Type 1 diabetes mellitus (T1DM) results from the destruction of pancreatic β-cells that is mediated by the immune system. Multiple genetic and environmental factors found in variable combinations in individual patients are involved in the development of T1DM. Genetic risk is defined by the presence of particular allele combinations, which in the major susceptibility locus (the HLA region) affect T cell recognition and tolerance to foreign and autologous molecules. Multiple other loci also regulate and affect features of specific immune responses and modify the vulnerability of β-cells to inflammatory mediators. Compared with the genetic factors, environmental factors that affect the development of T1DM are less well characterized but contact with particular microorganisms is emerging as an important factor. Certain infections might affect immune regulation, and the role of commensal microorganisms, such as the gut microbiota, are important in the education of the developing immune system. Some evidence also suggests that nutritional factors are important. Multiple islet-specific autoantibodies are found in the circulation from a few weeks to up to 20 years before the onset of clinical disease and this prediabetic phase provides a potential opportunity to manipulate the islet-specific immune response to prevent or postpone β-cell loss. The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments.
The incidence of type 1 diabetes mellitus in childhood has increased, and the age at diagnosis has decreased due to environmental changes during the last half of the twentieth century.
Inherited defects in central and peripheral immune tolerance allow the generation of autoimmune responses directed against pancreatic islets.
Environmental factors that modify the immune system, such as microbiota composition, microbial infections and nutrition, affect the development and course of the autoimmune response.
Type 1 diabetes mellitus is a heterogeneous disease with multiple different features, but two major pathways can be discerned with either insulin autoantibodies or glutamic acid decarboxylase autoantibodies as the first autoantibody indicating initiation of the autoimmune process.
Multiple trials aiming to prevent development of the disease in different phases of the autoimmune process are ongoing or being planned.
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Buzzetti, R., Zampetti, S. & Maddaloni, E. Adult-onset autoimmune diabetes: current knowledge and implications for management. Nature Rev. Endocrinol. 13, 674–686 (2017).
Harjutsalo, V., Sjöberg, L. & Tuomilehto, J. Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet 371, 1777–1782 (2008).
Songini, M., Mannu, C., Targhetta, C. & Bruno, G. Type 1 diabetes in Sardinia: facts and hypotheses in the context of worldwide epidemiological data. Acta Diabetol 54, 9–17 (2017).
Rawshani, A. et al. The incidence of diabetes among 0-34 year olds in Sweden: new data and better methods. Diabetologia 57, 1375–1381 (2014).
Dabelea, D. et al. Incidence of diabetes in youth in the United States. J. Am. Med. Assoc. 297, 2716–2724 (2007).
Patterson, C. C. et al. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study. Diabetologia 62, 408–417 (2018).
Gale, E. A. The rise of childhood type 1 diabetes in the 20th century. Diabetes 51, 3353–3361 (2002).
Karvonen, M. et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 23, 1516–1526 (2000).
Tuomi, T. et al. The many faces of diabetes: a disease with increasing heterogeneity. Lancet 383, 1084–1094 (2014).
Thomas, N. J. et al. Frequency and phenotype of type 1 diabetes in the first six decades of life: a cross-sectional, genetically stratified survival analysis from UK Biobank. Lancet Diabetes Endocrinol 6, 122–129 (2018).
Robertson, C. C. & Rich, S. S. Genetics of type 1 diabetes. Curr. Opin. Genet. Dev. 50, 7–16 (2018).
Ziegler, A. G. et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. J. Am. Med. Assoc. 309, 2473–2479 (2013).
Onkamo, P., Väänänen, S., Karvonen, M. & Tuomilehto, J. Worldwide increase in incidence of type I diabetes—the analysis of the data on published incidence trends. Diabetologia 42, 1395–1403 (1999).
Rewers, M. & Ludvigsson, J. Environmental risk factors for type 1 diabetes. Lancet 387, 2340–2348 (2016).
Ilonen, J. et al. Patterns of β-cell autoantibody appearance and genetic associations during the first years of life. Diabetes 62, 3636–3640 (2013).
Lempainen, J. et al. Non-HLA gene effects on the disease process of type 1 diabetes: from HLA susceptibility to overt disease. J. Autoimmun. 61, 45–53 (2015).
Giannopoulou, E. Z. et al. Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes. Diabetologia 58, 2317–2323 (2015).
Krischer, J. P. et al. Genetic and environmental interactions modify the risk of diabetes-related autoimmunity by 6 years of age: the TEDDY study. Diabetes Care 40, 1194–1202 (2017).
Erlich, H. et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 57, 1084–1092 (2008).
Thomson, G. et al. Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue Antigens 70, 110–127 (2007).
Kwok, W. W. et al. HLA-DQ molecules form alpha-beta heterodimers of mixed allotype. J. Immunol. 141, 3123–3127 (1988).
Todd, J. A. et al. Identification of susceptibility loci for insulin-dependent diabetes mellitus by trans-racial gene mapping. Nature 338, 587–589 (1989).
Hu, X. et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat Genet. 47, 898–905 (2015).
