• 1
    Sprent J, Webb SR. Intrathymic and extrathymic clonal deletion of T cells. Curr Opin Immunol 1995;7:196205.
  • 2
    Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol 2006;24:571606.
  • 3
    Pugliese A. Central and peripheral autoantigen presentation in immune tolerance. Immunology 2004;111:13846.
  • 4
    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;49:9537.
  • 5
    Diez J, Park Y, Zeller M et al. Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen. Diabetes 2001;50:895900.
  • 6
    Pugliese A, Zeller M, Fernandez A Jr et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 1997;15:2937.
  • 7
    Vafiadis P, Bennett ST, Todd JA et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997;15:28992.
  • 8
    Vafiadis P, Ounissi-Benkalha H, Palumbo M et al. Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J Clin Endocrinol Metab 2001;86:370510.
  • 9
    Taubert R, Schwendemann J, Kyewski B. Highly variable expression of tissue-restricted self-antigens in human thymus: implications for self-tolerance and autoimmunity. Eur J Immunol 2007;37:83848.
  • 10
    Derbinski J, Gabler J, Brors B et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 2005;202:3345.
  • 11
    Klein L, Klugmann M, Nave KA, Kyewski B. Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells. Nat Med 2000;6:5661.
  • 12
    Pugliese A. Insulin: a critical autoantigen and potential therapeutic agent in Type 1 diabetes. Expert Rev Clin Immunol 2006;2:41931.
  • 13
    Anderson MS, Bluestone JA. The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 2005;23:44785.
  • 14
    Nakayama M, Abiru N, Moriyama H et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005;435:2203.
  • 15
    Wentworth BM, Schaefer IM, Villa-Komaroff L, Chirgwin JM. Characterization of the two nonallelic genes encoding mouse preproinsulin. J Mol Evol 1986;23:30512.
  • 16
    Zhu M, Chin RK, Christiansen PA et al. NF-kappaB2 is required for the establishment of central tolerance through an AIRE-dependent pathway. J Clin Invest 2006;116:296471.
  • 17
    Anderson MS, Venanzi ES, Klein L et al. Projection of an immunological self shadow within the thymus by the AIRE protein. Science 2002;298:1395401.
  • 18
    Nakayama M, Babaya N, Miao D, Sikora K, Elliott JF, Eisenbarth GS. Thymic expression of mutated B16: a preproinsulin messenger RNA does not reverse acceleration of NOD diabetes associated with insulin 2 (thymic expressed insulin) knockout. J Autoimmun 2005;25:1938.
  • 19
    Chentoufi AA, Polychronakos C. Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes 2002;51:138390.
  • 20
    Chen W, Bergerot I, Elliott JF et al. Evidence that a peptide spanning the B-C junction of proinsulin is an early autoantigen epitope in the pathogenesis of type 1 diabetes. J Immunol 2001;167:492635.
  • 21
    Brimnes MK, Jensen T, Jorgensen TN, Michelsen BK, Troelsen J, Werdelin O. Low expression of insulin in the thymus of non-obese diabetic mice. J Autoimmun 2002;19:20313.
  • 22
    Pugliese A, Brown D, Garza D et al. Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. J Clin Invest 2001;107:55564.
  • 23
    Garcia CA, Prabakar KR, Diez J et al. Dendritic cells in human thymus and periphery display a proinsulin epitope in a transcription-dependent, capture-independent fashion. J Immunol 2005;175:211122.
  • 24
    Zheng X, Yin L, Liu Y, Zheng P. Expression of tissue-specific autoantigens in the hematopoietic cells leads to activation-induced cell death of autoreactive T cells in the secondary lymphoid organs. Eur J Immunol 2004;34:312634.
  • 25
    Lee JW, Epardaud M, Sun J et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol 2007;8:18190.
  • 26
    Gardner JM, DeVoss JJ, Friedman RS et al. Deletional tolerance mediated by extrathymic AIRE-expressing cells. Science 2008;321:8437.
  • 27
    Kodama K, Butte AJ, Creusot RJ et al. Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice. Clin Immunol 2008;129:195201.
  • 28
    Thebault-Baumont K, Dubois-Laforgue D, Krief P et al. Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J Clin Invest 2003;111:8517.
