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Open Access 01-07-2016 | Immunology and Transplantation (L Piemonti and V Sordi, Section Editors)

Where, How, and When: Positioning Posttranslational Modification Within Type 1 Diabetes Pathogenesis

Authors: Rene J. McLaughlin, Matthew P. Spindler, Menno van Lummel, Bart O. Roep

Published in: Current Diabetes Reports | Issue 7/2016

Abstract

Autoreactive T cells specific for islet autoantigens develop in type 1 diabetes (T1D) by escaping central as well as peripheral tolerance. The current paradigm for development of islet autoimmunity is just beginning to include the contribution of posttranslationally modified (PTM) islet autoantigens, for which the immune system may be ignorant rather than tolerant. As a result, PTM is the latest promising lead in the quest to understand how the break in peripheral tolerance occurs in T1D. However, it is not completely clear how, where, or when these modifications take place. Currently, only a few PTM antigens have been well-thought-out or identified in T1D, and methods for identifying and characterizing new PTM antigens are rapidly improving. This review will address both reported and potential new sources of modified islet autoantigens and discuss how islet neo-autoantigen generation may contribute to the development and progression of T1D.

Woittiez NJ, Roep BO. Impact of disease heterogeneity on treatment efficacy of immunotherapy in Type 1 diabetes: different shades of gray. Immunotherapy. 2015;7(2):163–74. doi:10.2217/imt.14.104.CrossRefPubMed

Lernmark A, Larsson HE. Immune therapy in type 1 diabetes mellitus. Nat Rev Endocrinol. 2013;9(2):92–103.CrossRefPubMed

Skyler JS. Primary and secondary prevention of Type 1 diabetes. Diabet Med. 2013;30(2):161–9.CrossRefPubMedPubMedCentral

von Herrath M, Peakman M, Roep B. Progress in immune-based therapies for type 1 diabetes. Clin ExpImmunol. 2013;172(2):186–202.

5.••

van Lummel M, Duinkerken G, van Veelen PA, de Ru A, Cordfunke R, Zaldumbide A, et al. Posttranslational modification of HLA-DQ binding islet autoantigens in type 1 diabetes. Diabetes. 2014;63:237–47. doi:10.2337/db12-1214. This is the first proof of ‘how’ PTM islet epitopes become modified to improve their binding to high-risk HLA-DQ molecules, leading to proinflammatory autoimmunity in T1D patients versus anti-inflammatory responses in healthy subjects.CrossRefPubMed

Mannering SI, Harrison LC, Williamson NA, Morris JS, Thearle DJ, Jensen KP, et al. The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J Exp Med. 2005;202(9):1191–7. doi:10.1084/jem.20051251.CrossRefPubMedPubMedCentral

International Human Genome Sequencing C. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–45. doi:10.1038/nature03001.CrossRef

Jensen ON. Modification-specific proteomics: characterization of post-translational modifications by mass spectrometry. Curr Opin Chem Biol. 2004;8(1):33–41. doi:10.1016/j.cbpa.2003.12.009.CrossRefPubMed

de Jong VM, Abreu JR, Verrijn Stuart AA, van der Slik AR, Verhaeghen K. Engelse MA et al. Diabetologia: Alternative splicing and differential expression of the islet autoantigen IGRP between pancreas and thymus contributes to immunogenicity of pancreatic islets but not diabetogenicity in humans; 2013.

10.

Dogra RS, Vaidyanathan P, Prabakar KR, Marshall KE, Hutton JC, Pugliese A. Alternative splicing of G6PC2, the gene coding for the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), results in differential expression in human thymus and spleen compared with pancreas. Diabetologia. 2006;49(5):953–7. doi:10.1007/s00125-006-0185-8.CrossRefPubMed

11.

Coppieters KT, Dotta F, Amirian N, Campbell PD, Kay TW, Atkinson MA, 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. 2012;209(1):51–60. doi:10.1084/jem.20111187.CrossRefPubMedPubMedCentral

12.

Bottazzo GF. Lawrence lecture. Death of a beta cell: homicide or suicide? Diabet Med. 1986;3(2):119–30.CrossRefPubMed

13.

