Advertisement

Immunologic Research

, Volume 55, Issue 1–3, pp 270–276 | Cite as

Type 1 diabetes: primary antigen/peptide/register/trimolecular complex

  • Tomasz Sosinowski
  • George S. EisenbarthEmail author
Immunology in Colorado

Abstract

Type 1A diabetes (autoimmune) is now immunologically predictable in man, but preventable only in animal models. What triggers the development of autoimmunity in genetically susceptible individuals remains unknown. Studies of non-obese diabetic (NOD) mice reveal that interactions between T-cell receptors of diabetogenic T cell and an MHC class II loaded with an autoantigen are key determinates of the disease. With insulin as the primary target in the NOD mouse, likely man, and possibly the RT1-U rat models, therapeutic targeting of the components of these anti-insulin trimolecular complexes we believe provide a fulcrum for development of preventive therapy. In particular for the NOD mouse model, there is extensive evidence that the dominant insulin peptide driving disease initiation is insulin B chain amino acids 9-23 (SHLVEALYLVCGERG) recognized predominantly by germ-line sequences of a specific T-cell receptor Valpha (TRAV5D-4), and small molecules or monoclonal antibodies directed at this recognition complex can prevent diabetes.

Keywords

Islet Autoantibody Diabetes Beta cells Autoimmunity Pancreas 

Notes

Acknowledgments

This work was supported by grants from the National Institute of Health (R01 DK 032083, U19AI050864, P30 DK 057516, NO1 AI 15416), the International Autoimmunity Center, the Juvenile Diabetes Research Foundation, the Brehm Coalition, the Helmsley Foundation, and the Children’s Diabetes Foundation.

Conflict of interest

Dr. Eisenbarth is on two university provisional patents for treating autoimmunity with small molecules. There is also a research grant from Novartis in the same area. Part of Dr. Sosinowski’s research is funded by a grant from Novartis.

