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Pathophysiology of Type 1 Diabetes

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Abstract

This chapter reviews the etiopathogenesis of type 1 diabetes, which includes genetic (such as a strong association with HLA haplotypes, genetic linkage with immune system genes), immunological (such as specificity for beta cells and the presence of antigen-specific T cells), environmental factors (such as age at onset) and gut microbiota. Since type 1 diabetes onset is triggered by an inappropriate activation of both the innate and adaptive immune systems, which causes a cascade that results in pancreatic islet destruction, and invariant natural killer T (NKT) cells interact with both systems, we will also discuss their role in the physiopathology of this disease. It should be noted that there are many opportunities for further study in this area, in both pediatric and adult populations and in various ethnicities.

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References

  1. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383(9911):69–82.

    Article  PubMed  Google Scholar 

  2. Todd JA, Bell JI, McDevitt HO. HLA-DQ gene contributes to susceptibility and resistance to IDDM. Nature. 1987;329:599–604.

    Article  CAS  PubMed  Google Scholar 

  3. Undlien DE, Lie BA, Thorsby E. HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Trends Genet. 2001;17:93–100.

    Article  CAS  PubMed  Google Scholar 

  4. Caillat-Zucman S, Garchon HJ, Timsit J, et al. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J Clin Invest. 1992;90:2242–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Knip M, Siljander H. Autoimmune mechanisms in type 1 diabetes. Autoimmun Rev. 2008;7:550–7.

    Article  CAS  PubMed  Google Scholar 

  6. Lambert AP, Gillespie KM, Thomson G, et al. Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. J Clin Endocrinol Metab. 2004;89:4037–43.

    Article  CAS  PubMed  Google Scholar 

  7. Dorman JS, McCarthy B, McCanlies E, et al. Molecular IDDM epidemiology: international studies. WHO DiaMond Molecular Epidemiology Sub-Project Group. Diabetes Res Clin Pract. 1996;34 Suppl:S107–16.

    Article  CAS  PubMed  Google Scholar 

  8. Notkins AL. Immunologic and genetic factors in type 1 diabetes. J Biol Chem. 2002;277:43545–8.

    Article  CAS  PubMed  Google Scholar 

  9. Erlich HA, Zeidler A, Chang J, et al. HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families. Nat Genet. 1993;3:358–64.

    Article  CAS  PubMed  Google Scholar 

  10. Godoresky C, Olivares A, Debezo H, et al. MHC-dependent molecular mechanisms of susceptibility and protection in type 1 diabetes in Mexicans. Gac Med Mex. 1995;131:395–402.

    Google Scholar 

  11. Thorsby E, Gjertsen HA, Lundin KE, Rønningen KS. Insulin dependent diabetes mellitus susceptibility or protection may be determined by certain HLA-DQ molecules. Bailliere Clin Endocrinol Metab. 1991;5:361–73.

    Article  CAS  Google Scholar 

  12. Vicario JL, Martinez-Laso J, Corell A, et al. Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as type 1 (insulin-dependent) diabetes mellitus predictive risk markers in the Spanish population. Diabetologia. 1992;35:475–81.

    Article  CAS  PubMed  Google Scholar 

  13. Eisenbarth GS. Banting lecture 2009: an unfinished journey: molecular pathogenesis to prevention of type 1A diabetes. Diabetes. 2010;59:759–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Thomson G, Robinson W, Kuhner M, et al. HLA and insulin gene associations with IDDM. Genet Epidemiol. 1989;6:155–60.

    Article  CAS  PubMed  Google Scholar 

  15. Bennett ST, Lucassen AM, Gough SCL, et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet. 1995;9:284–92.

    Article  CAS  PubMed  Google Scholar 

  16. Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984;33:176–83.

    Article  CAS  PubMed  Google Scholar 

  17. Todd JA, Farrall M. Panning for gold: genome-wide scanning for linkage in type 1 diabetes. Hum Mol Genet. 1995;5:1443–8.

    Article  Google Scholar 

  18. Pugliese A, Miceli D. The insulin gene in diabetes. Diabetes Metab Res Rev. 2002;18:13–25.

    Article  CAS  PubMed  Google Scholar 

  19. Davies JL, Kawaguchi Y, Bennett ST, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994;371:130–6.

    Article  CAS  PubMed  Google Scholar 

  20. Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36:337–8.

    Article  CAS  PubMed  Google Scholar 

  21. Thompson WS, Pekalski ML, Simons HZ, et al. Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes. Clin Exp Immunol. 2014;177:571–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Marron MP, Zeidler A, Raffel LJ, et al. Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33. Diabetes. 2000;49:492–9.

