CoChat
Sign Up
Cited by 1,265Diabetes and associated disordersT-cell and B-cell ImmunologyDiabetes Management and Research

Genetics, pathogenesis and clinical interventions in type 1 diabetes

Open access
Bluestone, Jeffrey A., Herold, Kevan, Eisenbarth, George·2010·Nature
DOI 10.1038/nature08933PMC PMC4959889
Open this paper in CoChat — free account

Abstract

Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/nature08933

Cites

10 of 10 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In type 1 diabetes, β-cell-specific CD8 T cells destroy insulin-producing β-cells.

    “In type 1 diabetes, β-cell-specific CD8 T cells destroy insulin-producing β-cells.”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [4]

    The Pathophysiology of type 1 diabetes in mouse and human section (page unavailable) says autoreactive, islet-antigen-reactive T cells play a dominant role in the disease and that CD8+ cells appeared to dominate infiltrates in one study of human pancreases. But it also says the mediators of islet destruction have not been precisely defined; it does not establish that β-cell-specific CD8 T cells directly destroy the β-cells. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Even in T1D in which tissue-specific T cells are involved, local initiators originating from senescent beta cells play critical roles.

    “Concerning age-related diseases, senescent cells themselves are critically involved in T1D and T2D, and the deletion of senescent beta cells prevents diabetes (57, 298), indicating that even in T1D in which tissue-specific T cells are involved (299–301), local initiators originating from senescent beta cells play critical roles.”

    From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [299]

  • Type 1 diabetes is generally thought to be precipitated by an immune-associated, if not directly immune-mediated, destruction of insulin-producing pancreatic β cells.

    “Type 1 diabetes is generally thought to be precipitated by an immune-associated, if not directly immune-mediated, destruction of insulin-producing pancreatic β cells.1,2”

    From Type 1 diabetes (2014) · cites this paper as [2]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 80