Nepom, G. T. A unified hypothesis for the complex genetics of HLA associations with IDDM. Diabetes 39, 1153–1157 (1990).
Matzaraki, V., Kumar, V., Wijmenga, C. & Zhernakova, A. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome Biol. 18, 76 (2017).
Klein, J. & Sato, A. The HLA system. First of two parts. N. Engl. J. Med. 343, 702–709 (2000).
Guilherme, L. & Kalil, J. Rheumatic fever: the T cell response leading to autoimmune aggression in the heart. Autoimmun Rev. 1, 261–266 (2002).
Ilonen, J. et al. Genetic susceptibility to type 1 diabetes in childhood — estimation of HLA class II associated disease risk and class II effect in various phases of islet autoimmunity. Pediatr. Diabetes 17 (Suppl. 22), 8–16 (2016).
Willcox, A., Richardson, S. J., Bone, A. J., Foulis, A. K. & Morgan, N. G. Analysis of islet inflammation in human type 1 diabetes. Clin. Exp. Immunol. 155, 173–181 (2009).
Nejentsev, S. et al. The effect of HLA-B allele on the IDDM risk defined by DRB1*04 subtypes and DQB1*0302. Diabetes 46, 1888–1892 (1997).
Nejentsev, S. et al. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A. Nature 450, 887–892 (2007).
Bilbao, J. R. et al. Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease. Genes Immun. 7, 550–554 (2006).
Noble, J. A. et al. HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium. Diabetes 59, 2972–2979 (2010).
Noble, J. A. et al. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am. J. Hum. Genet. 59, 1134–1148 (1996).
Mikk, M. L. et al. The association of the HLA-A*24:02, B*39:01 and B*39:06 alleles with type 1 diabetes is restricted to specific HLA-DR/DQ haplotypes in Finns. HLA 89, 215–224 (2017).
Mbunwe, E. et al. In antibody-positive first-degree relatives of patients with type 1 diabetes, HLA-A*24 and HLA-B*18, but not HLA-B*39, are predictors of impending diabetes with distinct HLA-DQ interactions. Diabetologia 56, 1964–1970 (2013).
Tait, B. D. et al. HLA genes associated with autoimmunity and progression to disease in type 1 diabetes. Tissue Antigens 61, 146–153 (2003).
Noble, J. A. & Erlich, H. A. Genetics of type 1 diabetes. Cold Spring Harb. Perspect. Med. 2, a007732 (2012).
Pugliese, A. 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. Nature Genet. 15, 293–297 (1997).
Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genet. 36, 337–338 (2004).
Pociot, F. & Lernmark, Å. Genetic risk factors for type 1 diabetes. Lancet 387, 2331–2339 (2016).
Lowe, C. E. et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat. Genet. 39, 1074–1082 (2007).
Ge, Y. & Concannon, P. Molecular-genetic characterization of common, noncoding UBASH3A variants associated with type 1 diabetes. Eur. J. Hum. Genet. 26, 1060–1064 (2018).
Barratt, B. J. et al. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 53, 1884–1889 (2004).
Brookes, K. J. The VNTR in complex disorders: the forgotten polymorphisms? A functional way forward? Genomics 101, 273–281 (2013).
Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15, 289–292 (1997).
Pociot, F. et al. Genetics of type 1 diabetes: what's next? Diabetes 59, 1561–1571 (2010).
Fierabracci, A. Type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED): a “rare” manifestation in a “rare” disease. Int. J. Mol. Sci. 17, E1106 (2016).
Barzaghi, F., Passerini, L. & Bacchetta, R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front. Immunol. 3, 211 (2012).
Hull, C. M., Peakman, M. & Tree, T. I. M. Regulatory T cell dysfunction in type 1 diabetes: what's broken and how can we fix it? Diabetologia 60, 1839–1850 (2017).
Bottini, N. & Peterson, E. J. Tyrosine phosphatase PTPN22: multifunctional regulator of immune signaling, development, and disease. Annu. Rev. Immunol. 32, 83–119 (2014).
Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J. A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).
Marroqui, L. et al. TYK2, a candidate gene for type 1 diabetes, modulates apoptosis and the innate immune response in human pancreatic β-cells. Diabetes 64, 3808–3817 (2015).
Ram, R. et al. Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility. J. Immunol. 196, 3043–3053 (2016).
Ram, R. & Morahan, G. Effects of type 1 diabetes risk alleles on immune cell gene expression. Genes 8, E167 (2017).
Lampasona, V. & Liberati, D. Islet autoantibodies. Curr. Diab. Rep. 16, 53 (2016).
Roep, B. O. & Peakman, M. Antigen targets of type 1 diabetes autoimmunity. Cold Spring Harb. Perspect. Med. 2, a007781 (2012).
McLaughlin, K. A. et al. Identification of tetraspanin-7 as a target of autoantibodies in type 1 diabetes. Diabetes 65, 1690–1698 (2016).
Ling, Q. et al. Risk of beta-cell autoimmunity presence for progression to type 1 diabetes: a systematic review and meta-analysis. J. Autoimmun. 86, 9–18 (2018).
