Diabetes pp 62-75 | Cite as

Impairment of Immune Systems in Diabetes

  • Christopher Ting
  • Vivek Bansal
  • Ibrahim Batal
  • Marwan Mounayar
  • Lola Chabtini
  • Ghania El Akiki
  • Jamil Azzi
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


Type 1 diabetes mellitus (T1DM) is an autoimmune disease that involves the progressive destruction of the insulin-producing β cells in the islets of langerhans. It is a complex process that results from the loss of tolerance to insulin and other β-cell-specific antigens. Various genetic and environmental factors have been studied so far, but precise causation has yet to be established. Numerous studies in rodents and human subjects have been performed in order to elucidate the role of B and T cells, which determine the risk of development and progression of diabetes. These studies have demonstrated that while T1DM is fundamentally a T-cell-mediated autoimmune response, the development of this disease results from complex interactions between the adaptive and innate immune systems, with numerous cell types thought to contribute to pathogenesis. Like any complex disease, the variation in severity and incidence of T1DM can be attributed to a combination of genetic and environmental factors.


Major Histocompatibility Complex Natural Killer Cell Beta Cell Human Leukocyte Antigen Major Histocompatibility Complex Molecule 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lorenzen T, Pociot F, Hougaard P et al. Long-term risk of IDDM in first-degree relatives of patients with IDDM. Diabetologia 1994; 37(3):321–327.PubMedCrossRefGoogle Scholar
  2. 2.
    Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and complications (EDIC) study. JAMA 2003; 290(16):2159–2167.Google Scholar
  3. 3.
    Centers for Disease control and Prevention. National Diabetes fact Sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and human Services, Centers for Disease Control and Prevention, 2011.Google Scholar
  4. 4.
    Harjutsalo V, Sjoberg L, Tuomilehto J. Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet 2008; 371(9626):1777–1782.Google Scholar
  5. 5.
    Bluestone JA, Herold K, Eisenbarth G. Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 2010; 464(7293):1293–1300.PubMedCrossRefGoogle Scholar
  6. 6.
    Imagawa A, Hanafusa T, Miyagawa J et al. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. N Engl J Med 2000; 342(5):301–307.PubMedCrossRefGoogle Scholar
  7. 7.
    Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Annu rev Immunol 2005; 23:447–485.PubMedCrossRefGoogle Scholar
  8. 8.
    Lehuen A, Diana J, Zaccone P et al. Immune cell crosstalk in type 1 diabetes. Nat rev Immunol 2010; 10(7):501–513.PubMedCrossRefGoogle Scholar
  9. 9.
    Knip M. Natural course of preclinical type 1 diabetes. Horm Res 2002; 57Suppl 1:6–11.PubMedCrossRefGoogle Scholar
  10. 10.
    Knip M, Veijola R, Virtanen SM et al. Environmental Triggers and determinants of type 1 diabetes. Diabetes 2005; 54Suppl 2:S125–S136.PubMedCrossRefGoogle Scholar
  11. 11.
    Eizirik DL, Colli ML, Ortis F. The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol 2009; 5(4):219–226.PubMedCrossRefGoogle Scholar
  12. 12.
    Hober D, Sauter P. Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host. Nat Rev Endocrinol 2010; 6(5):279–289.PubMedCrossRefGoogle Scholar
  13. 13.
    Faustman DL, Davis M. The primacy of CD8 T-lymphocytes in type 1 diabetes and implications for therapies. J Mol Med (Berl) 2009; 87(12):1173–1178.CrossRefGoogle Scholar
  14. 14.
    Pietropaolo M, Surhigh JM, Nelson PW et al. Primer: immunity and autoimmunity. Diabetes 2008; 57(11):2872–2882.PubMedCrossRefGoogle Scholar
  15. 15.
    Hoglund_P, Mintern J, Waltzinger C et al. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J Exp Med 1999; 189(2):331–339.PubMedCrossRefGoogle Scholar
  16. 16.
    Cobbold_S, Waldmann H. Infectious Tolerance. Curr Opin Immunol 1998; 10(5):518–524.PubMedCrossRefGoogle Scholar
