Autoimmune disease results from inflammatory destruction of tissues by aberrant self-reactive lymphocytes. We studied the autoimmune potential of T lymphocytes immunologically ignorant of viral antigens acting as self antigens and whether the host defense molecule IFN-gamma could stimulate these cells to cytotoxic competency. For this purpose, we produced double transgenic mice expressing pancreatic IFN-gamma as well as lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP) or glycoprotein (GP) antigen. 100% of the NP+/IFN-gamma+ mice became diabetic before 2 mo of age, while none of the NP single transgenic littermates and only 10% of IFN-gamma single transgenic littermates did. Strikingly, NP+/IFN-gamma+ mice spontaneously developed cytotoxic T lymphocyte activity on LCMV-infected targets and vaccinia virus-NP-infected ones without prior LCMV infection but NP+/IFN-gamma- mice did not, which indicates specific sensitization to the viral antigen by IFN-gamma. These results suggest that lymphocytes ignorant of self antigens can be activated by IFN-gamma released after immunologic stimulation such as viral infection. This mechanism may account for the loss of apparent tolerance to self antigens in autoimmune diseases such as insulin-dependent diabetes mellitus.
M S Lee, M von Herrath, H Reiser, M B Oldstone, N Sarvetnick
Title and authors | Publication | Year |
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Macrophages Require IFN-I Signaling to Permit Trafficking of Autoimmune T cells into the Islets To Cause Type 1 Diabetes
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JCI Insight | 2019 |
Advances in Immunology
E Pinaud, M Marquet, R Fiancette, S Péron, C Vincent-Fabert, Y Denizot, M Cogné |
Advances in Immunology Volume 110 | 2011 |
In situ recognition of autoantigen as an essential gatekeeper in autoimmune CD8+ T cell inflammation
J Wang, S Tsai, A Shameli, J Yamanouchi, G Alkemade, P Santamaria |
Proceedings of the National Academy of Sciences | 2010 |
Viruses and Cytotoxic T Lymphocytes in Type 1 Diabetes
KT Coppieters, MG von Herrath |
Clinical Reviews in Allergy & Immunology | 2010 |
Viruses and Cytotoxic T Lymphocytes in Type 1 Diabetes
KT Coppieters, MG Herrath |
Clinical Reviews in Allergy & Immunology | 2010 |
Molecular Mimicry: Infection-Inducing Autoimmune Disease
MB Oldstone |
2005 | |
Islet-specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development
A Rhode, ME Pauza, AM Barral, E Rodrigo, MB Oldstone, MG von Herrath, U Christen |
Journal of immunology (Baltimore, Md. : 1950) | 2005 |
Animal Models of T Cell-Mediated Skin Diseases
T Zollner, H Renz, K Asadullah |
2005 | |
Intracellular IFN-γProduction and IL-12 Serum Levels in Latent Autoimmune Diabetes of Adults (LADA) and in Type 2 Diabetes
A Tsiavou, D Degiannis, E Hatziagelaki, K Koniavitou, SA Raptis |
Journal of Interferon & Cytokine Research | 2004 |
Opinion: Microorganisms and autoimmunity: making the barren field fertile?
MG von Herrath, RS Fujinami, JL Whitton |
Nature Reviews Microbiology | 2003 |
Arenaviruses II
MB Oldstone |
2002 | |
Constitutive expression of IL-12 in pancreatic beta-cells does not break immunological tolerance to self-antigens but intensifies established autoimmune diabetes
Andreas Holz, Kelly Brett, and Michael B.A. Oldstone |
Journal of Clinical Investigation | 2001 |
IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death
K Suk, S Kim, YH Kim, KA Kim, I Chang, H Yagita, M Shong, MS Lee |
Journal of immunology (Baltimore, Md. : 1950) | 2001 |
A Dual Role for TNF-α in Type 1 Diabetes: Islet-Specific Expression Abrogates the Ongoing Autoimmune Process When Induced Late but Not Early During Pathogenesis
U Christen, T Wolfe, U Möhrle, AC Hughes, E Rodrigo, EA Green, RA Flavell, MG von Herrath |
Journal of immunology (Baltimore, Md. : 1950) | 2001 |
Virus-induced diabetes in a transgenic model: role of cross-reacting viruses and quantitation of effector T cells needed to cause disease
N Sevilla, D Homann, M Herrath, F Rodriguez, S Harkins, JL Whitton, MB Oldstone |
Journal of virology | 2000 |
A targeted mutation in the IL-4Ralpha gene protects mice against autoimmune diabetes
DL Radu, N Noben-Trauth, J Hu-Li, WE Paul, CA Bona |
Proceedings of the National Academy of Sciences | 2000 |
