Loss of gut barrier integrity triggers activation of islet-reactive T cells and autoimmune diabetes

Proceedings of the National Academy of Sciences of the United States of America

Volumn 116, Issue 30, 2019, Pages 15140-15149

  Sorini, Chiara ^a,b   Cosorich, Ilaria ^a   Conte, Marta Lo ^a   De Giorgi, Lorena ^a   Facciotti, Federica ^c   Lucianò, Roberta ^a   Rocchi, Martina ^a   Ferrarese, Roberto ^a   Sanvito, Francesca ^a   Canducci, Filippo ^d   Falcone, Marika ^a  

^a SAN RAFFAELE HOSPITAL   (Italy)

^b KAROLINSKA INSTITUTE   (Sweden)

^c EUROPEAN INSTITUTE OF ONCOLOGY   (Italy)

^d UNIVERSITY OF INSUBRIA   (Italy)

Author keywords

Autoimmune diabetes; Gut inflammation; Microbiota

Indexed keywords

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIBIOTIC THERAPY; ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CELL SPECIFICITY; COMMENSAL; CONTROLLED STUDY; DIABETOGENESIS; DISEASE COURSE; DISEASE MODEL; ENTEROPATHY; FEMALE; IMMUNOPATHOGENESIS; INSULIN DEPENDENT DIABETES MELLITUS; INTESTINE FLORA; INTESTINE MUCOSA; MOUSE; MUCUS; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; T LYMPHOCYTE ACTIVATION; ANIMAL; BACTERIUM; CLASSIFICATION; COLITIS; GENE EXPRESSION; GENETICS; GLUCOSE BLOOD LEVEL; HUMAN; IMMUNOLOGY; METABOLISM; MICROBIOLOGY; NONOBESE DIABETIC MOUSE; PANCREAS ISLET; PATHOLOGY; PERMEABILITY; SURVIVAL ANALYSIS; T LYMPHOCYTE; TRANSGENE; TRANSGENIC MOUSE;

DODECYL SULFATE SODIUM; LYMPHOCYTE ANTIGEN RECEPTOR;

ANIMALS; BACTERIA; BLOOD GLUCOSE; COLITIS; DIABETES MELLITUS, TYPE 1; DISEASE MODELS, ANIMAL; FEMALE; GASTROINTESTINAL MICROBIOME; GENE EXPRESSION; HUMANS; INTESTINAL MUCOSA; ISLETS OF LANGERHANS; MICE; MICE, INBRED NOD; MICE, TRANSGENIC; PERMEABILITY; RECEPTORS, ANTIGEN, T-CELL; SODIUM DODECYL SULFATE; SURVIVAL ANALYSIS; T-LYMPHOCYTES; TRANSGENES;

EID: 85069716044     PISSN: 00278424     EISSN: 10916490     Source Type: Journal    
DOI: 10.1073/pnas.1814558116     Document Type: Article

References (73)

