The etiology of autoimmune diseases is unknown, but previous exposure to environmental pathogens is thought to play an important role. In this application, the connection between Coxsackie virus infection and the prevalent autoimmune disease Insulin Dkependent Diabetes Mellitus is investigated. Coxsackie virus has been implicated to be causally associated with diabetes, but the pathway from infection to disease has not been defined. In the current project, three mechanistic hypotheses are tested experimentally to determine how the virus induces disease. The first hypothesis tested is that the virus shares a pathogenic similarity with the host, so that upon infection, the immune response to the virus also recognizes the host. This potential antigenic similarity has recently been demonstrated between the Coxsackie virus P2-C antigen and the pancreatic islet antigen glutamic acid decarboxylase, a target antigen strongly associated with pathogenesis of diabetes in both humans and spontaneous animal models. A second possible mechanism for the initiation of autoimmunity is that virus infection of the pancreas leads to immune activation and the elicitation of host defense molecules """"""""bystander damage"""""""" hypothesis then predicts that these released antigens could cause the priming of naïve islet-specific T cells. Lastly, previous exposure to pathogens causes the immune system to accumulate memory to those agents. The third hypothesis predicts that the re- exposure to the same or similar antigens causes reactivation of those specificities and a pathogenic T cells response is initiated, destroying the pancreatic beta cells. In the proposed experiments, specific predictions of these three mechanistic hypotheses will be approached experimentally using a murine system in which diabetes-prone strains are infected with the Coxsackie virus and either studied directly for the development of pancreatic islet sensitization or used as donors in a series of adoptive transfer protocols designed specifically to address each mechanism. They anticipate that these studies will lead to increased understanding of the mechanism of virus induced autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042231-03
Application #
6373749
Study Section
Special Emphasis Panel (ZRG1-SSS-4 (01))
Program Officer
Johnson, David R
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$365,470
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Horwitz, Marc S; Knudsen, Maria; Ilic, Alex et al. (2006) Transforming growth factor-beta inhibits coxsackievirus-mediated autoimmune myocarditis. Viral Immunol 19:722-33
Flodstrom-Tullberg, Malin; Hultcrantz, Monica; Stotland, Alexandr et al. (2005) RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection. J Immunol 174:1171-7
Flodstrom-Tullberg, Malin; Yadav, Deepak; Hagerkvist, Robert et al. (2003) Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse. Diabetes 52:2696-700
Flodstrom, Malin; Tsai, Devin; Fine, Cody et al. (2003) Diabetogenic potential of human pathogens uncovered in experimentally permissive beta-cells. Diabetes 52:2025-34
Flodstrom, Malin; Maday, Amy; Balakrishna, Deepika et al. (2002) Target cell defense prevents the development of diabetes after viral infection. Nat Immunol 3:373-82
Horwitz, Marc S; Ilic, Alex; Fine, Cody et al. (2002) Presented antigen from damaged pancreatic beta cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J Clin Invest 109:79-87