Roep BO, Kleijwegt FS, van Halteren AG, Bonato V, Boggi U, Vendrame F, et al. Islet inflammation and CXCL10 in recent-onset type 1 diabetes. Clin Exp Immunol. 2010;159(3):338–43. doi:10.1111/j.1365-2249.2009.04087.x.CrossRefPubMedPubMedCentral

14.

Bruce SE, Bjarnason I, Peters TJ. Human jejunal transglutaminase: demonstration of activity, enzyme kinetics and substrate specificity with special relation to gliadin and coeliac disease. Clin Sci (Lond). 1985;68(5):573–9.CrossRef

15.

van Bergen J, Mulder CJ, Mearin ML, Koning F. Local communication among mucosal immune cells in patients with celiac disease. Gastroenterology. 2015;148(6):1187–94. doi:10.1053/j.gastro.2015.01.030.CrossRefPubMed

16.

Sileno S, D’Oria V, Stucchi R, Alessio M, Petrini S, Bonetto V, et al. A possible role of transglutaminase 2 in the nucleus of INS-1E and of cells of human pancreatic islets. J Proteome. 2014;96:314–27. doi:10.1016/j.jprot.2013.11.011.CrossRef

17.•

McLaughlin RJ, de Haan A, Zaldumbide A, de Koning EJ, de Ru AH, van Veelen PA, et al. Human islets and dendritic cells generate post-translationally modified islet auto-antigens. Clin Exp Immunol. 2016. This report demonstrates ‘where’ protein modifications can occur: in target tissue, as well as in the immune system.

18.

Hodrea J, Demeny MA, Majai G, Sarang Z, Korponay-Szabo IR, Fesus L. Transglutaminase 2 is expressed and active on the surface of human monocyte-derived dendritic cells and macrophages. Immunol Lett. 2010;130(1–2):74–81. doi:10.1016/j.imlet.2009.12.010.CrossRefPubMed

19.

Vomund AN, Zinselmeyer BH, Hughes J, Calderon B, Valderrama C, Ferris ST, et al. Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells. Proc Natl Acad Sci U S A. 2015;112(40):E5496–502. doi:10.1073/pnas.1515954112.CrossRefPubMedPubMedCentral

20.

Piacentini M, D’Eletto M, Farrace MG, Rodolfo C, Del Nonno F, Ippolito G, et al. Characterization of distinct sub-cellular location of transglutaminase type II: changes in intracellular distribution in physiological and pathological states. Cell Tissue Res. 2014;358(3):793–805. doi:10.1007/s00441-014-1990-x.CrossRefPubMedPubMedCentral

21.

Belkin AM. Extracellular TG2: emerging functions and regulation. FEBS J. 2011;278(24):4704–16. doi:10.1111/j.1742-4658.2011.08346.x.CrossRefPubMedPubMedCentral

22.

Foulquier C, Sebbag M, Clavel C, Chapuy-Regaud S, Al Badine R, Mechin MC, et al. Peptidyl arginine deiminase type 2 (PAD-2) and PAD-4 but not PAD-1, PAD-3, and PAD-6 are expressed in rheumatoid arthritis synovium in close association with tissue inflammation. Arthritis Rheum. 2007;56(11):3541–53. doi:10.1002/art.22983.CrossRefPubMed

23.

Ireland JM, Unanue ER. Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells. J Exp Med. 2011;208(13):2625–32. doi:10.1084/jem.20110640.CrossRefPubMedPubMedCentral

24.

Chang KY, Unanue ER. Prediction of HLA-DQ8beta cell peptidome using a computational program and its relationship to autoreactive T cells. Int Immunol. 2009;21(6):705–13. doi:10.1093/intimm/dxp039.CrossRefPubMedPubMedCentral

25.

Nishimura Y, Oiso M, Fujisao S, Kanai T, Kira J, Chen YZ, et al. Peptide-based molecular analyses of HLA class II-associated susceptibility to autoimmune diseases. Int Rev Immunol. 1998;17(5–6):229–62.CrossRefPubMed

26.

van Lummel M, van Veelen PA, Zaldumbide A, de Ru A, Janssen GM, Moustakas AK, et al. Type 1 diabetes-associated HLA-DQ8 transdimer accommodates a unique peptide repertoire. J Biol Chem. 2012;287(12):9514–24. doi:10.1074/jbc.M111.313940.CrossRefPubMed

27.