1. J. A. Todd, Etiology of type 1 diabetes. Immunity 32, 457–467 (2010).
2. F. Dotta 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. U.S.A. 104, 5115–5120 (2007).
3. M. C. Honeyman et al., Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 49, 1319–1324 (2000).
4. O. Vaarala et al., Cow’s milk formula feeding induces primary immunization to insulin in infants at genetic risk for type 1 diabetes. Diabetes 48, 1389–1394 (1999).
5. J. M. Norris et al., Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 290, 1713–1720 (2003).
6. L. Wen et al., Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008).
7. A. Giongo et al., Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 5, 82–91 (2011).
8. C. T. Brown et al., Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One 6, e25792 (2011).
9. T. Vatanen et al.; DIABIMMUNE Study Group, Variation in microbiome LPS immu-nogenicity contributes to autoimmunity in humans. Cell 165, 842–853 (2016).
10. + T cells by small-intestinal dendritic cells in patients with type 1 diabetes. Diabetes 60, 2120–2124 (2011).
11. T. Vatanen et al., The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature 562, 589–594 (2018).
12. J. B. Meddings, J. Jarand, S. J. Urbanski, J. Hardin, D. G. Gall, Increased gastrointestinal permeability is an early lesion in the spontaneously diabetic BB rat. Am. J. Physiol. 276, G951–G957 (1999).
13. S. Graham et al., Enteropathy precedes type 1 diabetes in the BB rat. Gut 53, 1437–1444 (2004).
14. F. Maurano et al., Small intestinal enteropathy in non-obese diabetic mice fed a diet containing wheat. Diabetologia 48, 931–937 (2005).
15. A. D. Mooradian, J. E. Morley, A. S. Levine, W. F. Prigge, R. L. Gebhard, Abnormal intestinal permeability to sugars in diabetes mellitus. Diabetologia 29, 221–224 (1986).
16. R. Carratù et al., Altered intestinal permeability to mannitol in diabetes mellitus type I. J. Pediatr. Gastroenterol. Nutr. 28, 264–269 (1999).
17. M. Westerholm-Ormio, O. Vaarala, P. Pihkala, J. Ilonen, E. Savilahti, Immunologic activity in the small intestinal mucosa of pediatric patients with type 1 diabetes. Diabetes 52, 2287–2295 (2003).
18. M. Secondulfo et al., Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients. Dig. Liver Dis. 36, 35–45 (2004).
19. E. Bosi et al., Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49, 2824–2827 (2006).
20. J. Neu et al., Changes in intestinal morphology and permeability in the biobreeding rat before the onset of type 1 diabetes. J. Pediatr. Gastroenterol. Nutr. 40, 589–595 (2005).
21. O. Vaarala, M. A. Atkinson, J. Neu, The “perfect storm” for type 1 diabetes: The complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes 57, 2555–2562 (2008).
22. J. Sun et al., Pancreatic β-cells limit autoimmune diabetes via an immunoregulatory antimicrobial peptide expressed under the influence of the gut microbiota. Immunity 43, 304–317 (2015).
23. S. J. Turley, J. W. Lee, N. Dutton-Swain, D. Mathis, C. Benoist, Endocrine self and gut non-self intersect in the pancreatic lymph nodes. Proc. Natl. Acad. Sci. U.S.A. 102, 17729–17733 (2005).
24. A. Sapone et al., Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives. Diabetes 55, 1443–1449 (2006).
25. T. Pelaseyed et al., The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol. Rev. 260, 8–20 (2014).
26. M. E. Johansson, H. Sjövall, G. C. Hansson, The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 352–361 (2013).
27. P. M. Smith et al., The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
28. N. Arpaia et al., Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).
29. R. L. Gallo, L. V. Hooper, Epithelial antimicrobial defence of the skin and intestine. Nat. Rev. Immunol. 12, 503–516 (2012).
30. P. Chairatana, E. M. Nolan, Defensins, lectins, mucins, and secretory immunoglobulin A: Microbe-binding biomolecules that contribute to mucosal immunity in the human gut. Crit. Rev. Biochem. Mol. Biol. 52, 45–56 (2017).
31. M. Shan et al., Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342, 447–453 (2013).
32. Y. H. Sheng et al., MUC1 and MUC13 differentially regulate epithelial inflammation in response to inflammatory and infectious stimuli. Mucosal Immunol. 6, 557–568 (2013).
33. P. Courtois, C. Jurysta, A. Sener, F. W. Scott, W. J. Malaisse, Quantitative and qualitative alterations of intestinal mucins in BioBreeding rats. Int. J. Mol. Med. 15, 105–108 (2005).
34. I. Jaakkola, S. Jalkanen, A. Hänninen, Diabetogenic T cells are primed both in pancreatic and gut-associated lymph nodes in NOD mice. Eur. J. Immunol. 33, 3255–3264 (2003).
35. J. D. Katz, B. Wang, K. Haskins, C. Benoist, D. Mathis, Following a diabetogenic T cell from genesis through pathogenesis. Cell 74, 1089–1100 (1993).
36. K. Haskins, M. Portas, B. Bradley, D. Wegmann, K. Lafferty, T-lymphocyte clone specific for pancreatic islet antigen. Diabetes 37, 1444–1448 (1988).
37. R. Mueller, L. M. Bradley, T. Krahl, N. Sarvetnick, Mechanism underlying counter-regulation of autoimmune diabetes by IL-4. Immunity 7, 411–418 (1997).
38. M. S. Horwitz et al., Diabetes induced by Coxsackie virus: Initiation by bystander damage and not molecular mimicry. Nat. Med. 4, 781–785 (1998).
39. M. E. Johansson et al., Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. PLoS One 5, e12238 (2010).
