Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 11438K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by von Herrath, M. G. Articles by Oldstone, M. B.A. Search for Related Content PubMed PubMed Citation Articles by von Herrath, M. G. Articles by Oldstone, M. B.A. Social Bookmarking                            What's this?

Articles

Interferon- Is Essential for Destruction of β Cells and Development of Insulin-dependent Diabetes Mellitus

From The Scripps Research Institute, Division of Virology, Department of Neuropharmacology, La Jolla, California 92037

Autoimmune mediated destruction of β cells of the islets of Langerhans leads to insulin-dependent diabetes mellitus (IDDM). Rat insulin promoter (RIP) lymphocytic choriomeningitis virus (LCMV) transgenic mice that express the nucleoprotein (NP) or glycoprotein (GP) of LCMV under control of the RIP in their β cells develop IDDM after infection with LCMV and serve as a model for virus-induced IDDM. Recently, Kagi et al. (Kagi, D., B. Odermatt, P. Ohashi, R.M. Zinkernagel, and H. Hengartner. 1996. J. Exp. Med. 183:2143–2149) showed, using RIP LCMV perforin-deficient mice, that IDDM does not occur in the absence of perforin. They concluded that perforin-mediated killing by cytotoxic T lymphocytes (CTLs) is the main factor needed for β cell injury and destruction. Here we provide evidence that killing of β cells is more complex and multifactorial. By the use of our RIP LCMV model, we show that in perforin competent but interferon- (IFN-)–deficient mice, β cell injury is limited and IDDM does not occur. For these studies, double transgenic mice were generated that were genetically deficient in the production of IFN- and express LCMV NP or GP in their β cells. In such mice, IDDM was aborted despite the generation of LCMV-specific antiself CTLs that displayed normal cytolytic activity in vitro and in vivo and entered the pancreas. However, mononuclear infiltration into the islets did not occur, and upregulation of class I and II molecules usually found in islets of RIP LCMV single transgenic mice after LCMV infection preceding the onset of clinical IDDM was not present in these bigenic mice. Our findings indicate that in addition to perforin, β cell destruction, development of insulitis, and IDDM also depend on the cytokine INF-, presumably through enhancement of major histocompatibility complex expression and antigen presentation.

This work was supported by United States Public Health Service grant AG04342 to M.B.A. Oldstone and National Institutes of Health grant DK995005 and a Career Development Award of the Juvenile Diabetes Foundation International to Matthias G. von Herrath.

¹Abbreviations used in this paper: ARM, Armstrong; GP, glycoprotein; IDDM, insulin-dependent diabetes mellitus; LCMV, lymphocytic choriomeningitis virus; NOD, nonobese diabetic; NP, nucleoprotein; RIP, rat insulin promoter; tg, transgenic.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Brosi, H., Reiser, M., Rajasalu, T., Spyrantis, A., Oswald, F., Boehm, B. O., Schirmbeck, R. (2009). Processing in the Endoplasmic Reticulum Generates an Epitope on the Insulin A Chain that Stimulates Diabetogenic CD8 T Cell Responses. J. Immunol. 183: 7187-7195 [Abstract] [Full Text]  
• Horwitz, M. S., Efrat, S., Christen, U., von Herrath, M. G., Oldstone, M. B. A. (2009). Adenovirus E3 MHC inhibitory genes but not TNF/Fas apoptotic inhibitory genes expressed in {beta} cells prevent autoimmune diabetes. Proc. Natl. Acad. Sci. USA 106: 19450-19454 [Abstract] [Full Text]  