Gottlieb PA, Delong T, Baker RL, Fitzgerald-Miller L, Wagner R, Cook G, et al. Chromogranin A is a T cell antigen in human type 1 diabetes. J Autoimmun. 2014;50:38–41. doi:10.1016/j.jaut.2013.10.003.CrossRefPubMed

28.

Kooy-Winkelaar Y, van Lummel M, Moustakas AK, Schweizer J, Mearin ML, Mulder CJ, et al. Gluten-specific T cells cross-react between HLA-DQ8 and the HLA-DQ2alpha/DQ8beta transdimer. J Immunol. 2011;187(10):5123–9. doi:10.4049/jimmunol.1101179.CrossRefPubMed

29.

McGinty JW, Chow IT, Greenbaum C, Odegard J, Kwok WW, James EA. Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes. 2014;63(9):3033–40. doi:10.2337/db13-1952.CrossRefPubMedPubMedCentral

30.

Rondas D, Crevecoeur I, D’Hertog W, Ferreira GB, Staes A, Garg AD, et al. Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes. Diabetes. 2015;64(2):573–86. doi:10.2337/db14-0621.CrossRefPubMed

31.

Koning F. Recent insight in the pathophysiology of coeliac disease: relevance to rheumatoid arthritis. Clin Exp Rheumatol. 2015;33(4 Suppl 92):8–10.

32.

Koning F, Thomas R, Rossjohn J, Toes RE. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat Rev Rheumatol. 2015;11(8):450–61. doi:10.1038/nrrheum.2015.59.CrossRefPubMed

33.

Petersen J, Montserrat V, Mujico JR, Loh KL, Beringer DX, van Lummel M, et al. T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. Nat Struct Mol Biol. 2014;21(5):480–8. doi:10.1038/nsmb.2817.CrossRefPubMed

34.

Sollid LM, Jabri B. Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Curr Opin Immunol. 2011;23(6):732–8. doi:10.1016/j.coi.2011.08.006.CrossRefPubMedPubMedCentral

35.

Campbell-Thompson M, Wasserfall C, Montgomery EL, Atkinson MA, Kaddis JS. Pancreas organ weight in individuals with disease-associated autoantibodies at risk for type 1 diabetes. JAMA. 2012;308(22):2337–9. doi:10.1001/jama.2012.15008.CrossRefPubMed

36.

Dotta F, Censini S, van Halteren AG, Marselli L, Masini M, Dionisi S, 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. 2007;104(12):5115–20. doi:10.1073/pnas.0700442104.CrossRefPubMedPubMedCentral

37.

Marietta EV, Gomez AM, Yeoman C, Tilahun AY, Clark CR, Luckey DH, et al. Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome. PLoS One. 2013;8(11), e78687. doi:10.1371/journal.pone.0078687.CrossRefPubMedPubMedCentral

38.

Funda DP, Kaas A, Bock T, Tlaskalova-Hogenova H, Buschard K. Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab Res Rev. 1999;15(5):323–7.CrossRefPubMed

39.

Funda DP, Kaas A, Tlaskalova-Hogenova H, Buschard K. Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes. Diabetes Metab Res Rev. 2008;24(1):59–63. doi:10.1002/dmrr.748.CrossRefPubMed

40.

Sildorf SM, Fredheim S, Svensson J, Buschard K. Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus. BMJ Case Rep. 2012;2012. doi:10.1136/bcr.02.2012.5878

41.

Larsen J, Weile C, Antvorskov JC, Engkilde K, Nielsen SM, Josefsen K, et al. Effect of dietary gluten on dendritic cells and innate immune subsets in BALB/c and NOD mice. PLoS One. 2015;10(3), e0118618. doi:10.1371/journal.pone.0118618.CrossRefPubMedPubMedCentral

42.

Davis-Richardson AG, Triplett EW. A model for the role of gut bacteria in the development of autoimmunity for type 1 diabetes. Diabetologia. 2015;58(7):1386–93. doi:10.1007/s00125-015-3614-8.CrossRefPubMedPubMedCentral

43.