40. C. Hernández-Chirlaque et al., Germ-free and antibiotic-treated mice are highly susceptible to epithelial injury in DSS colitis. J. Crohns Colitis 10, 1324–1335 (2016).
41. N. Tai et al., Microbial antigen mimics activate diabetogenic CD8 T cells in NOD mice. J. Exp. Med. 213, 2129–2146 (2016).
42. F. R. Costa et al., Gut microbiota translocation to the pancreatic lymph nodes triggers NOD2 activation and contributes to T1D onset. J. Exp. Med. 213, 1223–1239 (2016).
43. X. Li, M. A. Atkinson, The role for gut permeability in the pathogenesis of type 1 diabetes—a solid or leaky concept? Pediatr. Diabetes 16, 485–492 (2015).
44. O. Vaarala, Leaking gut in type 1 diabetes. Curr. Opin. Gastroenterol. 24, 701–706 (2008).
45. O. Vaarala, Is the origin of type 1 diabetes in the gut? Immunol. Cell Biol. 90, 271–276 (2012).
46. A. Hänninen et al., Akkermansia muciniphila induces gut microbiota remodelling and controls islet autoimmunity in NOD mice. Gut 67, 1445–1453 (2018).
47. H. Brauner et al., Markers of innate immune activity in patients with type 1 and type 2 diabetes mellitus and the effect of the anti-oxidant coenzyme Q10 on inflammatory activity. Clin. Exp. Immunol. 177, 478–482 (2014).
48. D. L. Kaufman et al., Spontaneous loss of T-cell tolerance to glutamic acid de-carboxylase in murine insulin-dependent diabetes. Nature 366, 69–72 (1993).
49. K. Robinson, Z. Deng, Y. Hou, G. Zhang, Regulation of the intestinal barrier function by host defense peptides. Front. Vet. Sci. 2, 57 (2015).
50. L. M. Loonen et al., REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal Immunol. 7, 939–947 (2014).
51. H. W. Koon et al., Cathelicidin signaling via the Toll-like receptor protects against colitis in mice. Gastroenterology 141, 1852–1863.e1-3 (2011).
52. A. S. Lee et al., Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice. Diabetologia 53, 741–748 (2010).
53. K. Berer et al., Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).
54. B. D. Stadinski et al., Chromogranin A is an autoantigen in type 1 diabetes. Nat. Immunol. 11, 225–231 (2010).
55. C. M. Gleeson, W. J. Curry, C. F. Johnston, K. D. Buchanan, Occurrence of WE-14 and chromogranin A-derived peptides in tissues of the human and bovine gastro-entero-pancreatic system and in human neuroendocrine neoplasia. J. Endocrinol. 151, 409–420 (1996).
56. W. J. Curry et al., Chromogranin A and its derived peptides in the rat and porcine gastro-entero-pancreatic system. Expression, localization, and characterization. Adv. Exp. Med. Biol. 482, 205–213 (2000).
57. C. Sorini, M. Falcone, Shaping the (auto)immune response in the gut: The role of intestinal immune regulation in the prevention of type 1 diabetes. Am. J. Clin. Exp. Immunol. 2, 156–171 (2013).
58. M. Knip, H. Siljander, The role of the intestinal microbiota in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 12, 154–167 (2016).
59. J. D. Taurog et al., The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180, 2359–2364 (1994).
60. C. King, N. Sarvetnick, The incidence of type-1 diabetes in NOD mice is modulated by restricted flora not germ-free conditions. PLoS One 6, e17049 (2011).
61. M. W. Sadelain, H. Y. Qin, J. Lauzon, B. Singh, Prevention of type I diabetes in NOD mice by adjuvant immunotherapy. Diabetes 39, 583–589 (1990).
62. T. C. Martins, A. P. Aguas, Changes in B and T lymphocytes associated with mycobacteria-induced protection of NOD mice from diabetes. J. Autoimmun. 9, 501–507 (1996).
63. D. Elias, D. Markovits, T. Reshef, R. van der Zee, I. R. Cohen, Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. Proc. Natl. Acad. Sci. U.S.A. 87, 1576–1580 (1990).
64. P. Saï, A. S. Rivereau, Prevention of diabetes in the nonobese diabetic mouse by oral immunological treatments. Comparative efficiency of human insulin and two bacterial antigens, lipopolysacharide from Escherichia coli and glycoprotein extract from Klebsiella pneumoniae. Diabetes Metab. 22, 341–348 (1996).
65. R. Horai et al., Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site. Immunity 43, 343–353 (2015).
66. T. C. Fung et al., Lymphoid-tissue-resident commensal bacteria promote members of the IL-10 cytokine family to establish mutualism. Immunity 44, 634–646 (2016).
67. D. K. Cole et al., Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. J. Clin. Invest. 126, 3626 (2016).
68. S. Wirtz, C. Neufert, B. Weigmann, M. F. Neurath, Chemically induced mouse models of intestinal inflammation. Nat. Protoc. 2, 541–546 (2007).
69. R. L. Brown, R. P. Sequeira, T. B. Clarke, The microbiota protects against respiratory infection via GM-CSF signaling. Nat. Commun. 8, 1512 (2017).
70. K. Atarashi et al., Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).
71. B. Weigmann et al., Isolation and subsequent analysis of murine lamina propria mononuclear cells from colonic tissue. Nat. Protoc. 2, 2307–2311 (2007).
72. L. Lefrancois, N. Lycke, Isolation of mouse small intestinal intraepithelial lymphocytes, Peyer’s patch, and lamina propria cells. Curr. Protoc. Immunol. Chapter 3, Unit 3.19 (2001).
73. S. Ghosh et al., Colonic microbiota alters host susceptibility to infectious colitis by modulating inflammation, redox status, and ion transporter gene expression. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G39–G49 (2011).