Sosenko, J. M. Staging the progression to type 1 diabetes with prediagnostic markers. Curr. Opin. Endocrinol. Diabetes Obes. 23, 297–305 (2016).
Insel, R. A. et al. Staging presymptomatic type 1 diabetes: a Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 38, 1964–1974 (2015).
Knip, M., Selvenius, J., Siljander, H. & Veijola, R. Reclassification of asymptomatic beta cell autoimmunity: a critical perspective. Diabetologia 60, 39–42 (2017).
Vehik, K. et al. Reversion of β-cell autoimmunity changes risk of type 1 diabetes: TEDDY study. Diabetes Care 39, 1535–1542 (2016).
Hämäläinen, A. M. et al. Disease-associated autoantibodies during pregnancy and at birth in families affected by type 1 diabetes. Clin. Exp. Immunol. 126, 230–235 (2001).
Eising, S. et al. Danish children born with glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies at birth had an increased risk to develop type 1 diabetes. Eur. J. Endocrinol. 164, 247–252 (2011).
Lundgren, M., Lynch, K., Larsson, C. & Elding Larsson, H., Diabetes Prediction in Skåne study group. Cord blood insulinoma-associated protein 2 autoantibodies are associated with increased risk of type 1 diabetes in the population-based Diabetes Prediction in Skåne study. Diabetologia 58, 75–78 (2015).
Harjutsalo, V., Reunanen, A. & Tuomilehto, J. Differential transmission of type 1 diabetes from diabetic fathers and mothers to their offspring. Diabetes 55, 1517–1524 (2006).
Hinman, R. M. & Cambier, J. C. Role of B lymphocytes in the pathogenesis of type 1 diabetes. Curr. Diab. Rep. 14, 543 (2014).
van Montfoort, N. et al. Circulating specific antibodies enhance systemic cross-priming by delivery of complexed antigen to dendritic cells in vivo. Eur J. Immunol. 42, 598–606 (2012).
Pescovitz, M. D. et al. B-lymphocyte depletion with rituximab and β-cell function: two-year results. Diabetes Care 37, 453–459 (2014).
Gepts, W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14, 619–633 (1965).
Morgan, N. G. & Richardson, S. J. Fifty years of pancreatic islet pathology in human type 1 diabetes: insights gained and progress made. Diabetologia 61, 2499–2506 (2018).
Krogvold, L. et al. Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia 59, 492–501 (2016).
Foulis, A. K., Liddle, C. N., Farquharson, M. A., Richmond, J. A. & Weir, R. S. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 29, 267–274 (1986).
Campbell-Thompson, M. et al. Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes 65, 719–731 (2016).
Leete, P. et al. Differential insulitic profiles determine the extent of β-cell destruction and the age at onset of type 1 diabetes. Diabetes 65, 1362–1369 (2016).
Richardson, S. J. et al. Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 59, 2448–2458 (2016).
Imagawa, A. & Hanafusa, T. Fulminant type 1 diabetes—an important subtype in East Asia. Diabetes Metab. Res. Rev. 27, 959–964 (2011).
Iijima, T. et al. Circulating CD4+PD-1+ and CD8+PD-1+ T cells are profoundly decreased at the onset of fulminant type 1 diabetes and are restored by treatment, contrasting with CD4+CD25+FoxP3+ regulatory T cells. Diabetes Res. Clin. Pract. 133, 10–12 (2017).
Herold, K. C. et al. Validity and reproducibility of measurement of islet autoreactivity by T-cell assays in subjects with early type 1 diabetes. Diabetes 58, 2588–2595 (2009).
Danke, N. A., Yang, J., Greenbaum, C. & Kwok, W. W. Comparative study of GAD65-specific CD4+ T cells in healthy and type 1 diabetic subjects. J. Autoimmun. 25, 303–311 (2005).
Skowera, A. et al. β-cell-specific CD8 T cell phenotype in type 1 diabetes reflects chronic autoantigen exposure. Diabetes 64, 916–925 (2015).
Kent, S. C., Mannering, S. I., Michels, A. W. & Babon, J. A. B. Deciphering the pathogenesis of human type 1 diabetes (T1D) by interrogating T cells from the “scene of the crime”. Curr. Diab. Rep. 17, 95 (2017).
Coppieters, K. T. et al. Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J. Exp. Med. 209, 51–60 (2012).
Pathiraja, V. et al. Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes. Diabetes 64, 172–182 (2015).
Babon, J. A. et al. Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nature Med. 22, 1482–1487 (2016).
Nguyen, H. & James, E. A. Immune recognition of citrullinated epitopes. Immunology 149, 131–138 (2016).
Sollid, L. M. The roles of MHC class II genes and post-translational modification in celiac disease. Immunogenetics 69, 605–616 (2017).
James, E. A., Pietropaolo, M. & Mamula, M. J. Immune recognition of β-cells: neoepitopes as key players in the loss of tolerance. Diabetes 67, 1035–1042 (2018).
Delong, T. et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351, 711–714 (2016).