References

  1. 1.
    Steck AK, Johnson K, Barriga KJ, Miao D, Yu L, Hutton JC, et al. Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: diabetes autoimmunity study in the young. Diabetes Care. 2011;34(6):1397–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Mrena S, Virtanen SM, Laippala P, Kulmala P, Hannila ML, Akerblom HK, et al. Models for predicting type 1 diabetes in siblings of affected children. Diabetes Care. 2006;29(3):662–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Kurrer MO, Pakala SV, Hanson HL, Katz JD. Beta cell apoptosis in T cell-mediated autoimmune diabetes. PNAS USA. 1997;94(1):213–8.PubMedCrossRefGoogle Scholar
  4. 4.
    O’Brien BA, Harmon BV, Cameron DP, Allan DJ. Apoptosis is the mode of β-cell death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse. Diabetes. 1997;46:750–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Wegmann DR, Norbury-Glaser M, Daniel D. Insulin-specific T cells are a predominant component of islet infiltrates in pre-diabetic NOD mice. Eur J Immunol. 1994;24(8):1853–7.PubMedCrossRefGoogle Scholar
  6. 6.
    DiLorenzo TP, Serreze DV. The good turned ugly: immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice. Immunol Rev. 2005;204:250–63. (250–263).PubMedCrossRefGoogle Scholar
  7. 7.
    Burton AR, Vincent E, Arnold PY, Lennon GP, Smeltzer M, Li CS, et al. On the pathogenicity of autoantigen-specific T-cell receptors. Diabetes. 2008;57(5):1321–30.PubMedCrossRefGoogle Scholar
  8. 8.
    Roep BO, Peakman M. Diabetogenic T lymphocytes in human type 1 diabetes. Curr Opin Immunol. 2011;23(6):746–53.PubMedCrossRefGoogle Scholar
  9. 9.
    Calderon B, Suri A, Unanue ER. In CD4+ T-cell-induced diabetes, macrophages are the final effector cells that mediate islet beta-cell killing: studies from an acute model. Am J Pathol. 2006;169(6):2137–47.PubMedCrossRefGoogle Scholar
  10. 10.
    Mathis D, Vence L, Benoist C. Beta-cell death during progression to diabetes. Nature. 2001;414(6865):792–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005;435(7039):220–3.PubMedCrossRefGoogle Scholar
  12. 12.
    Wicker LS, Miller BJ, Coker LZ, McNally SE, Scott S, Mullen Y, et al. Genetic control of diabetes and insulitis in the nonobese diabetic (NOD) mouse. J Exp Med. 1987;165:1639–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Suri A, Katz JD. Dissecting the role of CD4+ T cells in autoimmune diabetes through the use of TCR transgenic mice. Immunol Rev. 1999;169:55–65.PubMedCrossRefGoogle Scholar
  14. 14.
    Driver JP, Serreze DV, Chen YG. Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease. Semin Immunopathol. 2011;33(1):67–87.PubMedCrossRefGoogle Scholar
  15. 15.
    Noble JA, Valdes AM, Cook M, Klitz W, Thomson G, Erlich HA. The role of HLA class II genes in insulin-dependent diabetes mellitus: molecular analysis of 180 Caucasian, multiplex families. Am J Human Genet. 1996;59(5):1134–48.Google Scholar
  16. 16.
    Baschal EE, Eisenbarth GS. Extreme genetic risk for type 1A diabetes in the post-genome era. J Autoimmun. 2008;31(1):1–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Slattery RM, Kjer-Nielsen L, Allison J, Charlton B, Mandel TE, Miller JFAP. Prevention of diabetes in non-obese diabetic I-Ak transgenic mice. Nature. 1990;345(6277):724–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med. 2009;360(16):1646–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P, et al. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008;57:1084–92.PubMedCrossRefGoogle Scholar
  20. 20.
    Burren OS, Adlem EC, Achuthan P, Christensen M, Coulson RM, Todd JA. T1DBase: update 2011, organization and presentation of large-scale data sets for type 1 diabetes research. Nucleic Acids Res. 2011;39:D997–1001.PubMedCrossRefGoogle Scholar
  21. 21.
    Yu L, Miao D, Scrimgeour L, Johnson K, Rewers M, Eisenbarth GS. Distinguishing persistent insulin autoantibodies with differential risk: nonradioactive bivalent proinsulin/insulin autoantibody assay. Diabetes. 2012;61(1):179–86.PubMedCrossRefGoogle Scholar
  22. 22.
    Krishnamurthy B, Dudek NL, McKenzie MD, Purcell AW, Brooks AG, Gellert S, et al. Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest. 2006;116(12):3258–65.PubMedCrossRefGoogle Scholar
  23. 23.
    Anjos S, Polychronakos C. Mechanisms of genetic susceptibility to type I diabetes: beyond HLA. Mol Genet Metab. 2004;81(3):187–95.PubMedCrossRefGoogle Scholar
  24. 24.
    Gardner JM, Fletcher AL, Anderson MS, Turley SJ. AIRE in the thymus and beyond. Curr Opin Immunol. 2009;21(6):582–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Dubois-Lafforgue D, Mogenet L, Thebault K, Jami J, Krief P, Boitard C. Proinsulin 2 knockout NOD mice: a model for genetic variation of insulin gene expression in type 1 diabetes. Diabetes. 2002;51(Suppl 3):S489–93.PubMedCrossRefGoogle Scholar