  1. [1]Anderson MS Bluestone JA The NOD mouse: a model of immune dysregulation Annu Rev Immunol 23 447 485 2005 15771578
  2. [2]Vauzelle-Kervroedan F Analysis of mortality in French diabetic patients from death certificates: a comparative study Diabete Metab 25 404 411 1999 10592863
  3. [3]Maahs DM Rewers M Editorial: mortality and renal disease in type 1 diabetes mellitus—progress made, more to be done J Clin Endocrinol Metab 91 3757 3759 2006 17028289
  4. [4]Steffes MW (EDIC Research Group). 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 J Am Med Assoc 290 2159 2167 2003 PMC2622725 14570951
  5. [5]Harjutsalo V Sjoberg L Tuomilehto J Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study Lancet 371 1777 1782 2008 18502302
  6. [6]Lorenzen T Pociot F Hougaard P Nerup J Long-term risk of IDDM in first-degree relatives of patients with IDDM Diabetology 37 321 327 1994 8174848
  7. [7]Mordes JP The BB/Wor rat and the balance hypothesis of autoimmunity Diabetes Metab Rev 12 103 109 1996 8877279
  8. [8]Makino S Breeding of a non-obese, diabetic strain of mice Exp Anim 29 1 13 1980 6995140
  9. [9]DiLorenzo TP Serreze DV The good turned ugly:immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice Immunol Rev 204 250 263 2005 15790363
  10. [10]Burton AR On the pathogenicity of autoantigen-specific T-cell receptors Diabetes 57 1321 1330 2008 18299317
  11. [11]Han B Developmental control of CD8 T cell-avidity maturation in autoimmune diabetes J Clin Invest 115 1879 1887 2005 15937548 PMC1142112
  12. [12]Serreze DV B lymphocytes are critical antigen-presenting cells for the initiation of T cell-mediated autoimmune diabetes in nonobese diabetic mice J Immunol 161 3912 3918 1998 9780157
  13. [13]Greeley SA Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice Nature Med 8 399 402 2002 11927947
  14. [14]Hu CY Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice J Clin Invest 117 3857 3867 2007 18060033 PMC2096456
  15. [15]Zipris D TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat J Immunol 178 693 701 2007 17202329
  16. [16]Devendra D Interferon-α as a mediator of polyinosinic:polycytidylic acid-induced type 1 diabetes Diabetes 54 2549 2556 2005 16123342
  17. [17]Concannon P Rich SS Nepom GT Genetics of type 1A diabetes N Engl J Med 360 1646 1654 2009 19369670
  18. [18]Wicker LS Type 1 diabetes genes and pathways shared by humans and NOD mice J Autoimmun 25 Suppl 29 33 2005 16257508
  19. [19]Turley S Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model J Exp Med 198 1527 1537 2003 14623908 PMC2194112
  20. [20]Lieberman SM DiLorenzo TP A comprehensive guide to antibody and T-cell responses in type 1 diabetes Tissue Antigens 62 359 377 2003 14617043
  21. [21]Medarova Z In vivo imaging of a diabetogenic CD8+ T cell response during type 1 diabetes progression Magn Reson Med 59 712 720 2008 18302224
  22. [22]Lennon GP T cell islet accumulation in type 1 diabetes is a tightly regulated, cell-autonomous event Immunity 31 643 653 2009 19818656 PMC2763021
  23. [23]Vafiadis P Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus Nature Genet 15 289 292 1997 9054944
  24. [25]Gardner JM Fletcher AL Anderson MS Turley SJ AIRE in the thymus and beyond Curr Opin Immunol 21 582 589 2009 19833494 PMC2787634
  25. [26]Kobayashi M Conserved T cell receptor alpha-chain induces insulin autoantibodies Proc Natl Acad Sci USA 105 10090 10094 2008 18626021 PMC2464615
  26. [28]Dotta F Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients Proc Natl Acad Sci USA 104 5115 5120 2007 17360338 PMC1829272
  27. [29]Gianani R Dimorphic histopathology of long-standing childhood-onset diabetes Diabetologia 53 4 690 698 2010 20062967
  28. [30]Itoh N Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients J Clin Invest 92 2313 2322 1993 8227346 PMC288412
  29. [31]Willcox A Analysis of islet inflammation in human type 1 diabetes Clin Exp Immunol 155 173 181 2009 19128359 PMC2675247
  30. [32]Esensten JH Lee MR Glimcher LH Bluestone JA T-bet-deficient NOD mice are protected from diabetes due to defects in both T cell and innate immune system function J Immunol 183 75 82 2009 19535634 PMC2732575
  31. [33]Bending D Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice J Clin Invest 119 3 565 572 2009 19188681 PMC2648686
  32. [34]Ogasawara K Impairment of NK cell function by NKG2D modulation in NOD mice Immunity 18 41 51 2003 12530974
  33. [35]Feuerer M How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets Immunity 31 654 664 2009 19818653 PMC2998796
  34. [36]Wong FS Investigation of the role of B-cells in type 1 diabetes in the NOD mouse Diabetes 53 2581 2587 2004 15448087
  35. [37]Xiu Y B lymphocyte depletion by CD20 monoclonal antibody prevents diabetes in nonobese diabetic mice despite isotype-specific differences in Fc gamma R effector functions J Immunol 180 2863 2875 2008 18292508
  36. [38]Boni-Schnetzler M Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta -cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation J Clin Endocrinol Metab 93 4065 4074 2008 18664535 PMC2579638
  37. [39]Koulmanda M Modification of adverse inflammation is required to cure new-onset type 1 diabetic hosts Proc Natl Acad Sci USA 104 13074 13079 2007 17670937 PMC1941818
  38. [40]Feuerer M Hill JA Mathis D Benoist C Foxp31 regulatory T cells: differentiation, specification, subphenotypes Nature Immunol 10 689 695 2009 19536194
  39. [42]Tang Q Bluestone JA The Foxp31 regulatory T cell: a jack of all trades, master of regulation Nature Immunol 9 339 344 2008 18285775 PMC3075612
  40. [43]Winer S Normalization of obesity-associated insulin resistance through immunotherapy Nature Med 15 921 929 2009 19633657 PMC3063199
  41. [45]Yan Z Garg SK Kipnis J Banerjee R Extracellular redox modulation by regulatory T cells Nature Chem Biol 5 721 723 2009 19718041 PMC2760945
  42. [46]Tang Q Central role of a defective IL-2 production in triggering islet autoimmune destruction Immunity 28 687 697 2008 18468463 PMC2394854
  43. [47]Zhou X Foxp3 instability leads to the generation of pathogenic memory T cells in vivo Nat Immun 10 1000 1007 2009 PMC2729804 19633673
  44. [48]Schneider A The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells J Immunol 181 7350 7355 2008 18981158 PMC2597079