  17. 17.
    Zheng XX, Sanchez-fueyo A, Sho M et al. Favorably tipping the balance between cytopathic and regulatory T-cells to create transplantation tolerance. Immunity 2003; 19(4):503–514.PubMedCrossRefGoogle Scholar
  18. 18.
    Lindley S, Dayan CM, Bishop A et al. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005; 54(1):92–99.PubMedCrossRefGoogle Scholar
  19. 19.
    Klinke DJ 2nd. Extent of beta cell destruction is important but insufficient to predict the onset of type 1 diabetes mellitus. PLoS One 2008; 3(1):e1374.PubMedCrossRefGoogle Scholar
  20. 20.
    Wong FS, Wen L. B-cells in autoimmune diabetes. Rev Diabet Stud 2005; 2(3):121–135.PubMedCrossRefGoogle Scholar
  21. 21.
    Concannon_P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009; 360(16): 1646–1654.PubMedCrossRefGoogle Scholar
  22. 22.
    Lennon GP, Bettini M, Burton AR et al. T-cell islet accumulation in type 1 diabetes is a tightly regulated, cell-autonomous event. Immunity 2009; 31(4):643–653.PubMedCrossRefGoogle Scholar
  23. 23.
    Ranheim EA, Kipps TJ. Activated T-cells induce expression of B7/BB1 on normal or leukemic B-cells through a CD40-dependent signal. J Exp Med 1993; 177(4):925–935.PubMedGoogle Scholar
  24. 24.
    Gardner JM, Fletcher AL, Anderson MS et al. AIRE in the thymus and beyond. Curr Opin Immunol 2009; 21(6):582–589.PubMedCrossRefGoogle Scholar
  25. 25.
    Liston A, Lesage S, Wilson J et al. Aire regulates negative selection of organ-specific T-cells. Nat Immunol 2003;4(4):350–354.PubMedCrossRefGoogle Scholar
  26. 26.
    Lieberman SM, DiLorenzo TP. A comprehensive guide to antibody and t-cell responses in type 1 diabetes. Tissue Antigens 2003; 62(5):359–377.PubMedCrossRefGoogle Scholar
  27. 27.
    Hyttinen V, Kaprio J, kinnunen L et al. Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs: a nationwide follow-up study. Diabetes 2003; 52(4): 1052–1055.PubMedCrossRefGoogle Scholar
  28. 28.
    Pociot F, Aakolkar B, Concannon P et al. Genetics of type 1 diabetes: what’s next? Diabetes 2010; 59(7):1561–1571.PubMedCrossRefGoogle Scholar
  29. 29.
    Erlich H, Valdes AM, Noble J et al. HLA Dr-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 2008; 57(4): 1084–1092.PubMedCrossRefGoogle Scholar
  30. 30.
    Turley S, Poirot L, Hattori M et al. Physiological beta cell death triggers priming of self-reactive t-cells by dendritic cells in a type-1 diabetes model. J Exp Med 2003; 198(10):1527–1537.PubMedCrossRefGoogle Scholar
  31. 31.
    Wen L, Ley RE, Volchkov PY et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 2008; 455(7216):1109–1113.PubMedCrossRefGoogle Scholar
  32. 32.
    Dooms H, Abbas Ak. Control of CD4+ t-cell memory by cytokines and costimulators. Immunol Rev 2006; 211:23–38.PubMedCrossRefGoogle Scholar
  33. 33.
    Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat rev Immunol 2002; 2(2):116–126.PubMedCrossRefGoogle Scholar
  34. 34.
    Vincenti F, Larsen C, Durrbach A et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med 2005; 353(8):770–781.PubMedCrossRefGoogle Scholar
  35. 35.
    Heit JJ, Apelqvist AA, Gu X et al. Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function. Nature 2006; 443(7109):345–349.PubMedCrossRefGoogle Scholar
  36. 36.
    Kukreja A, Cost G, Marker J et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 2002;109(1):131–140.PubMedGoogle Scholar
  37. 37.
    Cameron MJ, Arreaza GA, Zucker P et al. IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 1997; 159(10):4686–4692.PubMedGoogle Scholar
  38. 38.
    Feuerer M, Hill JA, Mathis D et al. Foxp3+ regulatory T-cells: differentiation, specification, subphenotypes. Nat Immunol 2009; 10(7):689–695.PubMedCrossRefGoogle Scholar
  39. 39.
    Tang Q, Henriksen KJ, Bi M et al. In vitro-expanded antigen-specific regulatory T-cells suppress autoimmune diabetes. J Exp Med 2004; 199(11): 1 55-1465.Google Scholar
  40. 40.
