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Neoepitopes: a new take on beta cell autoimmunity in type 1 diabetes

  • Stuart I. Mannering
  • Anthony R. Di Carluccio
  • Colleen M. Elso
Review

Abstract

Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of pancreatic insulin-producing beta cells. The epitopes recognised by pathogenic T cells in human type 1 diabetes are poorly defined; however, a growing body of evidence suggests that T cell responses against neoepitopes contribute to beta cell destruction in type 1 diabetes. Neoepitopes are formed when self-proteins undergo post-translational modification to create a new epitope that is recognised by T- or B cells. Here we review the role of human T cell responses against neoepitopes in the immune pathogenesis of type 1 diabetes. Specifically, we review the different approaches to identifying neoepitopes relevant to human type 1 diabetes and outline several advances in this field that have occurred over the past few years. We also discuss the application of neoepitopes to the development of antigen-specific therapies for type 1 diabetes and the unresolved challenges that need to be overcome before the full repertoire of neoepitopes recognised by pathogenic human T cells in type 1 diabetes can be determined. This information may then be used to develop antigen-specific therapies for type 1 diabetes and assays to monitor changes in pathogenic, beta cell-specific T cell responses.

Keywords

Antigen-specific therapy Beta cells Hybrid insulin peptides Neoepitopes Post-translational modification Review T cells Type 1 diabetes 

Abbreviations

GRP

Glucose-regulated protein

HIP

Hybrid insulin peptides

IAPP

Islet amyloid polypeptide

TCR

T cell receptor

Notes

Contribution statement

All authors were responsible for drafting the article and revising it critically for important intellectual content. All authors approved the version to be published.

Funding

Work in the authors’ laboratory is supported by: JDRF [JDRF 5-CDA-2014-210-A-N] (SM); The National Health and Medical Research Council (NHMRC GNT123586) (SM); Diabetes Australia Research Trust Millennium Award (Y17M1-MANS) (SM); Diabetes Australia Research Program (Y18G-ELSC) (CE); and the Operational Infrastructure Support Program of the Victorian Government (SM, AD and CE). The authors have no financial conflicts to declare.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