Acute Primary Infection with Cytomegalovirus (CMV) in Kidney Transplant Recipients Results in the Appearance of a Phenotypically Aberrant CD8 + T Cell Population
JG van Dam, JG Damoiseaux, MH Christiaans, CA Bruggeman |
Microbiology and Immunology | 2000 |
Molecular Mimicry, Microbes, and Autoimmunity
MW Cunningham, RS Fujinami |
2000 | |
Viruses, host responses, and autoimmunity
MS Horwitz, N Sarvetnick |
Immunological Reviews | 1999 |
Absence of significant Th2 response in diabetes-prone non-obese diabetic (NOD) mice
A Hartemann-Heurtier, MF Richard, C Boitard |
Clinical & Experimental Immunology | 1999 |
The pathogenesis of viral-induced diabetes
DM See, JG Tilles |
Clinical and Diagnostic Virology | 1998 |
Leukocyte Integrins in the Immune System and Malignant Disease
B Holzmann, H Wagner |
1998 | |
Molecular mimicry and immune‐mediated diseases
MB Oldstone |
The FASEB Journal | 1998 |
IFN-gamma, IGIF, and IDDM
N Sarvetnick |
Journal of Clinical Investigation | 1997 |
Transgenic Mice Expressing IFN-gamma in the Epidermis Have Eczema, Hair Hypopigmentation, and Hair Loss
JM Carroll, T Crornpton, JP Seery, FM Watt |
Journal of Investigative Dermatology | 1997 |
Interferon-gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus
MG von Herrath, MB Oldstone |
Journal of Experimental Medicine | 1997 |
Low-Affinity Cytotoxic T-Lymphocytes Require IFN-γ to Clear an Acute Viral Infection
MG von Herrath, B Coon, MB Oldstone |
Virology | 1997 |
Differential Immune Recognition of LCMV Nucleoprotein and Glycoprotein in Transgenic Mice Expressing LCMV cDNA Genes
JC Zeller, N Nguyen, PJ Southern |
Virology | 1997 |
Activation of autoreactive T cells by peptides from human pathogens
S Hausmann |
Current Opinion in Immunology | 1997 |
Oral insulin treatment suppresses virus-induced antigen-specific destruction of beta cells and prevents autoimmune diabetes in transgenic mice
MG von Herrath, T Dyrberg, MB Oldstone |
Journal of Clinical Investigation | 1996 |
Virus-induced autoimmune disease
MG von Herrath, MB Oldstone |
Current Opinion in Immunology | 1996 |
Interferon-γ in autoimmunity
A Billiau |
Cytokine & Growth Factor Reviews | 1996 |
Viruses, Hidden Self-Epitopes and Autoimmunity
V Barnaba |
Immunological Reviews | 1996 |
Using Transgenic Mouse Models to Dissect the Pathogenesis of Virus-Induced Autoimmune Disorders of the Islets of Langerhans and the Central Nervous System
MG Herrath, CF Evans, MS Horwitz, MB Oldstone |
Immunological Reviews | 1996 |
Virus-induced autoimmune disease: transgenic approach to mimic insulin-dependent diabetes mellitus and other autoimmune diseases:
MB Oldstone, M Herrath |
APMIS | 1996 |
B-Cell Activation by Superstimaulatory Influenza Virus Hemagglutinin: A Pathogenesis for Autoimmunity?
E Cash, J Charreire, O Rott |
Immunological Reviews | 1996 |
Viruses, cytokines, antigens, and autoimmunity
R Gianani, N Sarvetnick |
Proceedings of the National Academy of Sciences | 1996 |
Mechanisms of cytokine-mediated localized immunoprotection
N Sarvetnick |
Journal of Experimental Medicine | 1996 |
Genetic Models of Immune and Inflammatory Diseases
AK Abbas, RA Flavell |
1996 | |
Symposium in Immunology V
MM Eibl, C Huber, HH Peter, U Wahn |
1996 | |
Focal expression of interleukin-2 does not break unresponsiveness to "self" (viral) antigen expressed in beta cells but enhances development of autoimmune disease (diabetes) after initiation of an anti-self immune response
MG von Herrath, J Allison, JF Miller, MB Oldstone |
Journal of Clinical Investigation | 1995 |
Transgenic/knockout mice — tools to study autoimmunity
R Mueller, N Sarvetnick |
Current Opinion in Immunology | 1995 |
Coexpression of B7-1 and viral (“self”) transgenes in pancreatic β cells can break peripheral ignorance and lead to spontaneous autoimmune diabetes
MG von Herrath, S Guerder, H Lewicki, RA Flavell, MB Oldstone |
Immunity | 1995 |
The role of infiltrating macrophages in islet destruction and regrowth in a transgenic model
D Gu, L O'Reilly, L Molony, A Cooke, N Sarvetnick |
Journal of Autoimmunity | 1995 |
Insulitis and islet-cell antibody formation in rats with experimentally reduced beta-cell mass
EF Lampeter, M Tubes, C Klemens, U Brocker, J Friemann, V Kolb-Bachofen, FA Gries, H Kolb |
Diabetologia | 1995 |