    Schneider A, Rieck M, Sanda S et al. The effector T-cells of diabetic subjects are resistant to regulation via cD4+ foXP3+ regulatory T-cells. J Immunol 2008; 181(10):7350–7355.PubMedGoogle Scholar
  41. 41.
    Tang Q, Adams JY, Penaranda C et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 2008; 28(5):687–697.PubMedCrossRefGoogle Scholar
  42. 42.
    Tang Q, Bluestone JA. The Foxp3+regulatory T-cell: ajackof all trades, master of regulation. Nat Immunol 2008; 9(3):239–244.PubMedCrossRefGoogle Scholar
  43. 43.
    Lund FE, Randall TD. Effector and regulatory B-cells: modulators of CD4(+) T-cell immunity. Nat rev Immunol 2010; 10(4):236–247.PubMedCrossRefGoogle Scholar
  44. 44.
    Hu CY, Rodriguez-Pinto D, Du W et al. Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice. J clin Invest 2007; 117(12):3857–3867.PubMedCrossRefGoogle Scholar
  45. 45.
    Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H et al. Rituximab, B-lymphocyte depletion, andpreservation of beta-cell function. N Engl J Med 2009; 361(22):2143–2152.PubMedCrossRefGoogle Scholar
  46. 46.
    Martin S, Wolf-Eichbaum D, Duinkerken G et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N Engl J Med 2001; 345(14):1036–1040.PubMedCrossRefGoogle Scholar
  47. 47.
    Martin AP, Rankin S, Pitchford S et al. Increased expression of CCL2 in insulin-producing cells of transgenic mice promotes mobilization of myeloid cells from the bone marrow, marked insulitis, and diabetes. Diabetes 2008; 57(11):3025–3033.PubMedCrossRefGoogle Scholar
  48. 48.
    Yang LJ. Big mac attack: does it play a direct role for monocytes/macrophages in type 1 diabetes? Diabetes 2008; 57(11):2922–2923.PubMedCrossRefGoogle Scholar
  49. 49.
    Bradshaw EM, Raddassi K, Elyaman W et al. Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells. J Immunol 2009; 183(7):4432–4439.PubMedCrossRefGoogle Scholar
  50. 50.
    Tisch R, Wang B. Role of plasmacytoid dendritic cells in type 1 diabetes: friend or foe? Diabetes 2009; 58(1):12–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Marleau AM, Summers KL, Singh B. Differential contributions of APC subsets to T-cell activation in nonobese diabetic mice. J Immunol 2008; 180(8):5235–5249.PubMedGoogle Scholar
  52. 52.
    Ohnmacht C, Pullner A, King SBT et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T-cells and results in spontaneous fatal autoimmunity. J Exp Med 2009; 206(3):549–559.PubMedCrossRefGoogle Scholar
  53. 53.
    Ueno H, Klechevsky E, Morita R et al. Dendritic cell subsets in health and disease. Immunol Rev 2007; 219:118–142.PubMedCrossRefGoogle Scholar
  54. 54.
    Cnop M, Welsh N, Jonas JC et al. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 2005; 54Suppl 2:S97–S107.PubMedCrossRefGoogle Scholar
  55. 55.
    Brauner H, Elemans M, Lemos S et al. Distinct phenotype and function of Nk cells in the pancreas of nonobese diabetic mice. J Immunol 2010; 184(5):2272–2280.PubMedCrossRefGoogle Scholar
  56. 56.
    Dotta F, Censini S, van Halteren AG et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci USA 2007; 104(12):5115–5120.PubMedCrossRefGoogle Scholar
  57. 57.
    Gur C, Porgador A, Elboim M et al. The activating receptor Nkp46 is essential for the development of type 1 diabetes. Nat Immunol 2010; 11(2):121–128.PubMedCrossRefGoogle Scholar
  58. 58.
    Flodstrom M, Maday A, Balakrishna D et al. Target cell defense prevents the development of diabetes after viral infection. Nat Immunol 2002; 3(4):373–382.PubMedCrossRefGoogle Scholar
  59. 59.
    Poirot L, Benoist C, Mathis D. Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc Natl acad Sci USA 2004; 101(21):8102–8107.PubMedCrossRefGoogle Scholar
  60. 60.
    Alba A, Planas R, Clemente X et al. Natural killer cells are required for accelerated type 1 diabetes driven by interferon-beta. Clin Exp Immunol 2008; 151(3):467–475.PubMedCrossRefGoogle Scholar
  61. 61.
    Ogasawara K, Hamerman JA, Hsin H et al. Impairment of Nk cell function by NkG2D modulation in NOD mice. Immunity 2003; 18(1):41–51.PubMedCrossRefGoogle Scholar