Sabbah E, Savola K, Kulmala P, Reijonen H, Veijola R, Vahasalo P, et al. Disease-associated autoantibodies and HLA-DQB1 genotypes in children with newly diagnosed insulin-dependent diabetes mellitus (IDDM). The Childhood Diabetes in Finland Study Group. Clin Exp Immunol. 1999;116(1):78–83.CrossRefPubMedPubMedCentral

44.

Bernard NJ. Rheumatoid arthritis: changes in ACPA Fc glycosylation patterns prior to RA onset. Nat Rev Rheumatol. 2013;9(12):697. doi:10.1038/nrrheum.2013.162.CrossRefPubMed

45.

Rombouts Y, Willemze A, van Beers JJ, Shi J, Kerkman PF, van Toorn L, et al. Extensive glycosylation of ACPA-IgG variable domains modulates binding to citrullinated antigens in rheumatoid arthritis. Ann Rheum Dis. 2015. doi:10.1136/annrheumdis-2014-206598.

46.

Trigwell SM, Radford PM, Page SR, Loweth AC, James RF, Morgan NG, et al. Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus. Clin Exp Immunol. 2001;126(2):242–9.CrossRefPubMedPubMedCentral

47.

Strollo R, Rizzo P, Spoletini M, Landy R, Hughes C, Ponchel F, et al. HLA-dependent autoantibodies against post-translationally modified collagen type II in type 1 diabetes mellitus. Diabetologia. 2013;56(3):563–72. doi:10.1007/s00125-012-2780-1.CrossRefPubMed

48.•

Strollo R, Vinci C, Arshad MH, Perrett D, Tiberti C, Chiarelli F, et al. Antibodies to post-translationally modified insulin in type 1 diabetes. Diabetologia. 2015;58:2851–60. doi:10.1007/s00125-015-3746-x. These findings indicate ‘when’ PTM become important in disease pathogenesis by showing that identification of antibodies specific for modified insulin was more sensitive than current standard insulin-autoantibody assay. This may imply that PTM is an important factor in the early stages of the autoimmune response.CrossRefPubMed

49.

Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996;45(7):926–33.CrossRefPubMed

50.

Arif S, Leete P, Nguyen V, Marks K, Nor NM, Estorninho M, et al. Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes. 2014;63(11):3835–45. doi:10.2337/db14-0365.CrossRefPubMedPubMedCentral

51.

Jin Y, Sharma A, Bai S, Davis C, Liu H, Hopkins D, et al. Risk of type 1 diabetes progression in islet autoantibody-positive children can be further stratified using expression patterns of multiple genes implicated in peripheral blood lymphocyte activation and function. Diabetes. 2014;63(7):2506–15. doi:10.2337/db13-1716.CrossRefPubMedPubMedCentral

52.

Jin Y, She JX. Novel biomarkers in type 1 diabetes. Rev Diabet Stud. 2012;9(4):224–35. doi:10.1900/RDS.2012.9.224.CrossRefPubMed

53.

Zhi W, Sharma A, Purohit S, Miller E, Bode B, Anderson SW, 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 Proteomics. 2011;10:M111–012203. doi:10.1074/mcp.M111.012203.CrossRefPubMedPubMedCentral

54.

Gibson VB, Nikolic T, Pearce VQ, Demengeot J, Roep BO, Peakman M. Proinsulin multi-peptide immunotherapy induces antigen-specific regulatory T cells and limits autoimmunity in a humanized model. Clin Exp Immunol. 2015;182(3):251–60. doi:10.1111/cei.12687.CrossRefPubMed

55.

Kleijwegt FS, Jansen DT, Teeler J, Joosten AM, Laban S, Nikolic T, et al. Tolerogenic dendritic cells impede priming of naive CD8(+) T cells and deplete memory CD8(+) T cells. Eur J Immunol. 2013;43(1):85–92. doi:10.1002/eji.201242879.CrossRefPubMed

56.

Suwandi JS, Toes RE, Nikolic T, Roep BO. Inducing tissue specific tolerance in autoimmune disease with tolerogenic dendritic cells. Clin Exp Rheumatol. 2015;33(4 Suppl 92):97–103.

57.

Coppieters KT, Roep BO, von Herrath MG. Beta cells under attack: toward a better understanding of type 1 diabetes immunopathology. SeminImmunopathol. 2011;33(1):1–7.

58.

Eizirik DL, Miani M, Cardozo AK. Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia. 2013;56(2):234–41.CrossRefPubMed

59.

Melief CJ, van der Burg SH. Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat Rev Cancer. 2008;8(5):351–60. doi:10.1038/nrc2373.CrossRefPubMed

60.

Vehik K, Cuthbertson D, Ruhlig H, Schatz DA, Peakman M, Krischer JP, et al. Long-term outcome of individuals treated with oral insulin: diabetes prevention trial-type 1 (DPT-1) oral insulin trial. Diabetes Care. 2011;34(7):1585–90. doi:10.2337/dc11-0523.CrossRefPubMedPubMedCentral

61.

Ringers J, van der Torren CR, van de Linde P, van der Boog PJ, Mallat MJ, Bonifacio E, et al. Pretransplantation GAD-Autoantibody Status to Guide Prophylactic Antibody Induction Therapy in Simultaneous Pancreas and Kidney Transplantation. Transplantation. 2013;96(8):745–52. doi:10.1097/TP.0b013e3182a012cc.CrossRefPubMed

62.

Bradford CM, Ramos I, Cross AK, Haddock G, McQuaid S, Nicholas AP, et al. Localisation of citrullinated proteins in normal appearing white matter and lesions in the central nervous system in multiple sclerosis. J Neuroimmunol. 2014;273(1–2):85–95. doi:10.1016/j.jneuroim.2014.05.007.CrossRefPubMed

63.

Gudmann NS, Hansen NU, Jensen AC, Karsdal MA, Siebuhr AS. Biological relevance of citrullinations: diagnostic, prognostic and therapeutic options. Autoimmunity. 2015;48(2):73–9. doi:10.3109/08916934.2014.962024.CrossRefPubMed

64.

Greer JM, Pender MP. Myelin proteolipid protein: an effective autoantigen and target of autoimmunity in multiple sclerosis. J Autoimmun. 2008;31(3):281–7. doi:10.1016/j.jaut.2008.04.018.CrossRefPubMed

65.

Weimbs T, Stoffel W. Proteolipid protein (PLP) of CNS myelin: positions of free, disulfide-bonded, and fatty acid thioester-linked cysteine residues and implications for the membrane topology of PLP. Biochemistry. 1992;31(49):12289–96.CrossRefPubMed

66.

Baldwin AC, Green CD, Olson LK, Moxley MA, Corbett JA. A role for aberrant protein palmitoylation in FFA-induced ER stress and beta-cell death. Am J Physiol Endocrinol Metab. 2012;302(11):E1390–8. doi:10.1152/ajpendo.00519.2011.CrossRefPubMedPubMedCentral

67.

Pfender NA, Grosch S, Roussel G, Koch M, Trifilieff E, Greer JM. Route of uptake of palmitoylated encephalitogenic peptides of myelin proteolipid protein by antigen-presenting cells: importance of the type of bond between lipid chain and peptide and relevance to autoimmunity. J Immunol. 2008;180(3):1398–404.CrossRefPubMed

68.

Ntranos A, Casaccia P. Bromodomains: translating the words of lysine acetylation into myelin injury and repair. Neurosci Lett. 2015. doi:10.1016/j.neulet.2015.10.015.PubMed

69.

Zamvil SS, Mitchell DJ, Moore AC, Kitamura K, Steinman L, Rothbard JB. T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. Nature. 1986;324(6094):258–60. doi:10.1038/324258a0.CrossRefPubMed

70.

Battistini L, Piccio L, Rossi B, Bach S, Galgani S, Gasperini C, et al. CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1. Blood. 2003;101(12):4775–82. doi:10.1182/blood-2002-10-3309.CrossRefPubMed

71.

Broughton SE, Petersen J, Theodossis A, Scally SW, Loh KL, Thompson A, et al. Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease. Immunity. 2012;37(4):611–21. doi:10.1016/j.immuni.2012.07.013.CrossRefPubMed

72.