    Article  CAS  PubMed  Google Scholar 

  23. Ueda H, Howson JMM, Esposito L, et al. Association of the T cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423:506–11.

    Article  CAS  PubMed  Google Scholar 

  24. Tang W, Cui D, Jiang L, et al. Association of common polymorphisms in the IL2RA gene with type 1 diabetes: evidence of 32,646 individuals from 10 independent studies. J Cell Mol Med. 2015;19:2481–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Liu S, Wang H, Jin Y, et al. IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum Mol Genet. 2009;18:358–65.

    Article  CAS  PubMed  Google Scholar 

  26. Maziarz M, Hagopian W, Palmer JP, Swedish Childhood Diabetes Register, et al. Diabetes incidence in Sweden study group; type 1 diabetes genetics consortium. Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies. Genes Immun. 2015;16:541–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. http://www.t1base.org/page/Welcome/display. Accessed 9 Dec 2016.

  28. Mannering SI, Pathiraja V, Kay TW. The case for an autoimmune aetiology of type 1 diabetes. Clin Exp Immunol. 2016;183:8–15.

    Article  CAS  PubMed  Google Scholar 

  29. Foulis AK, Liddle CN, Farquharson MA, et al. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25 years review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia. 1986;29:267–74.

    Article  CAS  PubMed  Google Scholar 

  30. Willcox A, Richardson SJ, Bone AJ, et al. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol. 2009;155:173–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Barcala Tabarrozzi AE, Castro CN, Dewey RA, et al. Cell-based interventions to halt autoimmunity in type 1 diabetes mellitus. Clin Exp Immunol. 2013;171:135–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pugliese A. Insulitis in the pathogenesis of type 1 diabetes. Pediatr Diabetes. 2016;17(Suppl 22):31–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Krogvold L, Wiberg A, Edwin B, et al. Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia. 2016;59:492–501.

    Article  CAS  PubMed  Google Scholar 

  34. Zubkiewicz-Kucharska A, Noczyńska A. Abnormal distribution of gamma-delta T lymphocytes and their subsets in type 1 diabetes. Adv Clin Exp Med. 2016;25:665–71.

    Article  PubMed  Google Scholar 

  35. Lundberg M, Krogvold L, Kuric E, et al. Expression of interferon-stimulated genes in insulitic pancreatic islets of patients recently diagnosed with type 1 diabetes. Diabetes. 2016;65:3104–10.

    Article  CAS  PubMed  Google Scholar 

  36. von Herrath MG, Korsgren O, Atkinson MA. Factors impeding the discovery of an intervention-based treatment for type 1 diabetes. Clin Exp Immunol. 2016;183(1):1–7.

    Article  CAS  Google Scholar 

  37. Hannirn A, Jalkanen S, Salmi M, et al. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest. 1992;90:1901–10.

    Article  Google Scholar 

  38. Imagawa A, Hanafusa T, Tamura S, et al. Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes. Close correlation between serological markers and a histological evidence of cellular autoimmunity. Diabetes. 2001;50:1269–73.

    Article  CAS  PubMed  Google Scholar 

  39. Rabinovitch A, Suares-Pinzon WL, Sorensen O, et al. INF-γ gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice. J Immunol. 1995;154:4878–82.

    Google Scholar 

  40. Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulin- dependent) diabetes mellitus in ma-macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol. 1991;165:97–103.

    Article  CAS  PubMed  Google Scholar 

  41. Fowlkes BJ, Kruisbeek AM, Ton-That H, et al. A novel population of T-cell receptor alpha beta-bearing thymocytes which predominantly expresses a single V beta gene family. Nature. 1987;329:251–4.

    Article  CAS  PubMed  Google Scholar 

  42. Gomez-Tourino I, Arif S, Eichmann M, et al. T cells in type 1 diabetes: instructors, regulators and effectors: a comprehensive review. J Autoimmun. 2016;66:7–16.

    Article  CAS  PubMed  Google Scholar 

  43. Pathiraja V, Kuehlich JP, Campbell PD, et al. Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes. Diabetes. 2015;64:172–82.

    Article  CAS  PubMed  Google Scholar 

  44. Verge CF, Gianani R, Kawasaki E, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996;45:926–33.

    Article  CAS  PubMed  Google Scholar 

  45. Leslie D, Lipsky P, Notkins AL. Autoantibodies as predictors of disease. J Clin Invest. 2001;108:1417–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Wenzlau JM, Juhl K, Yu L, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A. 2007;104:17040–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Velluzzi F, Secci G, Sepe V, Sardinian Autoimmunity Study Group, et al. Prediction of type 1 diabetes in Sardinian schoolchildren using islet cell autoantibodies: 10-year follow-up of the Sardinian schoolchildren type 1 diabetes prediction study. Acta Diabetol. 2016;53(1):73–9.