  62. 62.
    Lee IF, Qin H, Trudeau J et al. Regulation of autoimmune diabetes by complete Freund’s adjuvant is mediated by Nk cells. J Immunol 2004; 172(2):937–942.PubMedGoogle Scholar
  63. 63.
    Beilke JN, Kuhl NR, Van Kaer L et al. NK cells promote islet allograft tolerance via a perforin-dependent mechanism. Nat Med 2005; 11(10): 1059–1065.PubMedCrossRefGoogle Scholar
  64. 64.
    Novak J, Griseri T, Beaudoin L et al. Regulation of type 1 diabetes by NKT cells. Int rev Immunol 2007; 26(1–2):49–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Beaudoin L, Laloux V, Novak J et al. NKT cells inhibit the onset of diabetes by impairing the development of pathogenic T-cells specific for pancreatic beta cells. Immunity 2002; 17(6):725–736.PubMedCrossRefGoogle Scholar
  66. 66.
    Dost a, Herbst a, Kintzel K et al. Shorter remission period in young versus older children with diabetes mellitus type 1. Exp Clin Endocrinol Diabetes 2007; 115(1):33–37.PubMedCrossRefGoogle Scholar
  67. 67.
    Vauzelle-Kervroedan F, Delcourt C, Forhan A et al. Analysis of mortality in French diabetic patients from death certificates: a comparative study. Diabetes Metab 1999; 25(5):404–411.Google Scholar
  68. 68.
    Kaprio J, Tuomilehto J, Kkoskenvuo M et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 1992;35(11):1060–1067.PubMedCrossRefGoogle Scholar
  69. 69.
    Sabbah E, Savola K, Ebeling T et al. Genetic, autoimmune, and clinical characteristics of childhood-and adult-onset type 1 diabetes. Diabetes care 2000; 23(9):1326–1332.Google Scholar
  70. 70.
    Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes 2008; 57(10):2555–2562.PubMedCrossRefGoogle Scholar
  71. 71.
    Jaidane H, Sane F, Gharbi J et al. Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models. Diabetes Metab Res Rev 2009; 25(7):591–603.PubMedCrossRefGoogle Scholar
  72. 72.
    Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002; 347(12):911–920.PubMedCrossRefGoogle Scholar
  73. 73.
    Goldberg E, Krause I. Infection and type 1 diabetes mellitus—a two edged sword? Autoimmun Rev 2009; 8(8):682–686.PubMedCrossRefGoogle Scholar
  74. 74.
    Christen U, von Herrath MG. Do viral infections protect from or enhance type 1 diabetes and how can we tell the difference? Cell Mol Immunol 2011; 8(3):193–198.PubMedCrossRefGoogle Scholar
  75. 75.
    Roivainen M, Ylipaasto P, Savolainen C et al. Functional impairment and killing of human beta cells by enteroviruses: the capacity is shared by a wide range of serotypes, but the extent is a characteristic of individual virus strains. Diabetologia 2002; 45(5):693–702.PubMedCrossRefGoogle Scholar
  76. 76.
    Hyoty H. Enterovirus infections and type 1 diabetes. Ann Med 2002; 34(3):138–147.PubMedGoogle Scholar
  77. 77.
    Haverkos HW, Battula N, Drotman DP et al. Enteroviruses andtype 1 diabetes mellitus. Biomed Pharmacother 2003; 57(9):379–385.PubMedCrossRefGoogle Scholar
  78. 78.
    Yin H, Berg AK, Tuvemo T et al. Enterovirus RNA is found in peripheral blood mononuclear cells in a majority of type 1 diabetic children at onset. Diabetes 2002; 51(6):1964–1971.PubMedCrossRefGoogle Scholar
  79. 79.
    Sarmiento L, Cabrera-rode E, Lekuleni L et al. Occurrence of enterovirus RNA in serum of children with newly diagnosed type 1 diabetes and islet cell autoantibody-positive subjects in a population with a low incidence of type 1 diabetes. Autoimmunity 2007; 40(7):540–545.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2013

Authors and Affiliations

  • Christopher Ting
    • 1
  • Vivek Bansal
    • 2
  • Ibrahim Batal
    • 1
  • Marwan Mounayar
    • 1
  • Lola Chabtini
    • 1
  • Ghania El Akiki
    • 2
  • Jamil Azzi
    • 1
  1. 1.Transplantation Research Center, Renal Division, BrighamWomen’s Hospital and Children’s Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Harvard Medical SchoolBeth Israel Deaconess HospitalBostonUSA

Personalised recommendations