Radenkovic, M. et al. Characterization of resident lymphocytes in human pancreatic islets. Clin. Exp. Immunol. 187, 418–427 (2017).
Kuric, E. et al. Demonstration of tissue resident memory CD8 T cells in insulitic lesions in adult patients with recent-onset type 1 diabetes. Am. J. Pathol. 187, 581–588 (2017).
Rodriguez-Calvo, T., Ekwall, O., Amirian, N., Zapardiel-Gonzalo, J. & von Herrath, M. G. Increased immune cell infiltration of the exocrine pancreas: a possible contribution to the pathogenesis of type 1 diabetes. Diabetes 63, 3880–3890 (2014).
Kondrashova, A. et al. Exocrine pancreas function decreases during the progression of the beta-cell damaging process in young prediabetic children. Pediatr. Diabetes 19, 398–402 (2018).
Skog, O., Korsgren, S., Melhus, A. & Korsgren, O. Revisiting the notion of type 1 diabetes being a T-cell-mediated autoimmune disease. Curr. Opin. Endocrinol. Diabetes Obes. 20, 118–123 (2013).
Skog, O. & Korsgren, O. Aetiology of type 1 diabetes: physiological growth in children affects disease progression. Diabetes Obes. Metab. 20, 775–785 (2018).
Hermann, R. et al. Temporal changes in the frequencies of HLA genotypes in patients with type 1 diabetes—indication of an increased environmental pressure? Diabetologia 46, 420–425 (2003).
Gillespie, K. M. et al. The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 364, 1699–1700 (2004).
Vehik, K. et al. Trends in high-risk HLA susceptibility genes among Colorado youth with type 1 diabetes. Diabetes Care 31, 1392–1396 (2008).
Fourlanos, S. et al. The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 31, 1546–1549 (2008).
Söderström, U., Aman, J. & Hjern, A. Being born in Sweden increases the risk for type 1 diabetes — a study of migration of children to Sweden as a natural experiment. Acta Paediatr. 101, 73–77 (2012).
Oilinki, T., Otonkoski, T., Ilonen, J., Knip, M. & Miettinen, P. J. Prevalence and characteristics of diabetes among Somali children and adolescents living in Helsinki, Finland. Pediatr. Diabetes 13, 176–180 (2012).
Peled, A. et al. Immigration to Israel during childhood is associated with diabetes at adolescence: a study of 2.7 million adolescents. Diabetologia 60, 2226–2230 (2017).
Hussen, H. I., Persson, M. & Moradi, T. The trends and the risk of type 1 diabetes over the past 40 years: an analysis by birth cohorts and by parental migration background in Sweden. BMJ Open 3, e003418 (2013).
Hussen, H. I., Moradi, T. & Persson, M. The risk of type 1 diabetes among offspring of immigrant mothers in relation to the duration of residency in Sweden. Diabetes Care 38, 934–936 (2015).
Muntoni, S. et al. Incidence of insulin-dependent diabetes mellitus among Sardinian-heritage children born in Lazio region, Italy. Lancet 349, 160–162 (1997).
Ji, J., Hemminki, K., Sundquist, J. & Sundquist, K. Ethnic differences in incidence of type 1 diabetes among second-generation immigrants and adoptees from abroad. J. Clin. Endocrinol. Metab. 95, 847–850 (2010).
Craig, M. E., Nair, S., Stein, H. & Rawlinson, W. D. Viruses and type 1 diabetes: a new look at an old story. Pediatr. Diabetes 14, 149–158 (2013).
Dahlquist, G. Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis. Diabetologia 49, 20–24 (2006).
Laron, Z., Shamis, I., Nitzan-Kaluski, D. & Ashkenazi, I. Month of birth and subsequent development of type I diabetes (IDDM). J. Pediatr. Endocrinol. Metab. 12, 397–402 (1999).
Songini, M., Casu, A., Ashkenazi, I. & Laron, Z. Seasonality of birth in children (0-14 years) and young adults (0-29 years) with type 1 diabetes mellitus in Sardinia differs from that in the general population. the Sardinian Collaborative Group for Epidemiology of IDDM. J. Pediatr. Endocrinol. Metab. 14, 781–783 (2001).
Kahn, H. S. et al. Association of type 1 diabetes with month of birth among U.S. youth: the SEARCH for Diabetes in Youth study. Diabetes Care 32, 2010–2015 (2009).
Kordonouri, O., Shuga, N., Lewy, H., Ashkenazi, I. & Laron, Z. Seasonality of month of birth of children and adolescents with type 1 diabetes mellitus in Berlin differs from the general population. Eur. J. Pediatr. 161, 291–292 (2002).
Vaiserman, A. M. et al. Seasonality of birth in children and young adults (0-29 years) with type 1 diabetes in Ukraine. Diabetologia 50, 32–35 (2007).
Niewiesk, S. Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies. Front. Immunol. 5, 446 (2014).
Yoon, J. W., Austin, M., Onodera, T. & Notkins, A. L. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N. Engl. J. Med. 300, 1173–1179 (1979).