  45. [49]D’Alise AM The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors Proc Natl Acad Sci USA 105 19857 19862 2008 19073938 PMC2604930
  46. [50]Qin HY Singh B BCG vaccination prevents insulin-dependent diabetes mellitus (IDDM) in NOD mice after disease acceleration with cyclophosphamide J Autoimmun 10 271 278 1997 9218754
  47. [52]Weintrob N Type 1 diabetes environmental factors and correspondence analysis of HLA class II genes in the Yemenite Jewish community in Israel Diabetes Care 24 650 653 2001 11315825
  48. [53]Virtanen SM Age at introduction of new foods and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes Diabetologia 49 1512 1521 2006 16596359
  49. [54]Akerblom HK Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study Diabetologia 48 829 837 2005 15838685
  50. [55]Norris JM Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes J Am Med Assoc 298 1420 1428 2007 17895458
  51. [56]Jun HS Yoon JW A new look at viruses in type 1 diabetes ILAR J 45 349 374 2004 15229381
  52. [57]Richardson SJ The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes Diabetologia 52 1143 1151 2009 19266182
  53. [59]Bougneres PF Factors associated with early remission of type I diabetes in children treated with cyclosporine N Engl J Med 318 663 670 1988 3125434
  54. [60]Stiller CR Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset Science 223 1362 1367 1984 6367043
  55. [62]Eisenbarth GS Anti-thymocyte globulin and prednisone immunotherapy of recent onset type I diabetes mellitus Diabetes Res 2 271 276 1985 3878262
  56. [63]Allen HF Effect of BCG vaccination on new-onset insulin-dependent diabetes mellitus: a randomized clinical study Diabetes Care 22 1703 1707 1998 10526739
  57. [64]Herold KC Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus N Engl J Med 346 1692 1698 2002 12037148
  58. [65]Keymeulen B Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes N Engl J Med 352 2598 2608 2005 15972866
  59. [66]Herold KC Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb teplizumab preserves insulin production for up to 5 years Clin Immunol 132 166 173 2009 19443276 PMC2735402
  60. [67]Chatenoud L Bluestone JA CD3-specific antibodies: a portal to the treatment of autoimmunity Nature Rev Immunol 7 622 632 2007 17641665
  61. [68]Bisikirska B TCR stimulation with modified anti-CD3 mAb expands CD8 T cell population and induces CD8 CD25 Tregs J Clin Invest 115 2904 2913 2005 16167085 PMC1201661
  62. [69]Hu CY Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice J Clin Invest 117 3857 3867 2007 18060033 PMC2096456
  63. [70]Bouaziz JD Yanaba K Tedder TF Regulatory B cells as inhibitors of immune responses and inflammation Immunol Rev 224 201 214 2008 18759928
  64. [72]Wise M CD4 T cells can reject major histocompatibility complex class I-incompatible skin grafts Eur J Immunol 29 156 167 1999 9933097
  65. [73]Homann D Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/Stat6 pathway Immunity 11 463 472 1999 10549628
  66. [74]Masteller EL Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice J Immunol 175 3053 3059 2005 16116193
  67. [75]Qin S ‘Infectious’ transplantation tolerance Science 259 974 977 1993 8094901
  68. [76]Waldmann H Cobbold S How do monoclonal antibodies induce tolerance? A role for infectious tolerance? Annu Rev Immunol 16 619 644 1998 9597144
  69. [77]Tang Q In vitro expanded antigen-specific regulatory T cells suppress autoimmune diabetes J Exp Med 199 1455 1465 2004 15184499 PMC2211775
  70. [80]Levings MK Sangregorio R Roncarolo MG Human CD25(+)CD4(+) T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function J Exp Med 193 1295 1302 2001 11390436 PMC2193376
  71. [81]Strom TB Koulmanda M Cytokine related therapies for autoimmune disease Curr Opin Immunol 20 676 681 2008 18940257 PMC3747560
  72. [82]Koulmanda M Curative and beta cell regenerative effects of α1-antitrypsin treatment in autoimmune diabetic NOD mice Proc Natl Acad Sci USA 105 16242 16247 2008 18852471 PMC2570971
  73. [83]Louvet C Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice Proc Natl Acad Sci USA 105 18895 18900 2008 19015530 PMC2596241
  74. [84]Couri CE Voltarelli JC Stem cell therapy for type 1 diabetes mellitus: a review of recent clinical trials Diabetol Metabol Syndr 1 1 19 2009 PMC2768673 19835616
  75. [85]Bresson D Anti-CD3 and nasal proinsulin combination therapy enhances remission from recent-onset autoimmune diabetes by inducing Tregs J Clin Invest 116 1371 1381 2006 16628253 PMC1440705
  76. [86]Suarez-Pinzon WL Combination therapy with epidermal growth factor and gastrin increases beta-cell mass and reverses hyperglycemia in diabetic NOD mice Diabetes 54 2596 2601 2005 16123347
  77. [87]Matthews JB Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group Clin Exp Immunol 10.1111/j.1365-2249.2010.04153.x in the press PMC2857940 20629979 · DOI
  78. [88]Skyler JS Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial–Type 1 Diabetes Care 28 1068 1075 2005 15855569
  79. [89]Herold KC A single course of anti-CD3 monoclonal antibody hOKT3γ1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of Type 1 diabetes Diabetes 54 1763 1769 2005 15919798 PMC5315015
  80. [90]Wong FS Investigation of the role of β-cells in type 1 diabetes in the NOD mouse Diabetes 53 2581 2587 2004 15448087

Cited by

Sorted by citations

Authors
Bluestone, J. A., Herold, K., & Eisenbarth, G.
Affiliations
  • University of California, San Francisco (US)
  • Yale University (US)
Corresponding author
Bluestone, Jeffrey A.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2010-04-01
Volume
464
Issue
7293
Pages
1293-1300
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature08933
PMC
PMC4959889
OpenAlex
W2011450045
Cited by
1,265
References
10
Citations by year
2026: 42 · 2025: 76 · 2024: 70 · 2023: 67 · 2022: 90 · 2021: 82 · 2020: 90 · 2019: 70 · 2018: 88 · 2017: 88 · 2016: 73 · 2015: 100 · 2014: 78 · 2013: 79 · 2012: 98
FWCI
8.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
National Institute of Allergy and Infectious Diseases (R01AI046643, R21AI107328)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
type 1 diabetes, islet autoimmunity, pathogenesis, genetic susceptibility, regulatory T cells, effector T cells, clinical intervention, autoimmune disease, disease prevention
MeSH terms
Animals, Diabetes Mellitus, Type 1, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review