    Article  CAS  PubMed  Google Scholar 

  48. Von Herrath MG, Holz A, Homann D, et al. Role of viruses in type I diabetes. Semin Immunol. 1998;10:87–100.

    Article  Google Scholar 

  49. Hyoty H, Hiltunen M, Reuranen A, et al. Decline of mumps antibodies in type 1(insulin-dependent) diabetic children with a plateau in the rising incidence of type 1 diabetes after introduction of the mumps-measles-rubella vaccine in Finland. Diabetologia. 1993;36:1303–8.

    Article  CAS  PubMed  Google Scholar 

  50. McIntosh EDG, Menser M. A fifty-year follow-up of congenital rubella. Lancet. 1992;340:414–5.

    Article  CAS  PubMed  Google Scholar 

  51. Tavares RG, Trevisol RB, Comerlato J, et al. Enterovirus infections and type 1 diabetes mellitus: is there any relationship? J Venom Anim Toxins Incl Trop Dis. 2012;18:3–15.

    Article  CAS  Google Scholar 

  52. de Beeck AO, Eizirik DL. Viral infections in type 1 diabetes mellitus – why the β cells? Nat Rev Endocrinol. 2016;12:263–73.

    Article  PubMed Central  CAS  Google Scholar 

  53. Petzold A, Solimena M, Knoch KP. Mechanisms of Beta cell dysfunction associated with viral infection. Curr Diab Rep. 2015;15:73.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Seewaldt S, Thomas HE, Ejrnaes M, et al. Virus-induced autoimmune diabetes: most beta-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes. 2000;49:1801–9.

    Article  CAS  PubMed  Google Scholar 

  55. Honeyman MC, Stone NL, Falk BA, Nepom G, Harrison LC. Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens. J Immunol. 2010;15(184):2204–10.

    Article  Google Scholar 

  56. Cooke A. Review series on helminths, immune modulation and the hygiene hypothesis: how might infection modulate the onset of type 1 diabetes? Immunology. 2009;126:12–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ylipaasto P, Klingel K, Lindberg AM, et al. Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia. 2004;47:225–39.

    Article  CAS  PubMed  Google Scholar 

  58. Krogvold L, Edwin B, Buanes T, et al. Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study. Diabetologia. 2014;57:841–3.

    Article  PubMed  Google Scholar 

  59. Oikarinen S, Tauriainen S, Hober D, VirDiab Study Group, et al. Virus antibody survey in different European populations indicates risk association between coxsackie virus B1 and type 1 diabetes. Diabetes. 2014;63:655–62.

    Article  CAS  PubMed  Google Scholar 

  60. Laitinen OH, Honkanen H, Pakkanen O, et al. Coxsackievirus B1 is associated with induction of β-cell autoimmunity that portends type 1 diabetes. Diabetes. 2014;63:446–55.

    Article  CAS  PubMed  Google Scholar 

  61. Rodriguez-Calvo T, von Herrath MG. Enterovirus infection and type 1 diabetes: closing in on a link? Diabetes. 2015;64:1503–5.

    Article  CAS  PubMed  Google Scholar 

  62. Nucci AM, Virtanen SM, Becker DJ. Infant feeding and timing of complementary foods in the development of type 1 diabetes. Curr Diab Rep. 2015;15:62.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Griebler U, Bruckmüller MU, Kien C, et al. Health effects of cow’s milk consumption in infants up to 3 years of age: a systematic review and meta-analysis. Public Health Nutr. 2016;19:293–307.

    Article  PubMed  Google Scholar 

  64. Krishna CS, Srikanta S. Type 1 diabetes pathogenesis – prevention??? Indian J Endocrinol Metab. 2015;19(Suppl 1):S58–63.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Lamb MM, Miller M, Seifert JA, et al. The effect of childhood cow’s milk intake and HLA-DR genotype on risk of islet autoimmunity and type 1 diabetes: the diabetes autoimmunity study in the young. Pediatr Diabetes. 2015;16:31–8.

    Article  CAS  PubMed  Google Scholar 

  66. Liu C, Lu M, Xia X, et al. Correlation of serum vitamin D level with type 1 diabetes mellitus in children: a meta-analysis. Nutr Hosp. 2015;32:1591–4.

    CAS  PubMed  Google Scholar 

  67. Mäkinen M, Mykkänen J, Koskinen M, et al. Serum 25-hydroxyvitamin D concentrations in children progressing to autoimmunity and clinical type 1 diabetes. J Clin Endocrinol Metab. 2016;101:723–9.