• Tanaka, S., Nishida, Y., Aida, K., Maruyama, T., Shimada, A., Suzuki, M., Shimura, H., Takizawa, S., Takahashi, M., Akiyama, D., Arai-Yamashita, S., Furuya, F., Kawaguchi, A., Kaneshige, M., Katoh, R., Endo, T., Kobayashi, T. (2009). Enterovirus Infection, CXC Chemokine Ligand 10 (CXCL10), and CXCR3 Circuit: A Mechanism of Accelerated {beta}-Cell Failure in Fulminant Type 1 Diabetes. Diabetes 58: 2285-2291 [Abstract] [Full Text]  
• Lang, P. A., Cervantes-Barragan, L., Verschoor, A., Navarini, A. A., Recher, M., Pellegrini, M., Flatz, L., Bergthaler, A., Honda, K., Ludewig, B., Ohashi, P. S., Lang, K. S. (2009). Hematopoietic cell-derived interferon controls viral replication and virus-induced disease. Blood 113: 1045-1052 [Abstract] [Full Text]  
• Dotta, F., Censini, S., van Halteren, A. G. S., Marselli, L., Masini, M., Dionisi, S., Mosca, F., Boggi, U., Muda, A. O., Prato, S. D., Elliott, J. F., Covacci, A., Rappuoli, R., Roep, B. O., Marchetti, P. (2007). Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc. Natl. Acad. Sci. USA 104: 5115-5120 [Abstract] [Full Text]  
• Long, M., Slaiby, A. M., Hagymasi, A. T., Mihalyo, M. A., Lichtler, A. C., Reiner, S. L., Adler, A. J. (2006). T-bet Down-Modulation in Tolerized Th1 Effector CD4 Cells Confers a TCR-Distal Signaling Defect That Selectively Impairs IFN-{gamma} Expression. J. Immunol. 176: 1036-1045 [Abstract] [Full Text]  
• Fujinami, R. S., von Herrath, M. G., Christen, U., Whitton, J. L. (2006). Molecular Mimicry, Bystander Activation, or Viral Persistence: Infections and Autoimmune Disease. Clin. Microbiol. Rev. 19: 80-94 [Abstract] [Full Text]  
• Yasunami, Y., Kojo, S., Kitamura, H., Toyofuku, A., Satoh, M., Nakano, M., Nabeyama, K., Nakamura, Y., Matsuoka, N., Ikeda, S., Tanaka, M., Ono, J., Nagata, N., Ohara, O., Taniguchi, M. (2005). V{alpha}14 NK T cell-triggered IFN-{gamma} production by Gr-1+CD11b+ cells mediates early graft loss of syngeneic transplanted islets. JEM 202: 913-918 [Abstract] [Full Text]  
• Medarova, Z., Bonner-Weir, S., Lipes, M., Moore, A. (2005). Imaging {beta}-Cell Death With a Near-Infrared Probe. Diabetes 54: 1780-1788 [Abstract] [Full Text]  
• Sarween, N., Chodos, A., Raykundalia, C., Khan, M., Abbas, A. K., Walker, L. S. K. (2004). CD4+CD25+ Cells Controlling a Pathogenic CD4 Response Inhibit Cytokine Differentiation, CXCR-3 Expression, and Tissue Invasion. J. Immunol. 173: 2942-2951 [Abstract] [Full Text]  
• Juedes, A. E., Rodrigo, E., Togher, L., Glimcher, L. H., von Herrath, M. G. (2004). T-bet Controls Autoaggressive CD8 Lymphocyte Responses in Type 1 Diabetes. JEM 199: 1153-1162 [Abstract] [Full Text]  
• Walker, L. S. K., Ausubel, L. J., Chodos, A., Bekarian, N., Abbas, A. K. (2002). CTLA-4 Differentially Regulates T Cell Responses to Endogenous Tissue Protein Versus Exogenous Immunogen. J. Immunol. 169: 6202-6209 [Abstract] [Full Text]  
• Pien, G. C., Nguyen, K. B., Malmgaard, L., Satoskar, A. R., Biron, C. A. (2002). A Unique Mechanism for Innate Cytokine Promotion of T Cell Responses to Viral Infections. J. Immunol. 169: 5827-5837 [Abstract] [Full Text]  
• Yu, S., Sharp, G. C., Braley-Mullen, H. (2002). Dual Roles for IFN-{gamma}, But Not for IL-4, in Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 Mice. J. Immunol. 169: 3999-4007 [Abstract] [Full Text]  
• Wilcox, R. A., Flies, D. B., Wang, H., Tamada, K., Johnson, A. J., Pease, L. R., Rodriguez, M., Guo, Y., Chen, L. (2002). Impaired Infiltration of Tumor-specific Cytolytic T Cells in the Absence of Interferon-{gamma} despite Their Normal Maturation in Lymphoid Organs during CD137 Monoclonal Antibody Therapy. Cancer Res. 62: 4413-4418 [Abstract] [Full Text]  
