Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin

Genes and Immunity

Volumn 11, Issue 2, 2010, Pages 188-193

  Durinovic Bello I ^a   Wu, R P ^a   Gersuk, V H ^a   Sanda, S ^a   Shilling, H G ^a   Nepom, G T ^a  

^a UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

Author keywords

Autoimmune diabetes; Genotype; INS VNTR; Insulin; Proinsulin; Tetramer

Indexed keywords

AUTOANTIGEN; CD4 ANTIGEN; HLA ANTIGEN CLASS 2; INSULIN; PROINSULIN;

ARTICLE; AUTOIMMUNITY; CELLULAR IMMUNITY; CONTROLLED STUDY; GENE CONTROL; GENE FREQUENCY; GENETIC ASSOCIATION; GENETIC POLYMORPHISM; GENETIC SUSCEPTIBILITY; GENOTYPE; HUMAN; HUMAN CELL; IMMUNOLOGICAL TOLERANCE; INSULIN DEPENDENT DIABETES MELLITUS; PHENOTYPE; PRIORITY JOURNAL; T LYMPHOCYTE; VARIABLE NUMBER OF TANDEM REPEAT;

AUTOANTIGENS; AUTOIMMUNITY; DIABETES MELLITUS, TYPE 1; DISEASE SUSCEPTIBILITY; GENOTYPE; HISTOCOMPATIBILITY ANTIGENS CLASS II; HUMANS; INSULIN; MINISATELLITE REPEATS; PHENOTYPE; POLYMORPHISM, GENETIC; PROINSULIN; T-LYMPHOCYTES;

EID: 77649338369     PISSN: 14664879     EISSN: 14765470     Source Type: Journal    
DOI: 10.1038/gene.2009.108     Document Type: Article

References (29)

1. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005; 435: 220-223.
2. Durinovic-Bello I, Boehm BO, Ziegler AG. Predominantly recognized proinsulin T helper cell epitopes in individuals with and without islet cell autoimmunity. J Autoimmun 2002; 18: 55-66.
3. Durinovic-Bello I, Hummel M, Ziegler AG. Cellular immune response to diverse islet cell antigens in IDDM. Diabetes 1996; 45: 795-800.
4. Yang J, Danke N, Roti M, Huston L, Greenbaum C, Pihoker C et al. CD4+ T cells from type 1 diabetic and healthy subjects exhibit different thresholds of activation to a naturally processed proinsulin epitope. J Autoimmun 2008; 31: 30-41.
5. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol 2006; 24: 571-606.
6. Sabater L, Ferrer-Francesch X, Sospedra M, Caro P, Juan M, Pujol-Borrell R. Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin expression in the thymus. J Autoimmun 2005; 25: 312-318.
7. Undlien DE, Bennett ST, Todd JA, Akselsen HE, Ikaheimo I, Reijonen H et al. Insulin gene region-encoded susceptibility to IDDM maps upstream of the insulin gene. Diabetes 1995; 44: 620-625.
8. Deng L, Mariuzza RA. Recognition of self-peptide-MHC complexes by autoimmune T-cell receptors. Trends Biochem Sci 2007; 32: 500-508.
9. Reijonen H, Elliott JF, van Endert P, Nepom G. Differential presentation of glutamic acid decarboxylase 65 (GAD65) T cell epitopes among HLA-DRB1*0401-positive individuals. J Immunol 1999; 163: 1674-1681.
10. van der Merwe PA, Davis SJ. Molecular interactions mediating T cell antigen recognition. Annu Rev Immunol 2003; 21: 659-684.
11. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002; 298: 1395-1401.
12. Brimnes MK, Jensen T, Jorgensen TN, Michelsen BK, Troelsen J, Werdelin O. Low expression of insulin in the thymus of non-obese diabetic mice. J Autoimmun 2002; 19: 203-213.
13. Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand JP, Halbout P, Vallon-Geoffroy K et al. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J Clin Invest 2003; 111: 851-857.
14. Barratt BJ, Payne F, Lowe CE, Hermann R, Healy B, Harold D et al. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 2004; 53: 1884-1889.
15. Pugliese A, Zeller M, Fernandez Jr A, Zalcberg LJ, Bartlett RJ, Ricordi C et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 1997; 15: 293-297.
16. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997; 15: 289-292.
17. Walter M, Albert E, Conrad M, Keller E, Hummel M, Ferber K et al. IDDM2/insulin VNTR modifies risk conferred by IDDM1/HLA for development of type 1 diabetes and associated autoimmunity. Diabetologia 2003; 46: 712-720.
18. Nielsen LB, Mortensen HB, Chiarelli F, Holl R, Swift P, de Beaufort C et al. Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: reduced insulin antibody titres and preserved beta cell function. Diabetologia 2006; 49: 71-74.
19. Hermann R, Laine AP, Veijola R, Vahlberg T, Simell S, Lahde J et al. The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell auto-immunity. Diabetologia 2005; 48: 1766-1775.
20. Concannon P, Chen WM, Julier C, Morahan G, Akolkar B, Erlich HA et al. Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the type 1 Diabetes Genetics Consortium. Diabetes 2009; 58: 1018-1022.
21. Motzo C, Contu D, Cordell HJ, Lampis R, Congia M, Marrosu MG et al. Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes. Diabetes 2004; 53: 3286-3291.
22. Durinovic-Bello I, Rosinger S, Olson JA, Congia M, Ahmad RC, Rickert M et al. DRB1*0401-restricted human T cell clone specific for the major proinsulin73-90 epitope expresses a down-regulatory T helper 2 phenotype. Proc Natl Acad Sci USA 2006; 103: 11683-11688.
23. Congia M, Patel S, Cope AP, De Virgiliis S, Sonderstrup G. Tcell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin. Proc Natl Acad Sci USA 1998; 95: 3833-3838.
24. Reijonen H, Novak EJ, Kochik S, Heninger A, Liu AW, Kwok WW et al. Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects. Diabetes 2002; 51: 1375-1382.
25. Novak EJ, Liu AW, Nepom GT, Kwok WW. MHC class II tetramers identify peptide-specific human CD4(+) T cells proliferating in response to influenza A antigen. J Clin Invest 1999; 104: R63-R67.
26. Durinovic-Bello I, Schlosser M, Riedl M, Maisel N, Rosinger S, Kalbacher H et al. Pro-and anti-inflammatory cytokine production by autoimmune T cells against preproinsulin in HLA-DRB1*04, DQ8 type 1 diabetes. Diabetologia 2004; 47: 439-450.
27. Gersuk VH, Nepom GT. A real-time PCR approach for rapid high resolution subtyping of HLA-DRB1*04. J Immunol Methods 2006; 317: 64-70.
28. Durinovic-Bello I, Jelinek E, Schlosser M, Eiermann T, Boehm BO, Karges W et al. Class III alleles at the insulin VNTR polymorphism are associated with regulatory T-cell responses to proinsulin epitopes in HLA-DR4, DQ8 individuals. Diabetes 2005; 54(Suppl 2): S18-S24.
29. James EA, LaFond R, Durinovic-Bello I, Kwok W. Visualizing antigen specific CD4+ T cells using MHC class II tetramers. J Vis Exp 2009; 25.