    Article  PubMed  CAS  Google Scholar 

  68. Talaat IM, Nasr A, Alsulaimani AA, et al. Association between type 1, type 2 cytokines, diabetic autoantibodies and 25-hydroxyvitamin D in children with type 1 diabetes. J Endocrinol Investig. 2016;39(12):1425–34.

    Article  CAS  Google Scholar 

  69. Gianchecchi E, Fierabracci A. On the pathogenesis of insulin-dependent diabetes mellitus: the role of microbiota. Immunol Res. 2017;65(1):242–56.

    Article  CAS  PubMed  Google Scholar 

  70. Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, Queipo-Ortuño MI. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 2013;11:46. https://doi.org/10.1186/1741-7015-11-46.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Mejía-León ME, Petrosino JF, Ajami NJ, Domínguez-Bello MG, de la Barca AM. Fecal microbiota imbalance in Mexican children with type 1 diabetes. Sci Rep. 2014;4:3814. https://doi.org/10.1038/srep03814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Armougom F, Henry M, Vialettes B, Raccah D, Raoult D. Monitoring bacterial community of human gut microbiota reveals an increase in lactobacillus in obese patients and methanogens in anorexic patients. PLoS One. 2009;4(9):e7125. https://doi.org/10.1371/journal.pone.0007125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Uusitalo U, Liu X, Yang J, TEDDY Study Group, et al. Association of early exposure of probiotics and islet autoimmunity in the TEDDY study. JAMA Pediatr. 2016;170(1):20–8.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Tard C, Rouxel O, Lehuen A. Regulatory role of natural killer T cells in diabetes. Biom J. 2015;38:484–95.

    Google Scholar 

  75. Porcelli S, Yockey CE, Brenner MB, et al. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several Vß genes and an invariant TCR alpha chain. J Exp Med. 1993;178:1–16.

    Article  CAS  PubMed  Google Scholar 

  76. Lantz O, Bendelac A. An invariant T cell receptor alpha chain is used by a unique subset of MHC class I-specific CD4+ and CD4-8- T cells in mice and humans. J Exp Med. 1994;180:1097–106.

    Article  CAS  PubMed  Google Scholar 

  77. Baxter AG, Hammond KJ, Scollay R, et al. Association between alphabeta TCR+CD-CD- T-cell deficiency and IDMM in NOD/Lt mice. Diabetes. 1997;46:572–82.

    Article  CAS  PubMed  Google Scholar 

  78. Kronenberg M, Gapin L. The unconventional lifestyle of NKT cells. Nat Rev Immunol. 2002;2:557–8.

    Article  CAS  PubMed  Google Scholar 

  79. Naumov YN, Bahjat KS, Gausling R, et al. Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets. Proc Natl Acad Sci U S A. 2001;98:13838–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hammond KJ, Pellicci DG, Poulton LD, et al. CD1d-restricted NKT cells: an interstrain comparison. J Immunol. 2001;167:1164–73.

    Article  CAS  PubMed  Google Scholar 

  81. Lehuen A, Lantz O, Beaudoin L, et al. Overexpression of natural killer T cells protects Va14-Ja281 transgenic nonobese mice against diabetes. J Exp Med. 1998;188:1831–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Falcone M, Brian Y, Tucker L, et al. A defect in interleukin 12-induced activation and interferon-gamma secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanism for insulin-dependent diabetes mellitus. J Exp Med. 1999;190:963–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Poulon LD, Smyth MJ, Hawke CG, et al. Cytometric and functional analysis of NK- and NKT cell deficiencies in NOD mice. Int Immunol. 2001;13:887–96.

    Article  Google Scholar 

  84. Berzins SP, Kyparissoudis K, Pellicci DG, et al. Systemic NKT cell deficiency in NOD mice is not detected in peripheral blood: implications for human studies. Immunol Cell Biol. 2004;82:247–52.

    Article  PubMed  Google Scholar 

  85. Wagner MJD, Hussain S, Mehan M, et al. A defect in lineage fate decision during fetal thymic invariant NKT cell development may regulate susceptibility to type 1 diabetes. J Immunol. 2005;174:6764–71.

    Article  CAS  PubMed  Google Scholar 

  86. Carnaud C, Gombert J, Donnars O, et al. Protection against diabetes and improved NK/NKT cell performance in NOD.NK1.1 mice congenic at the NK complex. J Immunol. 2001;166:2404–11.

    Article  CAS  PubMed  Google Scholar 

  87. Esteban LM, Tsoutsman T, Jordan MA, et al. Genetic control of NKT cell numbers maps to major diabetes and lupus loci. J Immunol. 2003;171:2873–8.