References

  1. 1.
    Mannering SI, Pathiraja V, Kay TW (2016) The case for an autoimmune aetiology of type 1 diabetes. Clin Exp Immunol 183(1):8–15.  https://doi.org/10.1111/cei.12699 CrossRefPubMedGoogle Scholar
  2. 2.
    Pugliese A (2017) Autoreactive T cells in type 1 diabetes. J Clin Invest 127(8):2881–2891.  https://doi.org/10.1172/JCI94549 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ziegler AG, Rewers M, Simell O et al (2013) Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309(23):2473–2479.  https://doi.org/10.1001/jama.2013.6285 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Noble JA (2015) Immunogenetics of type 1 diabetes: a comprehensive review. J Autoimmun 64:101–112.  https://doi.org/10.1016/j.jaut.2015.07.014 CrossRefPubMedGoogle Scholar
  5. 5.
    Todd JA, Bell JI, McDevitt HO (1987) HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329(6140):599–604.  https://doi.org/10.1038/329599a0 CrossRefPubMedGoogle Scholar
  6. 6.
    Bennett ST, Lucassen AM, Gough SC et al (1995) Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9(3):284–292.  https://doi.org/10.1038/ng0395-284 CrossRefPubMedGoogle Scholar
  7. 7.
    Insel RA, Dunne JL, Atkinson MA et al (2015) Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 38(10):1964–1974.  https://doi.org/10.2337/dc15-1419 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    van Lummel M, Zaldumbide A, Roep BO (2013) Changing faces, unmasking the beta-cell: post-translational modification of antigens in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 20(4):299–306.  https://doi.org/10.1097/MED.0b013e3283631417 CrossRefPubMedGoogle Scholar
  9. 9.
    James EA, Pietropaolo M, Mamula MJ (2018) Immune recognition of beta-cells: neoepitopes as key players in the loss of tolerance. Diabetes 67(6):1035–1042.  https://doi.org/10.2337/dbi17-0030 CrossRefPubMedGoogle Scholar
  10. 10.
    Harbige J, Eichmann M, Peakman M (2017) New insights into non-conventional epitopes as T cell targets: The missing link for breaking immune tolerance in autoimmune disease? J Autoimmun 84:12–20.  https://doi.org/10.1016/j.jaut.2017.08.001 CrossRefPubMedGoogle Scholar
  11. 11.
    Atkinson MA, Bluestone JA, Eisenbarth GS et al (2011) How does type 1 diabetes develop?: the notion of homicide or beta-cell suicide revisited. Diabetes 60(5):1370–1379.  https://doi.org/10.2337/db10-1797 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Marre ML, McGinty JW, Chow IT et al (2018) Modifying enzymes are elicited by ER stress, generating epitopes that are selectively recognized by CD4+ T cells in patients with type 1 diabetes. Diabetes 67(7):1356–1368.  https://doi.org/10.2337/db17-1166 CrossRefPubMedGoogle Scholar
  13. 13.
    Herold KC, Brooks-Worrell B, Palmer J et al (2009) Validity and reproducibility of measurement of islet autoreactivity by T cell assays in subjects with early type 1 diabetes. Diabetes 58(11):2588–2595.  https://doi.org/10.2337/db09-0249 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Nepom GT, Kwok WW (1998) Molecular basis for HLA-DQ associations with IDDM. Diabetes 47(8):1177–1184.  https://doi.org/10.2337/diab.47.8.1177 CrossRefPubMedGoogle Scholar
  15. 15.
    Mannering SI, Morris JS, Jensen KP et al (2003) A sensitive method for detecting proliferation of rare autoantigen-specific human T cells. J Immunol Methods 283(1-2):173–183.  https://doi.org/10.1016/j.jim.2003.09.004 CrossRefPubMedGoogle Scholar
  16. 16.
    McGinty JW, Chow I-T, Greenbaum C, Odegard J, Kwok WW, James EA (2014) Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes 63(9):3033–3040.  https://doi.org/10.2337/db13-1952 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Pathiraja V, Kuehlich JP, Campbell PD et al (2015) Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes. Diabetes 64(1):172–182.  https://doi.org/10.2337/db14-0858 CrossRefPubMedGoogle Scholar
  18. 18.
    Babon JA, DeNicola ME, Blodgett DM et al (2016) Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat Med 22(12):1482–1487.  https://doi.org/10.1038/nm.4203 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Michels AW, Landry LG, McDaniel KA et al (2017) Islet-derived CD4 T cells targeting proinsulin in human autoimmune diabetes. Diabetes 66(3):722–734.  https://doi.org/10.2337/db16-1025 CrossRefPubMedGoogle Scholar
  20. 20.
    Crevecoeur I, Rondas D, Mathieu C, Overbergh L (2015) The beta-cell in type 1 diabetes: what have we learned from proteomic studies? Proteomics Clin Appl 9(7-8):755–766.  https://doi.org/10.1002/prca.201400135 CrossRefPubMedGoogle Scholar
  21. 21.
    Rondas D, Crevecoeur I, D’Hertog W et al (2015) Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes. Diabetes 64(2):573–586.  https://doi.org/10.2337/db14-0621 CrossRefPubMedGoogle Scholar
  22. 22.