Ylipaasto, P. et al. Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia 47, 225–239 (2004).
Krogvold, L. et al. Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes 64, 1682–1687 (2015).
Busse, N. et al. Detection and localization of viral infection in the pancreas of patients with type 1 diabetes using short fluorescently-labelled oligonucleotide probes. Oncotarget 8, 12620–12636 (2017).
Richardson, S. J., Willcox, A., Bone, A. J., Foulis, A. K. & Morgan, N. G. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia 52, 1143–1151 (2009).
Alidjinou, E. K., Sané, F., Trauet, J., Copin, M. C. & Hober, D. Coxsackievirus B4 can infect human peripheral blood-derived macrophages. Viruses 7, 6067–6079 (2015).
Green, J., Casabonne, D. & Newton, R. Coxsackie B virus serology and type 1 diabetes mellitus: a systematic review of published case-control studies. Diabet Med. 21, 507–514 (2004).
Craig, M. E., Robertson, P., Howard, N. J., Silink, M. & Rawlinson, W. D. Diagnosis of enterovirus infection by genus-specific PCR and enzyme-linked immunosorbent assays. J. Clin. Microbiol. 41, 841–844 (2003).
Nairn, C., Galbraith, D. N., Taylor, K. W. & Clements, G. B. Enterovirus variants in the serum of children at the onset of type 1 diabetes mellitus. Diabet Med. 16, 509–513 (1999).
Federico, G. et al. Vitamin D status, enterovirus infection, and type 1 diabetes in Italian children/adolescents. Pediatr. Diabetes 19, 923–929 (2018).
Hiltunen, M. et al. Islet cell antibody seroconversion in children is temporally associated with enterovirus infections. Childhood Diabetes in Finland (DiMe) study group. J. Infect. Dis. 175, 554–560 (1997).
Lönnrot, M. et al. Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention study. Diabetes 49, 1314–1318 (2000).
Lönnrot, M. et al. Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) study group. J. Med. Virol. 61, 214–220 (2000).
Salminen, K. et al. Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study. J. Med. Virol. 69, 91–98 (2003).
Stene, L. C. et al. Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the diabetes and autoimmunity study in the young (DAISY). Diabetes 59, 3174–3180 (2010).
Honkanen, H. et al. Detection of enteroviruses in stools precedes islet autoimmunity by several months: possible evidence for slowly operating mechanisms in virus-induced autoimmunity. Diabetologia 60, 424–431 (2017).
Allen, D. W., Kim, K. W., Rawlinson, W. D. & Craig, M. E. Maternal virus infections in pregnancy and type 1 diabetes in their offspring: systematic review and meta-analysis of observational studies. Rev. Med. Virol. 28, e1974 (2018).
Hober, D. & Sauter, P. Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host. Nature Rev. Endocrinol. 6, 279–289 (2010).
Roivainen, M. 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 45, 693–702 (2002).
Lukashev, A. N. et al. Recombination in circulating enteroviruses. J. Virol. 77, 10423–10431 (2003).
Lukashev, A. N. et al. Recombination in circulating human enterovirus B: independent evolution of structural and non-structural genome regions. J. Gen. Virol. 86, 3281–3290 (2005).
Huang, S. W. et al. A selective bottleneck shapes the evolutionary mutant spectra of enterovirus A71 during viral dissemination in humans. J. Virol. 91, e01062–17 (2017).
Härkönen, T. et al. Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans. J. Med. Virol. 69, 426–440 (2003).
Honeyman, M. C., Stone, N. L., Falk, B. A., Nepom, G. & Harrison, L. C. Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens. J. Immunol. 184, 2204–2210 (2010).
Honeyman, M. C. et al. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 49, 1319–1324 (2000).
Blomqvist, M. et al. Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life. Clin. Exp. Immunol. 128, 511–515 (2002).
Perrett, K. P., Jachno, K., Nolan, T. M. & Harrison, L. C. Association of rotavirus vaccination with the incidence of type 1 diabetes in children. J. Am. Med. Assoc. Pediatr. 173, 280–282 (2019).
Rogers, M. A. M., Basu, T. & Kim, C. Lower incidence rate of type 1 diabetes after receipt of the rotavirus vaccine in the United States, 2001-2017. Sci. Rep. 9, 7727 (2019).
Vaarala, O., Jokinen, J., Lahdenkari, M. & Leino, T. Rotavirus vaccination and the risk of celiac disease or type 1 diabetes in Finnish children at early life. Pediatr. Infect. Dis. J. 36, 674–675 (2017).
Niegowska, M. et al. Recognition of ZnT8, proinsulin, and homologous MAP peptides in Sardinian children at risk of T1D precedes detection of classical islet antibodies. J. Diabetes Res. 2016, 5842701 (2016).
Vaarala, O. Leaking gut in type 1 diabetes. Curr. Opin. Gastroenterol. 24, 701–706 (2008).
Mäkelä, M. et al. Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin. J. Autoimmun. 27, 54–61 (2006).
Ahmed, T. et al. Circulating antibodies to common food antigens in Japanese children with IDDM. Diabetes Care 20, 74–76 (1997).