    Article  CAS  PubMed  Google Scholar 

  88. Rocha-Campos AC, Melki R, Zhu R, et al. Genetic and functional analysis of the Nkt1 locus using congenic NOD mice: improved Vα14-NKT cell performance but failure to protect against type 1 diabetes. Diabetes. 2006;55:1163–70.

    Article  CAS  PubMed  Google Scholar 

  89. Kent S, Chen Y, Clemmings SM, et al. Loss of IL-4 secretion from human type 1a diabetic pancreatic draining lymph node NKT cells. J Immunol. 2005;175:4458–64.

    Article  CAS  PubMed  Google Scholar 

  90. Kukreja A, Cost G, Marker J, et al. Multiple immuno-regulatory defects in type 1 diabetes. J Clin Invest. 2002;109:131–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rodacki M, Svoren B, Butty V, et al. Altered natural killer cells in type 1 diabetic patients. Diabetes. 2007;56:177–85.

    Article  CAS  PubMed  Google Scholar 

  92. Janos K, Engelmann P, Farkas K, et al. Reduced CD4- subset and Th1 bias of the human iNKT cells in type 1 diabetes mellitus. J Leukoc Biol. 2006;81:654–62.

    Google Scholar 

  93. Roman-Gonzalez A, Moreno ME, Alfaro JM, et al. Frequency and function of circulating invariant NKT cells in autoimmune diabetes mellitus and thyroid diseases in Colombian patients. Human Immunol. 2009;70:262–8.

    Article  CAS  Google Scholar 

  94. Montoya CJ, Pollard D, Martinson J, et al. Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11. Immunology. 2007;122:1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ortiz-Navarrete V, Canche-Pool E, Gómez-Díaz R, et al. CRTAM molecule is expressed at the cell surface of NKT cells from patients with type 1 diabetes mellitus. Clin Immunol. 2009;131:S145.

    Article  Google Scholar 

  96. Beristain-Covarrubias N, Canche-Pool E, Gomez-Diaz R, et al. Reduced iNKT cells numbers in type 1 diabetes patients and their first-degree relatives. Immun Inflamm Dis. 2015;3:411–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gómez-Díaz RA, Aguilar MV, Meguro EN, et al. The role of natural killer T (NKT) cells in the pathogenesis of type 1 diabetes. Curr Diabetes Rev. 2011;7:278–83.

    Article  PubMed  Google Scholar 

  98. Beristain-Covarrubias N, Canche-Pool EB, Ramirez-Velazquez C, et al. Class I-restricted T cell-associated molecule is a Marker for IFN-γ-producing iNKT cells in healthy subjects and patients with type 1 diabetes. J Interf Cytokine Res. 2017;37(1):39–49.

    Article  CAS  Google Scholar 

  99. Lombardi G, Burzyn D, Mundiñiano J, et al. Cathepsin-L influences the expression of extracellular matrix in lymphoid organs and plays a role in the regulation of thymic output and of peripheral T cell number. J Immunol. 2005;174:7022–32.

    Article  CAS  PubMed  Google Scholar 

  100. Gómez-Díaz RA, Medina-Santillán R, Castro Magdonel BE, et al. Association of NKT cells with expression of the CTSL gene in Mexican pediatric population with recently-diagnosed type 1 diabetes. Gac Med Mex. 2016;152:14–21.

    PubMed  Google Scholar 

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Glossary

Anti-GAD

Antibodies against glutamic acid decarboxylase

Anti-IA2

Anti-tyrosine

CRTAM

Class I-restricted T cell-associated molecule

CTLA-4

Cytotoxic T-lymphocyte antigen

CTSL

Cathepsin-L lysosomal protease

IA2

Insulinoma antigen 2

ICOS

Inducible gene costimulatory molecule

IFIH1

Induced interferon with dominion 1 helicase C

IFN-δ

Interferon gamma

IL2RA

Interleukin-2 receptor alpha chain

ISGs

Interferon-stimulated genes

MHC

Major histocompatibility complex

NKT

Natural killer lymphocyte-type

NOD

Non-obese diabetic mouse models

PTPN22

Protein tyrosine phosphatase, non-receptor type 22

T1D

Type 1 diabetes

TCR

Receptor for T lymphocyte antigen

WHO

World Health Organization

ZnT8

Zinc cation transporter

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Gómez-Díaz, R.A. (2019). Pathophysiology of Type 1 Diabetes. In: Rodriguez-Saldana, J. (eds) The Diabetes Textbook. Springer, Cham. https://doi.org/10.1007/978-3-030-11815-0_7

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