• Thomas, H. E., Darwiche, R., Corbett, J. A., Kay, T. W.H. (2002). Interleukin-1 Plus {gamma}-Interferon-Induced Pancreatic {beta}-Cell Dysfunction Is Mediated by {beta}-Cell Nitric Oxide Production. Diabetes 51: 311-316 [Abstract] [Full Text]  
• von Herrath, M. G., Wolfe, T., Mohrle, U., Coon, B., Hughes, A. (2001). Protection From Type 1 Diabetes in the Face of High Levels of Activated Autoaggressive Lymphocytes in a Viral Transgenic Mouse Model Crossed to the SV129 Strain. Diabetes 50: 2700-2708 [Abstract] [Full Text]  
• Savinov, A. Y., Wong, F. S., Chervonsky, A. V. (2001). IFN-{gamma} Affects Homing of Diabetogenic T Cells. J. Immunol. 167: 6637-6643 [Abstract] [Full Text]  
• Christen, U., Wolfe, T., Mohrle, U., Hughes, A. C., Rodrigo, E., Green, E. A., Flavell, R. A., von Herrath, M. G. (2001). A Dual Role for TNF-{{alpha}} in Type 1 Diabetes: Islet-Specific Expression Abrogates the Ongoing Autoimmune Process When Induced Late but Not Early During Pathogenesis. J. Immunol. 166: 7023-7032 [Abstract] [Full Text]  
• Pauza, M. E., Nguyen, A., Wolfe, T., Ho, I-C., Glimcher, L. H., von Herrath, M., Lo, D. (2001). Variable Effects of Transgenic c-Maf on Autoimmune Diabetes. Diabetes 50: 39-46 [Abstract] [Full Text]  
• Vizler, C., Bercovici, N., Heurtier, A., Pardigon, N., Goude, K., Bailly, K., Combadiere, C., Liblau, R. S. (2000). Relative Diabetogenic Properties of Islet-Specific Tc1 and Tc2 Cells in Immunocompetent Hosts. J. Immunol. 165: 6314-6321 [Abstract] [Full Text]  
• Varga, S. M., Wissinger, E. L., Braciale, T. J. (2000). The Attachment (G) Glycoprotein of Respiratory Syncytial Virus Contains a Single Immunodominant Epitope That Elicits Both Th1 and Th2 CD4+ T Cell Responses. J. Immunol. 165: 6487-6495 [Abstract] [Full Text]  
• Matthys, P., Vermeire, K., Heremans, H., Billiau, A. (2000). The protective effect of IFN-{gamma} in experimental autoimmune diseases: a central role of mycobacterial adjuvant-induced myelopoiesis. J. Leukoc. Biol. 68: 447-454 [Abstract] [Full Text]  
• Diamond, A. S., Gill, R. G. (2000). An Essential Contribution by IFN-{gamma} to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts. J. Immunol. 165: 247-255 [Abstract] [Full Text]  
• Sevilla, N., Homann, D., von Herrath, M., Rodriguez, F., Harkins, S., Whitton, J. L., Oldstone, M. B. A. (2000). Virus-Induced Diabetes in a Transgenic Model: Role of Cross-Reacting Viruses and Quantitation of Effector T Cells Needed To Cause Disease. J. Virol. 74: 3284-3292 [Abstract] [Full Text]  
• Su, X., Hu, Q., Kristan, J. M., Costa, C., Shen, Y., Gero, D., Matis, L. A., Wang, Y. (2000). Significant Role for Fas in the Pathogenesis of Autoimmune Diabetes. J. Immunol. 164: 2523-2532 [Abstract] [Full Text]  
• Nugent, C. T., Morgan, D. J., Biggs, J. A., Ko, A., Pilip, I. M., Pamer, E. G., Sherman, L. A. (2000). Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas. J. Immunol. 164: 191-200 [Abstract] [Full Text]  
• Holz, A., Bot, A., Coon, B., Wolfe, T., Grusby, M. J., von Herrath, M. G. (1999). Disruption of the STAT4 Signaling Pathway Protects from Autoimmune Diabetes While Retaining Antiviral Immune Competence. J. Immunol. 163: 5374-5382 [Abstract] [Full Text]  
• Kreuwel, H. T. C., Morgan, D. J., Krahl, T., Ko, A., Sarvetnick, N., Sherman, L. A. (1999). Comparing the Relative Role of Perforin/Granzyme Versus Fas/Fas Ligand Cytotoxic Pathways in CD8+ T Cell-Mediated Insulin-Dependent Diabetes Mellitus. J. Immunol. 163: 4335-4341 [Abstract] [Full Text]  