Vincentini O, Maialetti F, Gonnelli E, Silano M. Gliadin-dependent cytokine production in a bidimensional cellular model of celiac intestinal mucosa. Clin Exp Med. 2015;15(4):447–54. doi:10.1007/s10238-014-0325-2.CrossRefPubMed

73.

Clancy KW, Weerapana E, Thompson PR. Detection and identification of protein citrullination in complex biological systems. Curr Opin Chem Biol. 2015;30:1–6. doi:10.1016/j.cbpa.2015.10.014.CrossRefPubMed

74.

Scally SW, Petersen J, Law SC, Dudek NL, Nel HJ, Loh KL, et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J Exp Med. 2013;210(12):2569–82. doi:10.1084/jem.20131241.CrossRefPubMedPubMedCentral

75.

Mastrangelo A, Colasanti T, Barbati C, Pecani A, Sabatinelli D, Pendolino M, et al. The role of posttranslational protein modifications in rheumatological diseases: focus on rheumatoid arthritis. J Immunol Res. 2015;2015:712490. doi:10.1155/2015/712490.CrossRefPubMedPubMedCentral

76.

Pruijn GJ. Citrullination and carbamylation in the pathophysiology of rheumatoid arthritis. Front Immunol. 2015;6:192. doi:10.3389/fimmu.2015.00192.CrossRefPubMedPubMedCentral

77.

Khan MW, Sherwani S, Khan WA, Ali R. Characterization of hydroxyl radical modified GAD65: a potential autoantigen in type 1 diabetes. Autoimmunity. 2009;42(2):150–8. doi:10.1080/08916930802468276.CrossRefPubMed

78.

Mirarabshahi P, Abdelatti M, Krilis S. Post-translational oxidative modification of beta2-glycoprotein I and its role in the pathophysiology of the antiphospholipid syndrome. Autoimmun Rev. 2012;11(11):779–80. doi:10.1016/j.autrev.2011.12.007.CrossRefPubMed

79.

Passam FH, Giannakopoulos B, Mirarabshahi P, Krilis SA. Molecular pathophysiology of the antiphospholipid syndrome: the role of oxidative post-translational modification of beta 2 glycoprotein I. J Thromb Haemost. 2011;9 Suppl 1:275–82. doi:10.1111/j.1538-7836.2011.04301.x.CrossRefPubMed

80.

Kondo A, Miyamoto T, Yonekawa O, Giessing AM, Osterlund EC, Jensen ON. Glycopeptide profiling of beta-2-glycoprotein I by mass spectrometry reveals attenuated sialylation in patients with antiphospholipid syndrome. J Proteomics. 2009;73(1):123–33. doi:10.1016/j.jprot.2009.08.007.CrossRefPubMed

81.

Neugebauer KM, Merrill JT, Wener MH, Lahita RG, Roth MB. SR proteins are autoantigens in patients with systemic lupus erythematosus. Importance of phosphoepitopes. Arthritis Rheum. 2000;43(8):1768–78. doi:10.1002/1529-0131(200008)43:8<1768::AID-ANR13>3.0.CO;2-9.CrossRefPubMed

82.

Dwivedi N, Neeli I, Schall N, Wan H, Desiderio DM, Csernok E, et al. Deimination of linker histones links neutrophil extracellular trap release with autoantibodies in systemic autoimmunity. FASEB J. 2014;28(7):2840–51. doi:10.1096/fj.13-247254.CrossRefPubMedPubMedCentral

83.

Doyle HA, Yang ML, Raycroft MT, Gee RJ, Mamula MJ. Autoantigens: novel forms and presentation to the immune system. Autoimmunity. 2014;47(4):220–33. doi:10.3109/08916934.2013.850495.CrossRefPubMed

Title: Where, How, and When: Positioning Posttranslational Modification Within Type 1 Diabetes Pathogenesis
Authors: Rene J. McLaughlin
Matthew P. Spindler
Menno van Lummel
Bart O. Roep
Publication date: 01-07-2016
Publisher: Springer US
Published in: Current Diabetes Reports / Issue 7/2016
Print ISSN: 1534-4827
Electronic ISSN: 1539-0829
DOI: https://doi.org/10.1007/s11892-016-0752-4

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