  26. 26.
    Moriyama H, Abiru N, Paronen J, Sikora K, Liu E, Miao D, et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. PNAS USA. 2003;100(18):10376–81.PubMedCrossRefGoogle Scholar
  27. 27.
    Alleva DG, Maki RA, Putnam AL, Robinson JM, Kipnes MS, Dandona P, et al. Immunomodulation in type 1 diabetes by NBI-6024, an altered peptide ligand of the insulin B(9–23) epitope. Scand J Immunol. 2006;63(1):59–69.PubMedCrossRefGoogle Scholar
  28. 28.
    Kash SF, Condie BG, Baekkeskov S. Glutamate decarboxylase and GABA in pancreatic islets: lessons from knock-out mice. Horm Metab Res. 1999;31(5):340–4.PubMedCrossRefGoogle Scholar
  29. 29.
    Kubosaki A, Miura J, Notkins AL. IA-2 is not required for the development of diabetes in NOD mice. Diabetologia. 2004;47(1):149–50.PubMedCrossRefGoogle Scholar
  30. 30.
    Kubosaki A, Gross S, Miura J, Saeki K, Zhu M, Nakamura S, et al. Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice. Diabetes. 2004;53(7):1684–91.PubMedCrossRefGoogle Scholar
  31. 31.
    Delong T, Baker RL, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, et al. Islet amyloid polypeptide is a target antigen for diabetogenic CD4+ T cells. Diabetes. 2011;60(9):2325–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Oeser JK, Parekh VV, Wang Y, Jegadeesh NK, Sarkar SA, Wong R, et al. Deletion of the G6pc2 gene encoding the islet-specific glucose-6-phosphatase catalytic subunit-related protein does not affect the progression or incidence of type 1 diabetes in NOD/ShiLtJ mice. Diabetes. 2011;60(11):2922–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Daniel D, Gill RG, Schloot N, Wegmann D. Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur J Immunol. 1995;25(4):1056–62.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang L, Nakayama M, Eisenbarth GS. Insulin as an autoantigen in NOD/human diabetes. Curr Opin Immunol. 2008;20(1):111–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Stadinski BD, Zhang L, Crawford F, Marrack P, Eisenbarth GS, Kappler JW. Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. PNAS USA. 2010;107(24):10978–83.PubMedCrossRefGoogle Scholar
  36. 36.
    Levisetti MG, Suri A, Petzold SJ, Unanue ER. The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form. J Immunol. 2007;178(10):6051–7.PubMedGoogle Scholar
  37. 37.
    Crawford F, Stadinski B, Jin N, Michels A, Nakayama M, Pratt P, et al. Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. PNAS USA. 2011;108(40):16729–34.PubMedCrossRefGoogle Scholar
  38. 38.
    Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat Immunol. 2010;11(4):350–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Daniel C, Weigmann B, Bronson R. von BH. Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope. J Exp Med. 2011;208(7):1501–10.PubMedCrossRefGoogle Scholar
  40. 40.
    Simone E, Daniel D, Schloot N, Gottlieb P, Babu S, Kawasaki E, et al. T cell receptor restriction of diabetogenic autoimmune NOD T cells. Proc Natl Acad Sci USA. 1997;94(6):2518–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Nakayama M, Castoe T, Sosinowski T, He X, Johnson K, Haskins K, et al. Germline TRAV5D-4 T-Cell Receptor Sequence Targets a Primary Insulin Peptide of NOD Mice. Diabetes. 2012;61(4):857–65.PubMedCrossRefGoogle Scholar
  42. 42.
    Zhang L, Jasinski JM, Kobayashi M, Davenport B, Johnson K, Davidson H, et al. Analysis of T cell receptor beta chains that combine with dominant conserved TRAV5D-4*04 anti-insulin B:9–23 alpha chains. J Autoimmun. 2009;33(1):42–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Liu Z, Cort L, Eberwine R, Herrmann T, Leif JH, Greiner DL, et al. Prevention of type 1 diabetes in the rat with an allele-specific anti-T-cell receptor antibody: Vbeta13 as a therapeutic target and biomarker. Diabetes. 2012;61(5):1160–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Zhang L, Stadinski BD, Michels A, Kappler JW, Eisenbarth GS. Immunization with an insulin peptide-MHC complex to prevent type 1 diabetes of NOD mice. Diabetes Metab Res Rev. 2011;27(8):784–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Michels AW, Ostrov DA, Zhang L, Nakayama M, Fuse M, McDaniel K, et al. Structure-based selection of small molecules to alter allele-specific MHC class II antigen presentation. J Immunol. 2011;187(11):5921–30.PubMedCrossRefGoogle Scholar
  46. 46.
    Prediction of type IA diabetes: the natural history of the prediabetic period, chapter 11. Barbara Davis Center for Diabetes online book. http://barbaradaviscenter.org/. Accessed August 2012.

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Barbara Davis Center for Childhood DiabetesUniversity of Colorado Anschutz Medical CampusAuroraUSA

Personalised recommendations