Jalonen, T. et al. Increased beta-lactoglobulin absorption during rotavirus enteritis in infants: relationship to sugar permeability. Pediatr. Res. 30, 290–293 (1991).
Bosi, E. et al. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49, 2824–2827 (2006).
Luopajärvi, K. et al. Enhanced levels of cow's milk antibodies in infancy in children who develop type 1 diabetes later in childhood. Pediatr. Diabetes 9, 434–441 (2008).
Ekman, I. et al. Early childhood CMV infection may decelerate the progression to clinical type 1 diabetes. Pediatr. Diabetes 20, 73–77 (2019).
Plot, L. et al. Infections may have a protective role in the etiopathogenesis of celiac disease. Ann. N. Y. Acad. Sci. 1173, 670–674 (2009).
Zhao, Q. & Elson, C. O. Adaptive immune education by gut microbiota antigens. Immunology 154, 28–37 (2018).
Knip, M. & Siljander, H. The role of the intestinal microbiota in type 1 diabetes mellitus. Nature Rev. Endocrinol. 12, 154–167 (2016).
Vatanen, T. et al. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell 165, 1551 (2016).
Giongo, A. et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5, 82–91 (2011).
de Goffau, M. C. et al. Fecal microbiota composition differs between children with β-cell autoimmunity and those without. Diabetes 62, 1238–1244 (2013).
Davis-Richardson, A. G. et al. Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. Front. Microbiol. 5, 678 (2014).
Brown, C. T. et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLOS ONE 6, e25792 (2011).
Davis-Richardson, A. G. & Triplett, E. W. A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetes. Diabetologia 58, 1386–1393 (2015).
Vatanen, T. et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature 562, 589–594 (2018).
Stewart, C. J. et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 562, 583–588 (2018).
Insel, R. & Knip, M. Prospects for primary prevention of type 1 diabetes by restoring a disappearing microbe. Pediatr. Diabetes 19, 1400–1406 (2018).
Uusitalo, U. et al. Association of early exposure of probiotics and islet autoimmunity in the TEDDY study. J. Am. Med. Assoc. Pediatr. 170, 20–28 (2016).
Zhao, G. et al. Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. Proc. Natl Acad. Sci. USA 114, E6166–E6175 (2017).
Iliev, I. D. & Leonardi, I. Fungal dysbiosis: immunity and interactions at mucosal barriers. Nat. Rev. Immunol. 17, 635–646 (2017).
Corbin, K. D. et al. Obesity in type 1 diabetes: pathophysiology, clinical impact and mechanisms. Endocr. Rev. 39, 629–663 (2018).
Carlsson, A. et al. Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden. Int. J. Obes. 36, 718–724 (2012).
Nucci, A. M., Virtanen, S. M. & Becker, D. J. Infant feeding and timing of complementary foods in the development of type 1 diabetes. Curr. Diab. Rep. 15, 62 (2015).
Niinistö, S. et al. Fatty acid status in infancy is associated with the risk of type 1 diabetes-associated autoimmunity. Diabetologia 60, 1223–1233 (2017).
Calder, P. C. Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim. Biophys. Acta 1851, 469–484 (2015).
Turroni, F. et al. Bifidobacteria and the infant gut: an example of co-evolution and natural selection. Cell Mol. Life Sci. 75, 103–118 (2018).
Beyerlein, A. et al. Timing of gluten introduction and islet autoimmunity in young children: updated results from the BABYDIET study. Diabetes Care 37, e194–195 (2014).
Norris, J. M. et al. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. J. Am. Med. Assoc. 290, 1713–1720 (2003).
Uusitalo, U. et al. Early infant diet and islet autoimmunity in the TEDDY study. Diabetes Care 41, 522–530 (2018).
Hakola, L. et al. Infant feeding in relation to the risk of advanced islet autoimmunity and type 1 diabetes in children with increased genetic susceptibility: a cohort study. Am. J. Epidemiol. 187, 34–44 (2018).
Colotta, F., Jansson, B. & Bonelli, F. Modulation of inflammatory and immune responses by vitamin D. J. Autoimmun. 85, 78–97 (2017).
Littorin, B. et al. Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: results from the nationwide Diabetes Incidence Study in Sweden (DISS). Diabetologia 49, 2847–2852 (2006).
Dong, J. Y. et al. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients 5, 3551–3562 (2013).
Simpson, M. et al. No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 54, 2779–2788 (2011).
Mäkinen, M. et al. Serum 25-hydroxyvitamin D concentrations in children progressing to autoimmunity and clinical type 1 diabetes. J. Clin. Endocrinol. Metab. 101, 723–729 (2016).
Norris, J. M. et al. Plasma 25-hydroxyvitamin D concentration and risk of islet autoimmunity. Diabetes 67, 146–154 (2018).
Uusitalo, L. et al. Serum alpha- and gamma-tocopherol concentrations and risk of advanced beta cell autoimmunity in children with HLA-conferred susceptibility to type 1 diabetes mellitus. Diabetologia 51, 773–780 (2008).
