Jump to ContentJump to Main Navigation
Show Summary Details

Acta Medica Martiniana

The Journal of Comenius University in Bratislava

3 Issues per year

Open Access
See all formats and pricing

Genetic Determination and Immunopathogenesis of Type 1 Diabetes Mellitus in Humans

D. Kantarova
  • Department of Internal Medicine, Jessenius Faculty of Medicine and University Hospital, Comenius University, Martin
/ M. Vrlik
  • Martin Centre of Immunology, Martin
/ M. Buc
  • Department of Immunology, Faculty of Medicine, Comenius University, Bratislava, Slovakia
Published Online: 2012-09-11 | DOI: https://doi.org/10.2478/v10201-011-0034-4

Genetic Determination and Immunopathogenesis of Type 1 Diabetes Mellitus in Humans

Type 1 diabetes comprises autoimmune-mediated and idiopathic beta-cell destruction of the pancreatic islets of Langerhans resulting to absolute insulin deficiency. Susceptibility to T1D is influenced by both genetic and environmental factors. It is generally believed that environmental agents, such as viral infections, dietary factors in early infancy or climatic influences, trigger disease development in genetically susceptible individuals. Many candidate regions for diabetes genes have been reported, the insulin, glutamic acid 65, insuloma associated antigen 2, and zinc transporter ZnT8 genes being among the most important. The destruction of b cells is mediated mainly by cellular mechanisms; antibodies seem to reflect the ongoing autoimmune process only, not being directly involved in tissue damage. They, however, appear prior to the onset of insulin deficiency what makes us to profit from in prevention of the disease.

Keywords: type 1 diabetes mellitus; autoantigens; autoantibodies; regulatory T cells; HLA alleles

  • ADA. Diagnosis and classification of diabetes mellitus. Diabetes care 2010; 33 (Suppl 1): S62-69.

  • Aguilera E, Casamitjana R, Ercilla, G, Oriola J, Gomis R, Conget I. Adult-onset atypical (type 1) diabetes: additional insights and differences with type 1A diabetes in a European Mediterranean population. Diabetes Care 2004; 27: 1108-1114.

  • Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 2001; 358: 221-229.

  • Todd JA, Knip M, Mathieu C. Strategies for the prevention of autoimmune type 1 diabetes. Diabet Med 2011; 28: 1141-1143. [Crossref] [PubMed]

  • Kantarova D, Buc M. Genetic susceptibility to type 1 diabetes mellitus in humans. Physiol Res 2007; 56: 255-266.

  • Maier LM, Wicker LS. Genetic susceptibility to type 1 diabetes. Curr Opin Immunol 2005; 17: 601-608. [PubMed] [Crossref]

  • Todd JA. Etiology of type 1 diabetes. Immunity 2010; 32: 457-467. [PubMed] [Crossref]

  • Jahromi MM, Eisenbarth GS. Genetic determinants of type 1 diabetes across populations. Ann New York Acad Sci 2006; 1079: 289-299.

  • Eisenbart GS. Diabetes and related autoimmune disease. 1035-1053. In: Rich RE (ed). Clinical Immunology. Principles and Practice. 3rd ed. Philadelphia; Elsevier, 2008.

  • Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. New Engl J Med 2009; 360: 1646-1654.

  • Nepom GT. HLA and type I diabetes. In: Lechler R, Warrens A (eds): HLA in health and disease. New York, Boston, London, Sydney, Tokyo, San Diego, San Francisco: Academic Press; 2000. p. 231-237.

  • Buc M, Bucova M, Javor J, Krivosikova M, Stuchlikova M, Shawkatova I, Michalkova D, Barak L, Jancova E, Petrek M. Associations between HLA class II alleles and type 1 diabetes mellitus in the Slovak population. Endocrine Regulations 2006; 40: 1-6. [PubMed]

  • Concannon P, Erlich HA, Julier C, Morahan G, Nerup J, Pociot F, Todd JA, Rich SS. Type 1 diabetes: evidence for susceptibility loci from four genome-wide linkage scans in 1,435 multiplex families. Diabetes 2005; 54: 2995-3001.

  • Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity 2010; 32: 468-478. [Crossref] [PubMed]

  • Noble JA, Valdes AM, Thomson G, Erlich HA. The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes. Diabetes 2000; 49: 121-125.

  • Stuchlikova M, Kantarova D, Michalkova D, Barak L, Buc M. Association of HLA-DPB1 alleles with type I diabetes mellitus in Slovak population. Bratislava Med J 2006; 107: 73-75.

  • Valdes AM, Noble JA, Genin E, Clerget-Darpoux F, Erlich HA, Thomson G. Modeling of HLA class II susceptibility to Type I diabetes reveals an effect associated with DPB1. Genetic Epidemiol 2001; 21: 212-223.

  • Santamaria P. The long and winding road to understanding and conquering type 1 diabetes. Immunity 2010; 32: 437-445. [Crossref]

  • Durinovic-Bello I, Wu RP, Gersuk VH, Sanda S, Shilling HG, Nepom GT. Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin. Genes Immunity 2010; 11: 188-193. [Crossref]

  • Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow, DB, Hunter KM, Smith AN, Di Genova G. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423: 506-511.

  • Atabani SF, Thio CL, Divanovic S, Trompette A, Belkaid Y, Thomas D, Karp CL. Association of CTLA4 polymorphism with regulatory T cell frequency. Eur J Immunol 2005; 35: 2157-2162.

  • Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M et a. (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genetics 3: 337-338 [PubMed]

  • Smyth D, Cooper JD, Collins JE, Heward JM, Franklyn JA, Howson JM, Vella A, Nutland S, Rance HE, Maier L. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004; 53: 3020-3023.

  • Long SA, Cerosaletti K, Bollyky PL, Tatum M, Shilling H, Zhang S, Zhang, ZY, Pihoker C, Sanda S, Greenbaum C, Buckner JH. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+)CD25(+) regulatory T-cells of type 1 diabetic subjects. Diabetes 2010; 59: 407-415.

  • Vella A, Cooper JD, Lowe CE, Walker N, Nutland S, Widmer B, Jones R, Ring, SM, McArdle W, Pembrey ME. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Human Genet 2005; 76: 773-779.

  • Dendrou CA, Plagnol V, Fung E, Yang JH, Downes K, Cooper JD, Nutland S, Coleman G, Himsworth M, Hardy M. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nature Genet 209; 41: 1011-1015.

  • Dendrou CA, Wicker LS. The IL-2/CD25 pathway determines susceptibility to T1D in humans and NOD mice. J Clin Immunol 2008; 28: 685-696.

  • Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nature Rev Immunol 2010; 10: 490-500. [Crossref]

  • Sandor F, Buc M. Toll-like receptors. I. Structure, function and their ligands. Folia Biol 2005; 51: 148-157.

  • Svoren BM, Volkening LK, Wood JR, Laffel LM. Significant vitamin D deficiency in youth with type 1 diabetes mellitus. J Pediatrics 2009; 154: 132-134. [Crossref]

  • Winkler C, Lauber C, Adler K, Grallert H, Illig T, Ziegler AG, Bonifacio E. An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes. Diabetes 2011; 60: 685-690.

  • Witso E, Tapia G, Cinek O, Pociot FM, Stene LC, Ronningen KS. Polymorphisms in the innate immune IFIH1 gene, frequency of enterovirus in monthly fecal samples during infancy, and islet autoimmunity. PloS One 2011; 6: e27781.

  • Salminen K, Sadeharju, K, Lonnrot M, Vahasalo P, Kupila A, Korhonen S, Ilonen J, Simell O, Knip M, Hyoty H. Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study. J Med Virol 2003; 69: 91-98.

  • Yoon JW, Austin M, Onodera T, Notkins AL. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. The New England journal of medicine 1979; 300: 1173-1179.

  • Kukreja A, Maclaren NK. Autoimmunity and diabetes. J Clin Endocrinol Metabolism 1999; 84: 4371-4378. [Crossref]

  • Heino L, Lonnrot M, Knip M, Kupila A, Erkkila S, Toivonen A, Vahasalo P, Ilonen, J, Simell O, Hyoty H. No evidence of abnormal regulation of antibody response to coxsackievirus B4 antigen in prediabetic children. Clin Exp Immunol 2001; 126: 432-436. [Crossref]

  • Horwitz MS, Bradley LM, Harbertson J, Krahl T, Lee J, Sarvetnick N. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nature Med 1998; 4: 781-785. [Crossref]

  • Hoe E, McKay FC, Schibeci SD, Gandhi K, Heard RN, Stewart GJ, Booth DR. Functionally significant differences in expression of disease-associated IL-7 receptor alpha haplotypes in CD4 T cells and dendritic cells. J Immunol 2010; 184: 2512-2517.

  • Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes, K, Yang JH, Howson JM, Stevens H, McManus R, Wijmenga C. Shared and distinct genetic variants in type 1 diabetes and celiac disease. New Engl J Med 2008; 359: 2767-2777.

  • Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. Philadelphia; 7. Saunders, Elsevier, 2012: 545.

  • Buc M. Basic and Clinical immunology. Bratislava; Veda, 2012, in press (in Slovak).

  • Stadinski B, Kappler J, Eisenbarth GS. Molecular targeting of islet autoantigens. Immunity 2010; 32: 446-456. [Crossref] [PubMed]

  • Achenbach P, Bonifacio E, Ziegler AG. Predicting type 1 diabetes. Curr Diabetes Rep 2005; 5: 98-103. [Crossref]

  • Haskins K, Bradley B, Powers K, Fadok V, Flores S, Ling X. Pugazhenthi S, Reusch, J, Kench J. Oxidative stress in type 1 diabetes. Ann New York Acad Sci 2003; 1005: 43-54.

  • Kent SC, Chen Y, Bregoli L, Clemmings SM, Kenyon NS, Ricordi C, Hering BJ, Hafler DA. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature 2005; 435: 224-228.

  • Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 2005;23: 447-485. [PubMed] [Crossref]

  • Miyazaki A, Hanafusa T, Yamada K, Miyagawa J, Fujino-Kurihara H, Nakajima H, Nonaka K, Tarui S. Predominance of T lymphocytes in pancreatic islets and spleen of pre-diabetic non-obese diabetic (NOD) mice: a longitudinal study. Clin Exp Immunol 1985; 60: 622-630. [PubMed]

  • Christianson SW, Shultz LD, Leiter EH. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 1993; 42: 44-55.

  • Like AA, Biron CA, Weringer EJ, Byman K, Sroczynski E, Guberski DL. Prevention of diabetes in BioBreeding/Worcester rats with monoclonal antibodies that recognize T lymphocytes or natural killer cells. J Exp Med 1986; 164, 1145-1159.

  • Groen H, Klatter F, Pater J, Nieuwenhuis P, Rozing J. Temporary, but essential requirement of CD8+ T cells early in the pathogenesis of diabetes in BB rats as revealed by thymectomy and CD8 depletion. Clin Develop Immunol 2003; 10: 141-151. [Crossref]

  • Wu Q, Salomon B, Chen M, Wang Y, Hoffman LM, Bluestone J.A, Fu YX. Reversal of spontaneous autoimmune insulitis in nonobese diabetic mice by soluble lymphotoxin receptor. J Exp Med 2001; 193: 1327-1332.

  • Gommerman JL, Browning JL. Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nature Rev Immunol 2003; 3: 642-655. [Crossref]

  • Valdes AM, Thomson G, Barcellos LF. Genetic variation within the HLA class III influences T1D susceptibility conferred by high-risk HLA haplotypes. Genes Immunity 2010; 11: 209-218. [Crossref]

  • Link M, Salur L, Kisand K, Rajasalu T, Tillmann V, Uibo R. Higher FoxP3 mRNA expression in peripheral blood mononuclear cells of GAD65 or IA-2 autoantibody-positive compared with autoantibody-negative persons. Apmis 2008; 116: 896-902.

  • Luczynski W, Stasiak-Barmuta A, Urban R, Urban M, Florys B, Hryszko M. Lower percentages of T regulatory cells in children with type 1 diabetes - preliminary report. Pediatric Endocrinol, Diabetes Metabolism 2009; 15: 34-38.

  • Vrabelova Z, Hrotekova Z, Hladikova Z, Bohmova K, Stechova K, Michalek J. CD 127- and FoxP3+ expression on CD25+CD4+ T regulatory cells upon specific diabetogeneic stimulation in high-risk relatives of type 1 diabetes mellitus patients. Scand J Immunol 2008; 67: 404-410.