• Schell, T. D., Mylin, L. M., Georgoff, I., Teresky, A. K., Levine, A. J., Tevethia, S. S. (1999). Cytotoxic T-Lymphocyte Epitope Immunodominance in the Control of Choroid Plexus Tumors in Simian Virus 40 Large T Antigen Transgenic Mice. J. Virol. 73: 5981-5993 [Abstract] [Full Text]  
• Pakala, S. V., Chivetta, M., Kelly, C. B., Katz, J. D. (1999). In Autoimmune Diabetes the Transition from Benign to Pernicious Insulitis Requires an Islet Cell Response to Tumor Necrosis Factor {alpha}. JEM 189: 1053-1062 [Abstract] [Full Text]  
• Zhang, G.-X., Xiao, B.-G., Bai, X.-F., van der Meide, P. H., Orn, A., Link, H. (1999). Mice with IFN-{gamma} Receptor Deficiency Are Less Susceptible to Experimental Autoimmune Myasthenia Gravis. J. Immunol. 162: 3775-3781 [Abstract] [Full Text]  
• Bradley, L. M., Asensio, V. C., Schioetz, L.-K., Harbertson, J., Krahl, T., Patstone, G., Woolf, N., Campbell, I. L., Sarvetnick, N. (1999). Islet-Specific Th1, But Not Th2, Cells Secrete Multiple Chemokines and Promote Rapid Induction of Autoimmune Diabetes. J. Immunol. 162: 2511-2520 [Abstract] [Full Text]  
• Ludewig, B., Odermatt, B., Landmann, S., Hengartner, H., Zinkernagel, R. M. (1998). Dendritic Cells Induce Autoimmune Diabetes and Maintain Disease via De Novo Formation of Local Lymphoid Tissue. JEM 188: 1493-1501 [Abstract] [Full Text]  
• Oldstone, M. B. A. (1998). Molecular mimicry and immune-mediated diseases. FASEB J. 12: 1255-1265 [Abstract] [Full Text]  
• Yoshida, H., Yoshida, O., Iwamoto, H., Nishino, K., Hashida, M., Fukushima, A., Ueno, H. (1998). Analysis of effects of stimulation in vitro of ovalbumin primed lymph node cells on adoptive transfer of experimental immune mediated blepharoconjunctivitis in Lewis rats. Br J Ophthalmol 82: 1189-1194 [Abstract] [Full Text]  
• Baldeon, M. E., Chun, T., Gaskins, H. R. (1998). Interferon-alpha and interferon-gamma differentially affect pancreatic beta -cell phenotype and function. Am. J. Physiol. Cell Physiol. 275: C25-C32 [Abstract] [Full Text]  
• Kono, D. H., Balomenos, D., Pearson, D. L., Park, M. S., Hildebrandt, B., Hultman, P., Pollard, K. M. (1998). The Prototypic Th2 Autoimmunity Induced by Mercury Is Dependent on IFN-{gamma} and Not Th1/Th2 Imbalance. J. Immunol. 161: 234-240 [Abstract] [Full Text]  
• Abina, M.-A., Tulliez, M., Duffour, M.-T., Debili, N., Lacout, C., Villeval, J.-L., Wendling, F., Vainchenker, W., Haddada, H. (1998). Thrombopoietin (TPO) Knockout Phenotype Induced by Cross-Reactive Antibodies Against TPO Following Injection of Mice with Recombinant Adenovirus Encoding Human TPO. J. Immunol. 160: 4481-4489 [Abstract] [Full Text]  
• Wang, B., Andre, I., Gonzalez, A., Katz, J. D., Aguet, M., Benoist, C., Mathis, D. (1997). Interferon-gamma impacts at multiple points during the progression of autoimmune diabetes. Proc. Natl. Acad. Sci. USA 94: 13844-13849 [Abstract] [Full Text]  
• von Herrath, M. G., Efrat, S., Oldstone, M. B. A., Horwitz, M. S. (1997). Expression of adenoviral E3 transgenes in beta  cells prevents autoimmune diabetes. Proc. Natl. Acad. Sci. USA 94: 9808-9813 [Abstract] [Full Text]  
• Cottet, S., Dupraz, P., Hamburger, F., Dolci, W., Jaquet, M., Thorens, B. (2001). SOCS-1 Protein Prevents Janus Kinase/STAT-dependent Inhibition of beta Cell Insulin Gene Transcription and Secretion in Response to Interferon-gamma. J. Biol. Chem. 276: 25862-25870 [Abstract] [Full Text]  
• Radu, D. L., Noben-Trauth, N., Hu-Li, J., Paul, W. E., Bona, C. A. (2000). A targeted mutation in the IL-4Ralpha gene protects mice against autoimmune diabetes. Proc. Natl. Acad. Sci. USA 97: 12700-12704 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS