Virus-induced autoimmune disease

Abstract

The breaking of tolerance or unresponsiveness to self-antigens, involving the activation of autoreactive lymphocytes, is a critical event leading to autoimmune diseases. The precise mechanisms by which this can occur are mostly unknown. Viruses have been implicated in this process, among other etiological factors, such as genetic predisposition and cytokine activity. Several ways have been proposed by which a viral infection might break tolerance to self and trigger an autoreactive cascade that ultimately leads to the destruction of a specific cell type or an entire organ. The process termed "molecular mimicry' and the use of transgenic models in which viral and host genes can be manipulated to analyze their effects in causing autoimmunity have been particular focuses for research. For example, there is a transgenic murine model of virus-induced autoimmune disease, in which a known viral gene is selectively expressed as a self-antigen in beta cells of the pancreas. In these mice, insulin-dependent diabetes develops after either a viral infection, the release of a cytokine such as IFN-gamma, or the expression of the costimulatory molecule B7.1 in the islets of Langerhans. Recent studies using this model have contributed to the understanding of the pathogenesis of virus-induced autoimmune disease and have furthered the design and testing of novel immunotherapeutic approaches.

Pancreatic β-Cell Damage Mediated by β-Cell Production of Interleukin-1

“…The synthetic dsRNA molecule poly(I-C) has been shown to induce an antiviral response that is similar to the antiviral response activated following viral infection (8,16). Since viruses from both RNA and DNA genome families have been associated with the development of autoimmune diabetes (3,4), the synthetic dsRNA molecule, poly(I-C), was used to examine mechanisms of virally induced islet dysfunction and degeneration. In this study, we show that poly(I-C), in the presence of IFN-␥, stimulates iNOS expression and nitrite formation, inhibits insulin secretion, and induces rat islet degeneration by an IL-1-dependent mechanism.…”

“…Viruses have been isolated from pancreata, and virus-specific IgM antibodies have been identified in newly diagnosed diabetic patients (2,3). Diabetes can be induced in genetically susceptible strains of mice, rats, and primates by infection with encephalomyocarditis virus, Coxsackie B4 virus, Kilham's rat virus, rubella virus, and retrovirus (3,4). Encephalomyocarditis-induced diabetes in mice is associated with increased expression of iNOS 1 and macrophage-derived cytokines IL-1␤, IL-12, and TNF-␣.…”

Viruses and Autoimmune Diseases

“…Other viruses, including retroviruses, cause a similar phenomenon. In human autoimmune diseases like multiple sclerosis (MS), insulin dependent diabetes mellitus (IDDM) or ankylosing spondylitis, the incidence of disease varies in monozygotic twins suggesting that factors other than genetic and likely environmental also play a role [3][4][5]. It has been observed that infectious agents [6][7][8] or cytokines [9][10][11][12] [3,[13][14][15].…”

“…When the cytokine profile in the islet of Langerhans milieu was changed from a Th1 to a Th2 phenotype (g-interferon to IL-4, IL-10, TGFb), IDDM was blocked [4,5,40,46]. One interesting way this occurred was through the oral administration of porcine insulin [46,49,50].…”

“…2. Information generated from the transgenic model for IDDM [5,8,9,11,37,38,40,[44][45][46][47][48]. Data generated for this model were obtained primarily with Drs Matthias von Herrath and Nora Sarvetnick.…”