  • Long SA, Walker MR, Rieck M, James E, Kwok WW, Sanda S, Pihoker C, Greenbaum C, Nepom GT, Buckner JH. Functional islet-specific Treg can be generated from CD4+CD25- T cells of healthy and type 1 diabetic subjects. Eur J Immunol 2009; 39: 612-620.

  • Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, Atkinson MA, Bluestone JA. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 2009; 58: 652-662. [PubMed]

  • Schneider A, Rieck M, Sanda S, Pihoker C, Greenbaum C, Buckner JH. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J Immunol 2008; 181: 7350-7355.

  • Ferencik M, Stvrtinova V, Hulin I, Novak M. Inflammation - a lifelong companion. Attempt at a non-analytical holistic view. Folia Microbiol 2007; 52: 159-173. [Crossref]

  • Robles DT, Eisenbarth GS. Diabetes and related autoimmune diseases. In: Rich RR (ed.) Clinical Immunology, Principles and Practice, 2nd edn. London, Edinburg, New York, Philadelphia, St. Louis, Sydney, Toronto; Mosby, 2001. p. 82. 1-82. 8.

  • Luo X, Herold KC, Miller SD. Immunotherapy of type 1 diabetes: where are we and where should we be going? Immunity 2010; 32: 488-499. [PubMed] [Crossref]

  • Flodstrom M, Maday A, Balakrishna D, Cleary MM, Yoshimura A, Sarvetnick N. Target cell defense prevents the development of diabetes after viral infection. Nature Immunol 2002; 3: 373-382. [Crossref]

  • Kukreja A, Costi G, Marker J, Zhang CH, Sinha S, Sun Z, Maclaren N. NKT cell defects in NOD mice suggest therapeutic opportunities. J Autoimmunity 2002; 19: 117-128. [Crossref]

  • Oikawa Y, Shimada A, Yamada S, Motohash, Y, Nakagawa Y, Irie J, Maruyama T, Saruta T. High frequency of valpha24(+) vbeta11(+) T-cells observed in type 1 diabetes. Diabetes Care 2002; 25: 1818-1823. [Crossref]

  • Diana J, Gahzarian L, Simoni Y, Lehuen A. Innate immunity in type 1 diabetes. Discovery Med 2011; 11: 513-520.

  • Serreze DV, Chapman HD, Varnum DS, Hanson MS, Reifsnyder PC, Richard SD, Fleming SA, Leiter EH, Shultz LD. B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new "speed congenic" stock of NOD. Ig mu null mice. J Exp Med 1996; 184: 2049-2053.

  • Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland, R, Gottlieb PA, Marks JB, McGee PF, Moran AM. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. New Engl J Med 2009; 361: 2143-2152.

  • Hu CY, Rodriguez-Pinto D, Du W, Ahuja A, Henegariu O, Wong FS, Shlomchik, MJ, Wen L. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J Clin Inv 2007; 117: 3857-3867. [Crossref]

  • Bingley PJ, Gale EA. Progression to type 1 diabetes in islet cell antibody-positive relatives in the European Nicotinamide Diabetes Intervention Trial: the role of additional immune, genetic and metabolic markers of risk. Diabetologia 2006; 49: 881-890. [PubMed]

  • Hummel M, Bonifacio E, Schmid S, Walter M, Knopff A, Ziegler AG. Brief communication: early appearance of islet autoantibodies predicts childhood type 1 diabetes in offspring of diabetic parents. Ann Int Med 2004; 140:882-886.

  • Hanzu F, Gomis R. Autoimmune diabetes mellitus. In: Shoenfeld Y, Cervera R, Gerschwin ME (eds) Diagnostic criteria in autoimmune diseases. Totowa; Hamana Press, 2008. p. 241-249.

  • Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth, GS, Jensen J, Davidson HW, Hutton JC. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Nat Acad Sci USA 2007; 104: 17040-17045. [Crossref]

Published Online: 2012-09-11

Published in Print: 2012-08-01

Citation Information: Acta Medica Martiniana. Volume 12, Issue 2, Pages 19–31, ISSN (Print) 1335-8421, DOI: https://doi.org/10.2478/v10201-011-0034-4, September 2012

This content is open access.

Comments (0)

Please log in or register to comment.