[en] BACKGROUND: Insulin and multiple other autoantigens have been implicated in the pathogenesis of autoimmune type 1 diabetes, but the origin of immunological self-reactivity specifically oriented against insulin-secreting islet beta-cells remains obscure. The primary objective of the present study was to investigate the hypothesis that a defect in thymic central T-cell self-tolerance of the insulin hormone family could contribute to the pathophysiology of type 1 diabetes. This hypothesis was investigated in a classic animal model of type 1 diabetes, the Bio-Breeding (BB) rat. METHODS: The expression of the mammalian insulin-related genes (Ins, Igf1 and Igf2) was analysed in the thymus of inbred Wistar Furth rats (WF), diabetes-resistant BB (BBDR) and diabetes-prone BB (BBDP) rats. RESULTS: RT-PCR analyses of total RNA from WF, BBDP and BBDR thymi revealed that Igf1 and Ins mRNAs are present in 15/15 thymi from 2-day-old, 5-day-old and 5-week-old WF, BBDR and BBDP rats. In contrast, a complete absence of Igf2 mRNA was observed in more than 80% of BBDP thymi. The absence of detectable Igf2 transcripts in the thymus of BBDP rats is tissue-specific, since Igf2 mRNAs were detected in all BBDP brains and livers examined. Using a specific immunoradiometric assay, the concentration of thymic IGF-2 protein was significantly lower in BBDP than in BBDR rats (p<0.01). CONCLUSIONS: The present study suggests an association between the emergence of autoimmune diabetes and a defect in Igf2 expression in the thymus of BBDP rats. This tissue-specific defect in gene expression could contribute both to the lymphopenia of these rats (by impaired T-cell development) and the absence of central T-cell self-tolerance of the insulin hormone family (by defective negative selection of self-reactive T-cells).
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Semple J.W., Lang Y., Speck E.R., Delovitch T.L. (1992) Processing and presentation of insulin. III. Insulin degrading enzyme: A neutral metalloendoproteinase that is non-homologous to classical endoproteinases mediates the processing of insulin epitopes for helper T cells. Int Immunol 4:1161-1167.
Wegmann D.R., Gill R.G., Norbury-Glaser M., Schloot N., Daniel D. (1994) Analysis of the spontaneous T cell response to insulin in NOD mice. J Autoimmun 7:833-843.
Rudy G., Stone N., Harrison L.C. (1995) Similar peptides from two beta cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes. Mol Med 1:625-633.
Griffin A.C., Zhao W., Wegmann K.W., Hickley W.F. (1995) Experimental autoimmune insulitis. Induction by T lymphocytes specific for a peptide of proinsulin. Am J Pathol 147:845-857.
Martens H., Goxe B., Geenen V. (1996) The thymic repertoire of neuroendocrine self-antigens: Physiological implications in T-cell life and death. Immunol Today 17:312-317.
Geenen V., Lefebvre P.J. (1998) The intrathymic expression of insulin-related genes: Implications for pathophysiology and prevention of type 1 diabetes. Diabetes Metab Rev 14:95-103.
Geenen V., Kecha O., Martens H. (1998) Thymic expression of neuroendocrine self-peptide precursors: Role in T cell survival and self-tolerance. J Neuroendocrinol 10:811-822.
Kisielow P., Bluthmann H., Staerz U.D., Steinmetz M., von Boehmer H. (1988) Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333:742-746.
Bonomo A., Matzinger P. (1993) Thymus epithelium induces tissue-specific tolerance. J Exp Med 177:1153-1164.
Sprent J. (1995) Central tolerance of T cells. Int Rev Immunol 13:95-105.
Geenen V., Achour I., Robert F. (1993) Evidence that insulin-like growth factor 2 (IGF2) is the dominant thymic peptide of the insulin superfamily. Thymus 21:115-127.
Arkins S., Rebeiz N., Biragyn A., Reese D., Kelley K. (1993) Murine macrophages express abundant insulin-like growth factor-I class I Ea and Eb transcripts. Endocrinology 133:2334-2343.
Van der Ven L.T., Roholl P.J., Reijnen-Gresnigt M.G., Bloemen R.J., van Buul-Offers S.C. (1997) Expression of insulin-like growth factor II (IGF-II) and histological changes in the thymus and spleen of transgenic mice overexpressing IGF-II. Histochem Cell Biol 107:193-203.
Kecha O., Martens H., Franchimont N. (1999) Characterization of the insulin-like growth factor axis in the human thymus. J Neuroendocrinol 11:435-440.
Kecha O., Brilot F., Martens H. (2000) Involvement of insulin-like growth factors in early T cell development: A study using fetal thymic organ cultures. Endocrinology 141:1209-1217.
Jolicoeur C., Hanahan D., Smith K.M. (1994) T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus. Proc Natl Acad Sci U S A 91:6707-6711.
Vafiadis P., Bennett S.T., Todd J.A. (1997) Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 15:289-292.
Pugliese A., Zeller M., Fernandez A. (1997) The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 15:293-297.
Throsby M., Homo-Delarche F., Chevenne D., Goya R., Dardenne M., Pleau J.M. (1998) Pancreatic hormone expression in the murine thymus: Localization in dendritic cells and macrophages. Endocrinology 139:2399-2406.
Heath V.L., Moore N.C., Parnell S.M., Mason D.W. (1998) Intrathymic expression of genes involved in organ specific autoimmune disease. J Autoimmun 11:309-318.