Sanna, A., Firinu, D., Zavattari, P. & Valera, P. Zinc status and autoimmunity: a systematic review and meta-analysis. Nutrients 10, E68 (2018).
Bahadoran, Z., Ghasemi, A., Mirmiran, P., Azizi, F. & Hadaegh, F. Nitrate-nitrite-nitrosamines exposure and the risk of type 1 diabetes: a review of current data. World J. Diabetes 7, 433–440 (2016).
Zhi, W. et al. Discovery and validation of serum protein changes in type 1 diabetes patients using high throughput two dimensional liquid chromatography-mass spectrometry and immunoassays. Mol. Cell Proteom. 10, M111.012203 (2011).
Zhang, Q. et al. Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes. J. Exp. Med. 210, 191–203 (2013).
Moulder, R. et al. Serum proteomes distinguish children developing type 1 diabetes in a cohort with HLA-conferred susceptibility. Diabetes 64, 2265–2278 (2015).
von Toerne, C. et al. Peptide serum markers in islet autoantibody-positive children. Diabetologia 60, 287–295 (2017).
Sorensen, C. M. et al. Perturbations in the lipid profile of individuals with newly diagnosed type 1 diabetes mellitus: lipidomics analysis of a diabetes antibody standardization program sample subset. Clin. Biochem. 43, 948–956 (2010).
Oresic, M. et al. Cord serum lipidome in prediction of islet autoimmunity and type 1 diabetes. Diabetes 62, 3268–3274 (2013).
Oresic, M. et al. Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. J. Exp. Med. 205, 2975–2984 (2008).
Lamichhane, S. et al. A longitudinal plasma lipidomics dataset from children who developed islet autoimmunity and type 1 diabetes. Sci. Data 5, 180250 (2018).
Beyersdorf, N. & Müller, N. Sphingomyelin breakdown in T cells: role in activation, effector functions and immunoregulation. Biol. Chem. 396, 749–758 (2015).
Campbell-Thompson, M. L. et al. The influence of type 1 diabetes on pancreatic weight. Diabetologia 59, 217–221 (2016).
Williams, A. J. et al. Pancreatic volume is reduced in adult patients with recently diagnosed type 1 diabetes. J. Clin. Endocrinol. Metab. 97, E2109–E2113 (2012).
Campbell-Thompson, M. L. et al. Relative pancreas volume is reduced in first-degree relatives of patients with type 1 diabetes. Diabetes Care 42, 281–287 (2019).
Bonnet-Serrano, F., Diedisheim, M., Mallone, R. & Larger, E. Decreased α-cell mass and early structural alterations of the exocrine pancreas in patients with type 1 diabetes: an analysis based on the nPOD repository. PLOS ONE 13, e0191528 (2018).
Koskinen, M. K. et al. Reduced β-cell function in early preclinical type 1 diabetes. Eur. J. Endocrinol. 174, 251–259 (2016).
Koskinen, M. K. et al. Class II HLA genotype association with first-phase insulin response is explained by islet autoantibodies. J. Clin. Endocrinol. Metab. 103, 2870–2878 (2018).
Sosenko, J. M. et al. Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants. Diabetes 62, 4179–4183 (2013).
Sims, E. K., Evans-Molina, C., Tersey, S. A., Eizirik, D. L. & Mirmira, R. G. Biomarkers of islet beta cell stress and death in type 1 diabetes. Diabetologia 61, 2259–2265 (2018).
Ilonen, J. et al. Primary islet autoantibody at initial seroconversion and autoantibodies at diagnosis of type 1 diabetes as markers of disease heterogeneity. Pediatr. Diabetes 19, 284–292 (2018).
Arif, S. et al. Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes 63, 3835–3845 (2014).
Gorus, F. K. et al. Twenty-year progression rate to clinical onset according to autoantibody profile, age, and HLA-DQ genotype in a registry-based group of children and adults with a first-degree relative with type 1 diabetes. Diabetes Care 40, 1065–1072 (2017).
Arif, S. et al. β-cell specific T-lymphocyte response has a distinct inflammatory phenotype in children with type 1 diabetes compared with adults. Diabet Med. 34, 419–425 (2017).
Krischer, J. P. et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia 58, 980–987 (2015).
Bosi, E. et al. Impact of age and antibody type on progression from single to multiple autoantibodies in type 1 diabetes relatives. J. Clin. Endocrinol. Metab. 102, 2881–2886 (2017).
Jacobsen, L. M. et al. Immune mechanisms and pathways targeted in type 1 diabetes. Curr. Diab. Rep. 18, 90 (2018).
Dupré, J. et al. Clinical trials of cyclosporin in IDDM. Diabetes Care 11 (Suppl. 1), 37–44 (1988).
Knip, M. et al. Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial. J. Am. Med. Assoc. 319, 38–48 (2018).
Winkler, C. et al. A strategy for combining minor genetic susceptibility genes to improve prediction of disease in type 1 diabetes. Genes Immun. 13, 549–555 (2012).