    Gonzalez-Duque S, Azoury ME, Colli ML et al (2018) Conventional and neo-antigenic peptides presented by β cells are targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab 28:1–15CrossRefGoogle Scholar
  23. 23.
    Delong T, Wiles TA, Baker RL et al (2016) Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351(6274):711–714.  https://doi.org/10.1126/science.aad2791 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Strollo R, Rizzo P, Spoletini M et al (2013) HLA-dependent autoantibodies against post-translationally modified collagen type II in type 1 diabetes mellitus. Diabetologia 56(3):563–572.  https://doi.org/10.1007/s00125-012-2780-1 CrossRefPubMedGoogle Scholar
  25. 25.
    Strollo R, Vinci C, Arshad MH et al (2015) Antibodies to post-translationally modified insulin in type 1 diabetes. Diabetologia 58(12):2851–2860.  https://doi.org/10.1007/s00125-015-3746-x CrossRefPubMedGoogle Scholar
  26. 26.
    Strollo R, Vinci C, Napoli N, Pozzilli P, Ludvigsson J, Nissim A (2017) Antibodies to post-translationally modified insulin as a novel biomarker for prediction of type 1 diabetes in children. Diabetologia 60(8):1467–1474.  https://doi.org/10.1007/s00125-017-4296-1 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mannering SI, Harrison LC, Williamson NA et al (2005) The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J Exp Med 202(9):1191–1197.  https://doi.org/10.1084/jem.20051251 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    van Lummel M, Duinkerken G, van Veelen PA et al (2014) Posttranslational modification of HLA-DQ binding islet autoantigens in type 1 diabetes. Diabetes 63(1):237–247.  https://doi.org/10.2337/db12-1214 CrossRefPubMedGoogle Scholar
  29. 29.
    Kracht MJ, van Lummel M, Nikolic T et al (2017) Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes. Nat Med 23(4):501–507.  https://doi.org/10.1038/nm.4289 CrossRefPubMedGoogle Scholar
  30. 30.
    McGinty JW, Marre ML, Bajzik V, Piganelli JD, James EA (2015) T cell epitopes and post-translationally modified epitopes in type 1 diabetes. Curr Diab Rep 15(11):90.  https://doi.org/10.1007/s11892-015-0657-7 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Roep BO, Kracht MJ, van Lummel M, Zaldumbide A (2016) A roadmap of the generation of neoantigens as targets of the immune system in type 1 diabetes. Curr Opin Immunol 43:67–73.  https://doi.org/10.1016/j.coi.2016.09.007 CrossRefPubMedGoogle Scholar
  32. 32.
    Mannering SI, So M, Elso CM, Kay TWH (2018) Shuffling peptides to create T cell epitopes: does the immune system play cards? Immunol Cell Biol 96(1):34–40.  https://doi.org/10.1111/imcb.1015 CrossRefPubMedGoogle Scholar
  33. 33.
    Baker RL, Jamison BL, Wiles TA et al (2018) CD4 T cells reactive to hybrid insulin peptides are indicators of disease activity in the NOD mouse. Diabetes 67(9):1836–1846.  https://doi.org/10.2337/db18-0200 CrossRefPubMedGoogle Scholar
  34. 34.
    Seay HR, Yusko E, Rothweiler SJ et al (2016) Tissue distribution and clonal diversity of the T and B cell repertoire in type 1 diabetes. JCI Insight 1:e88242CrossRefGoogle Scholar
  35. 35.
    Heninger AK, Eugster A, Kuehn D et al (2017) A divergent population of autoantigen-responsive CD4+ T cells in infants prior to beta cell autoimmunity. Sci Transl Med 9(378):eaaf8848.  https://doi.org/10.1126/scitranslmed.aaf8848 CrossRefPubMedGoogle Scholar
  36. 36.
    Koch R (1882) Die Aetiologie der Tuberculose. Berl Klin Wscht 19:221 [article in German]Google Scholar
  37. 37.
    Viehmann Milam AA, Maher SE, Gibson JA et al (2014) A humanized mouse model of autoimmune insulitis. Diabetes 63(5):1712–1724.  https://doi.org/10.2337/db13-1141 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Tan S, Li Y, Xia J et al (2017) Type 1 diabetes induction in humanized mice. Proc Natl Acad Sci U S A 114(41):10954–10959.  https://doi.org/10.1073/pnas.1710415114 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Curin M, Khaitov M, Karaulov A et al (2018) Next-generation of allergen-specific immunotherapies: molecular approaches. Curr Allergy Asthma Rep 18(7):39.  https://doi.org/10.1007/s11882-018-0790-x CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Serra P, Santamaria P (2015) Nanoparticle-based autoimmune disease therapy. Clin Immunol 160(1):3–13.  https://doi.org/10.1016/j.clim.2015.02.003 CrossRefPubMedGoogle Scholar
  41. 41.
    Smith EL, Peakman M (2018) Peptide immunotherapy for type 1 diabetes-clinical advances. Front Immunol 9:392.  https://doi.org/10.3389/fimmu.2018.00392 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Immunology and Diabetes UnitSt. Vincent’s Institute of Medical ResearchFitzroy, MelbourneAustralia
  2. 2.Department of MedicineUniversity of MelbourneFitzroy, MelbourneAustralia

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