  • 29
    Moriyama H, Abiru N, Paronen J et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proc Natl Acad Sci USA 2003;100:1037681.
  • 30
    Faideau B, Briand JP, Lotton C et al. Expression of preproinsulin-2 gene shapes the immune response to preproinsulin in normal mice. J Immunol 2004;172:2533.
  • 31
    Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D. The cellular mechanism of AIRE control of T cell tolerance. Immunity 2005;23:22739.
  • 32
    Narendran P, Neale AM, Lee BH et al. Proinsulin is encoded by an RNA splice variant in human blood myeloid cells. Proc Natl Acad Sci USA 2006;103:164305.
  • 33
    Throsby M, Homo-Delarche F, Chevenne D, Goya R, Dardenne M, Pleau JM. Pancreatic hormone expression in the murine thymus: localization in dendritic cells and macrophages. Endocrinology 1998;139:2399406.
  • 34
    Gotter J, Brors B, Hergenhahn M, Kyewski B. Medullary epithelial cells of the human thymus express a highly diverse selection of tissue-specific genes colocalized in chromosomal clusters. J Exp Med 2004;199:15566.
  • 35
    Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2001;2:10329.
  • 36
    Pugliese A, Diez J. Lymphoid organs contain diverse cells expressing self-molecules. Nat Immunol 2002;3:3356.
  • 37
    Carlsen M, Cilio CM. Evidence for de novo expression of thymic insulin by peripheral bone marrow-derived cells. Scand J Immunol 2008;68:6774.
  • 38
    Faideau B, Lotton C, Lucas B et al. Tolerance to proinsulin-2 is due to radioresistant thymic cells. J Immunol 2006;177:5360.
  • 39
    Paronen J, Moriyama H, Abiru N et al. Establishing insulin 1 and insulin 2 knockout congenic strains on NOD genetic background. Ann N Y Acad Sci 2003;1005:20510.
  • 40
    Schaefer BC, Schaefer ML, Kappler JW, Marrack P, Kedl RM. Observation of antigen-dependent CD8+ T-cell/dendritic cell interactions in vivo. Cell Immunol 2001;214:11022.
  • 41
    Halbout P, Briand JP, Becourt C, Muller S, Boitard C. T cell response to preproinsulin I and II in the nonobese diabetic mouse. J Immunol 2002;169:243643.
  • 42
    French MB, Allison J, Cram DS et al. Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes 1997;46:349.
  • 43
    Steptoe RJ, Ritchie JM, Harrison LC. Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes. J Clin Invest 2003;111:135763.
  • 44
    Chan J, Clements W, Field J et al. Transplantation of bone marrow genetically engineered to express proinsulin II protects against autoimmune insulitis in NOD mice. J Gene Med 2006;8:128190.
  • 45
    Tarbell KV, Petit L, Zuo X et al. Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med 2007;204:191201.
  • 46
    Tarbell KV, Yamazaki S, Steinman RM. The interactions of dendritic cells with antigen-specific, regulatory T cells that suppress autoimmunity. Semin Immunol 2006;18:93102.
  • 47
    Yamazaki S, Inaba K, Tarbell KV, Steinman RM. Dendritic cells expand antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of alloreactivity. Immunol Rev 2006;212:31429.
  • 48
    Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 2004;199:146777.
  • 49
    Kuroda N, Mitani T, Takeda N et al. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of AIRE-deficient mice. J Immunol 2005;174:186270.
  • 50
    Nomura T, Sakaguchi S. Foxp3 and AIRE in thymus-generated Treg cells: a link in self-tolerance. Nat Immunol 2007;8:3334.
  • 51
    Chen W. Dendritic cells and (CD4+)CD25+ T regulatory cells: crosstalk between two professionals in immunity versus tolerance. Front Biosci 2006;11:136070.
  • 52
    Tang Q, Adams JY, Penaranda C et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 2008;28:68797.
  • 53
    Jasinski JM, Yu L, Nakayama M et al. Transgenic insulin (B: 9-23) T-cell receptor mice develop autoimmune diabetes dependent upon RAG genotype, H-2g7 homozygosity, and insulin 2 gene knockout. Diabetes 2006;55:197884.