Mordes J.P., Bortell R., Doukas J. (1996) The BB/Wor rat and the balance hypothesis of autoimmunity. Diabetes Metab Rev 12:103-109.
Schechter R., Beju D., Gaffney T., Schaefer F., Whetsell L. (1996) Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res 736:16-27.
Purnelle G., Gerard A., Czajkowski V., Bourguignon J.P. (1997) Pulsatile secretion of gonadotropin-releasing hormone by rat hypothalamic explants without cell bodies of GnRH neurons. Neuroendocrinology , [corrected] [published erratum appears in Neuroendocrinology 1998; 67: 57]; 66:305-312.
Miles L.E., Lipschitz D.A., Bieber C.P., Cook J.D. (1974) Measurement of serum ferritin by a 2-site immunoradiometric assay. Anal Biochem 61:209-224.
Bach J.F. (1994) Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev 15:516-542.
Doukas J., Mordes J.P., Swymer C. (1994) Thymic epithelial defects and predisposition to autoimmune disease in BB rats. Am J Pathol 145:1517-1525.
Whalen B.J., Weiser P., Marounek J., Rossini A.A., Mordes J.P., Greiner D.L. (1999) Recapitulation of normal and abnormal BioBreeding rat T cell development in adult thymus organ culture. J Immunol 162:4003-4012.
Bieg S., Moller C., Olsson T., Lernmark A. (1997) The lymphopenia (lyp) gene controls the intrathymic cytokine ratio in congenic BioBreeding rats. Diabetologia 40:786-792.
Soares M.B., Ishii D.N., Efstratiadis A. (1985) Developmental and tissue-specific expression of a family of transcripts related to rat insulin-like growth factor II mRNA. Nucleic Acids Res 13:1119-1134.
Soares M.B., Turken A., Ishii D. (1986) Rat insulin-like growth factor II gene. A single gene with two promoters expressing a multitranscript family. J Mol Biol 192:737-752.
Graham D.E., Rechler M.M., Brown A.L. (1986) Coordinate developmental regulation of high and low molecular weight mRNAs for rat insulin-like growth factor II. Proc Natl Acad Sci U S A 83:4519-4523.
Frunzio R., Chiariotti L., Brown A.L., Graham D.E., Rechler M.M., Bruni C.B. (1986) Structure and expression of the rat insulin-like growth factor II (rIGF- II) gene. Rigf-II RNAs are transcribed from two promoters. J Biol Chem 261:17138-17149.
Brown A.L., Graham D.E., Nissley S.P., Hill D.J., Strain A.J., Rechler M.M. (1986) Developmental regulation of insulin-like growth factor II mRNA in different rat tissues. J Biol Chem 261:13144-13150.
Lund P.K., Moats-Staats B.M., Hynes M.A. (1986) Somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II mRNAs in rat fetal and adult tissues. J Biol Chem 261:14539-14544.
Rotwein P., Pollock K.M., Watson M., Milbrandt J.D. (1987) Insulin-like growth factor gene expression during rat embryonic development. Endocrinology 121:2141-2144.
Gray A., Tam A.W., Dull T.J. (1987) Tissue-specific and developmentally regulated transcription of the insulin-like growth factor 2 gene. DNA 6:283-295.
Stylianopoulou F., Herbert J., Soares M.B., Efstratiadis A. (1988) Expression of the insulin-like growth factor II gene in the choroid plexus and the leptomeninges of the adult rat central nervous system. Proc Natl Acad Sci U S A 85:141-145.
Crisa L., Mordes J.P., Rossini A.A. (1992) Autoimmune diabetes mellitus in the BB rat. Diabetes Metab Rev 8:4-37.
Martin A.M., Maxson M.N., Leif J., Mordes J.P., Greiner D.L., Blankenhorn E.P. (1999) Diabetes-prone and diabetes-resistant BB rats share a common major diabetes susceptibility locus, iddm4. Additional evidence for a "universal autoimmunity locus" on rat chromosome 4. Diabetes 48:2138-2144.
Martin A.M., Blankenhorn E.P., Maxson M.N. (1999) Non-major histocompatibility complex-linked diabetes susceptibility loci on chromosomes 4 and 13 in a backcross of the DP-BB/Wor rat to the WF rat. Diabetes 48:50-58.
Kloting I., Schmidt S., Kovacs P. (1998) Mapping of novel genes predisposing or protecting diabetes development in the BB/OK rat. Biochem Biophys Res Commun 245:483-486.
Bennett S.T., Wilson A.J., Cucca F. (1996) IDDM2-VNTR-encoded susceptibility to type 1 diabetes: Dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun 9:415-421.
Vafiadis P., Bennett S.T., Todd J.A., Grabs R., Polychronakos C. (1998) Divergence between genetic determinants of IGF2 transcription levels in leukocytes and of IDDM2-encoded susceptibility to type 1 diabetes. J Clin Endocrinol Metab 83:2933-2939.
Paquette J., Giannoukakis N., Polychronakos C., Vafiadis P., Deal C. (1998) The INS 5′ variable number of tandem repeats is associated with IGF2 expression in humans. J Biol Chem 273:14158-14164.
Pozzilli P., Pitocco D., Visalli N. (2000) No effect of oral insulin on residual beta-cell function in recent-onset type 1 diabetes. Diabetologia 43:1000-1004.
Chaillous L., Lefevre H., Thivolet C. (2000) Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: A multicentre randomised controlled trial. Lancet , Diabetes Insulin Oral Group; 356:545-549.
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.