorphism in Crohn’s disease and ulcerative colitis. Tissue antigens. 2001;58(4):243-9.
87. Romphruk A V, Naruse TK, Romphruk A, Kawata H, Puapairoj C, Kulski JK, et al. Diversity of MICA (PERB11.1) and HLA haplotypes in Northeastern Thais. Tissue antigens. 2001;58(2):83-9.
88. Zhang Y, Han M, Vorhaben R, Giang C, Lavingia B, Stastny P. Study of MICA alleles in 201 African Americans by multiplexed single nucleotide extension (MSNE) typing. Human immunology. 2003;64(1):130-6.
89. Cambra A, Muñoz-Saá I, Crespí C, Serra A, Etxagibel A, Matamoros N, et al. MICA-HLA-B haplotype diversity and linkage disequilibrium in a population of Jewish descent from Majorca (the Balearic Islands). Human immunology. 2009;70(7):513-7.
90. Pyo C-W, Hur S-S, Kim Y-K, Choi H-B, Kim T-Y, Kim T-G. Distribution of MICA alleles and haplotypes associated with HLA in the Korean population. Human immunology. 2003;64(3):378-84.
91. Zhu F, Zhao H, He Y, Zhang W, He J, Xu X, et al. Distribution of MICA diversity in the Chinese Han population by polymerase chain reaction sequence-based typing for exons 2-6. Tissue antigens. 2009;73(4):358-63.
92. Sohn Y-H, Cha C-H, Oh H-B, Kim MH, Choi S-E, Kwon O-J. MICA polymorphisms and haplotypes with HLA-B and HLADRB1 in Koreans. Tissue antigens. 2010;75(1):48-55.
93. Zhang Y, Lazaro AM, Lavingia B, Stastny P. Typing for all known MICA alleles by group-specific PCR and SSOP. Human immunology. 2001;62(6):620-31.