Sharp, S. A. et al. Development and standardization of an improved type 1 diabetes genetic risk score for use in newborn screening and incident diagnosis. Diabetes Care 42, 200–207 (2019).
Redondo, M. J. et al. A type 1 diabetes genetic risk score predicts progression of islet autoimmunity and development of type 1 diabetes in individuals at risk. Diabetes Care 41, 1887–1894 (2018).
Noble, J. A., Johnson, J., Lane, J. A. & Valdes, A. M. HLA class II genotyping of African American type 1 diabetic patients reveals associations unique to African haplotypes. Diabetes 62, 3292–3299 (2013).
Yasunaga, S., Kimura, A., Hamaguchi, K., Ronningen, K. S. & Sasazuki, T. Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). Tissue Antigens 47, 37–48 (1996).
Kawabata, Y. et al. Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. Diabetes 51, 545–551 (2002).
Varney, M. D. et al. HLA DPA1, DPB1 alleles and haplotypes contribute to the risk associated with type 1 diabetes: analysis of the type 1 diabetes genetics consortium families. Diabetes 59, 2055–2062 (2010).
Törn, C. et al. Role of type 1 diabetes-associated SNPs on risk of autoantibody positivity in the TEDDY study. Diabetes 64, 1818–1829 (2015).
Krischer, J. P. et al. The Influence of type 1 diabetes genetic susceptibility regions, age, sex, and family history on the progression from multiple autoantibodies to type 1 diabetes: a TEDDY study report. Diabetes 66, 3122–3129 (2017).
Bottini, N., Vang, T., Cucca, F. & Mustelin, T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin. Immunol. 18, 207–213 (2006).
Garg, G. et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J Immunol 188, 4644–4653 (2012).
de Jong, V. M. et al. Variation in the CTLA4 3' UTR has phenotypic consequences for autoreactive T cells and associates with genetic risk for type 1 diabetes. Genes Immun 17, 75–78 (2016).
Winkler, C. et al. An interferon-induced helicase (IFIH1) gene polymorphism associates with different rates of progression from autoimmunity to type 1 diabetes. Diabetes 60, 685–690 (2011).
Kaur, S. et al. The genetic and regulatory architecture of ERBB3-type 1 diabetes susceptibility locus. Mol. Cell Endocrinol. 419, 83–91 (2016).
Wang, H. et al. Genetically dependent ERBB3 expression modulates antigen presenting cell function and type 1 diabetes risk. PLOS ONE 5, e11789 (2010).
Santin, I. & Eizirik, D. L. Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis. Diabetes Obes. Metab. 15, 71–81 (2013).
Wiede, F., Sacirbegovic, F., Leong, Y. A., Yu, D. & Tiganis, T. PTPN2-deficiency exacerbates T follicular helper cell and B cell responses and promotes the development of autoimmunity. J. Autoimmun. 76, 85–100 (2017).
Fløyel, T. et al. CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. Proc. Natl Acad. Sci. USA 111, 10305–10310 (2014).
Smyth, D. J. et al. FUT2 nonsecretor status links type 1 diabetes susceptibility and resistance to infection. Diabetes 60, 3081–3084 (2011).
Marroquí, L. et al. BACH2, a candidate risk gene for type 1 diabetes, regulates apoptosis in pancreatic β-cells via JNK1 modulation and crosstalk with the candidate gene PTPN2. Diabetes 63, 2516–2527 (2014).
Sioofy-Khojine, A. B. et al. Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes. Diabetologia 61, 1193–1202 (2018).
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- Class II HLA region
The gene region where class II HLA genes encoding HLA-DR, HLA-DQ and HLA-DP molecules that present antigen epitopes to T cells are located.
Antibodies that recognize and bind an individual’s own proteins or tissue constituents.
- Antigenic cross-reaction
Antibodies or T cells that recognize two different molecules by their antigen-specific receptor.
- Molecular mimicry
Two different molecules have an antigenic structure resembling each other enough to allow antigenic cross-reaction.
The time period when a specific antibody develops and becomes detectable.
- Complement components
A number of small proteins that circulate in the blood as inactive components; after activation, they cause bacterial opsonization and lysis and attract inflammatory cells.
- Linkage disequilibrium
Allelic association, nonrandom association of alleles at two or more gene loci in the general population.
- Ectopic expression
An abnormal expression of a gene in a tissue where it is not usually expressed.
- Thymic education
T cells go through positive and negative selection where most of the T cell precursors that recognize autologous structures too weakly or too strongly are deleted.
- Humoral immunity
- Macromolecular crowding
This phenomenon alters the properties of molecules in a solution when high concentrations of macromolecules such as proteins are present.
- Complement cascade
The process where complement components interact with each other in a specific sequence called a complement pathway to achieve cell lysis and an inflammatory response.
- Overload hypothesis
The assumption that increased insulin demand caused by multiple mechanisms might stress β-cells and sensitize them to immune damage and apoptosis.
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Ilonen, J., Lempainen, J. & Veijola, R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 15, 635–650 (2019). https://doi.org/10.1038/s41574-019-0254-y
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