News and Publications

Autoimmunity: Growth and Destruction

Coxsackieviruses are small, single-stranded RNA viruses that belong to the enteroviral group of picornaviruses. Although most coxsackievirus infections in humans are asymptomatic or have minor clinical manifestations, cases of coxsackievirus-induced pancreatitis, myocarditis, aseptic meningitis, and hepatitis have been reported. Coxsackieviruses have also been proposed as etiologic agents of idiopathic hepatitis and pancreatitis. In addition, seroepidemiologic data from studies in humans and experiments in animals indicate that coxsackievirus infections may contribute to the initiation or acceleration of autoimmune (type 1) insulin-dependent diabetes mellitus.

In vitro, coxsackievirus B type 4 (CBV-4) and other members of the CBV family infect human and rodent beta cells, and many of these infections result in widespread death of the cells. In stark contrast, studies in mice revealed that although a systemic CBV-4 infection can cause nearly complete destruction of the exocrine pancreas, the pancreatic islet cells, including beta cells, are selectively spared from CBV-4-induced pathologic changes. These observations indicate that although systemic infection is associated with a strong viral tropism for the exocrine pancreas, the net infectivity of beta cells appears to be very low. Accordingly, most systemic infections with CBVs are cleared without destruction of beta cells and development of diabetes.

Nonetheless, several reports of diabetes caused by a CBV infection suggested that CBV infection in susceptible persons may still lead to destruction of beta cells. In addition, CBV antigens have been found in residual beta cells from humans who died of a lethal viral infection, and enteroviruses, including CBVs (e.g., CBV-4), have been isolated from patients with recently diagnosed type 1 diabetes. These reports and the in vitro findings described raise the intriguing possibility that beta cell permissiveness to CBV-4 infection may, in part, govern susceptibility to CBV-4-induced diabetes.

To date, host factors that regulate the permissiveness of pancreatic beta cells to CBV-4 infection have not been fully explored. Both genetic and environmental factors are involved in the etiology of autoimmune disease, and viral infections have been implicated as nongenetic triggers of autoimmune reactions to self-antigens. Understanding how CBVs mediate diabetes has been complicated by the unique tropism of these viruses for the pancreas and the apparent molecular similarity between the viral P2C gene product of CBV-4 and the pancreatic islet antigen GAD65. On the basis of animal studies, different models for virus-induced reactions to self, including CBV-4-induced diabetes, have been proposed. The models include molecular mimicry, bystander activation of self-reactive T cells, and a direct viral cytolysis of infected target cells.

Although CBV antigens have been found in pancreatic beta cells of patients with newly diagnosed type 1 diabetes, surprisingly little is known about the antiviral defenses expressed by target beta cells and how these defenses can regulate susceptibility to virus-induced diabetes. Furthermore, although the prevailing notion is that islets are indirectly damaged during an immune response, the connection between the damage and the development of disease is still unclear. We are exploring these unanswered questions.

Type 1 diabetes mellitus is due to the selective destruction of the pancreatic islets. The etiology of this disease is not fully understood. Although genetic components are important in the development of the disease, the lack of concordance between identical twins indicates that environmental factors also play a role. It has long been suspected that viral infection may be a critical trigger of pathogenic autoimmunity directed against pancreatic beta cells. Indeed, recent evidence suggests that CBV-4 infection is associated with the development of type 1 diabetes in humans. Results of epidemiologic studies indicated that the development of type 1 diabetes is often preceded by one or more exposures to CBV-4. This virus infects the exocrine pancreas, causing severe pancreatitis; however, the pathway from infection to destruction of beta cells has not been elucidated. Many studies in humans revealed that infection leads to the development of islet-reactive T cells and hallmarks of systemic autoimmunity such as autoantibodies. The mechanism by which a T cell becomes sensitized to islet antigens is still controversial.

We studied animal models of CBV-4 infection and hypothesized that islet-specific T cells proliferate after exposure to antigens released from islet cells with virus-induced damage. Furthermore, we showed that professional antigen-presenting cells mediate the sensitization of T cells to islet cells. More recently, we focused on factors that stimulate expansion of islet-reactive T cells after infection with CBV-4. Our findings suggest that these cells may initially divide homeostatically after viral infection, possibly as a result of T-cell depletion.

Publications

Flodstrom, M., Tsai, D., Fine, C., Maday, A., Sarvetnick, N. Diabetogenic potential of human pathogens uncovered in experimentally permissive beta-cells. Diabetes 52:2025, 2003.

Flodstrom, M., Yadav, D., Hagerkvist, R., Tsai, D., Secrest, P., Stotland, A., Sarvetnick, N. Target cell expression of suppressor of cytokine signaling-1 (SOCS-1) prevents diabetes in the NOD mouse. Diabetes, in press.

Hill, N.J., Van Gunst, K., Sarvetnick, N. Th1 and Th2 pancreatic inflammation differentially affects homing of islet-reactive CD4 cells in nonobese diabetic mice. J. Immunol. 170:1649, 2003.

Horwitz, M., Ilic, A., Fine, C., Rodriguez, E., Sarvetnick, N. Coxsackievirus-mediated hyperglycemia is enhanced by re-infection and this occurs independent of T cells. Virology 314:510, 2003.

Jie, H.-B., Sarvetnick, N. The role of NK cells and NK cell receptors in autoimmune disease. Autoimmunity, in press.

Zhang, Y.Q., Sarvetnick, N. Development of cell markers for the identification and expansion of islet progenitor cells. Diabetes Metab. Res. Rev. 19:363, 2003.