Using Transgenic Mouse Models to Dissect the Pathogenesis of Virus‐Induced Autoimmune Disorders of the Islets of Langerhans and the Central Nervous System

Abstract

Viruses have often been associated with autoimmune diseases. One mechanism by which self-destruction can be triggered is molecular mimicry. Many examples of cross-reactive immune responses between pathogens and self-antigens have been described. This review presents two transgenic models of autoimmune disease induced by a virus through activation of anti-self lymphocytes. Viral antigens are expressed as transgenes either in beta-cells of the pancreas or in the oligodendrocytes of the CNS. Infection by a virus encoding the same gene activated autoreactive T cells that cleared the viral infection, and as a consequence of transgene expression resulted in organ-specific autoimmune disease. In both transgenic mouse models, autoreactive lymphocytes that escaped thymic negative selection were present in the periphery. Several factors are described that play a role in the regulation of the self-reactive process precipitated by a viral infection. These include the quantity of activated autoreactive T cells, the affinity of these T cells, the number of memory T cells generated following primary infection, costimulation by accessory molecules, and the types and locations of cytokines produced. In addition, unique barriers exist in target tissues that prevent or suppress autoreactive responses and define to a large extent the outcome of disease. Restimulation of autoreactive memory lymphocytes may be required to bypass these barriers and enhance autoimmune disease. Therapy directed at modifying these factors can reduce and even prevent autoimmune disease after it has been initiated.

Preferential Escape of Subdominant CD8+ T Cells During Negative Selection Results in an Altered Antiviral T Cell Hierarchy

“…Nevertheless, our work, combined with these previous studies (47,48), suggests that preferential escape of subdominant T cells from negative selection is probably far more common than previously believed. Self-reactive T cells require activation by an exogenous trigger such as a cross-reactive viral infection before they can cause symptoms of autoimmunity (49), and our studies (Fig. 3) suggest that negative selection preferentially deletes the most promiscuous or cross-reactive T cell populations, which might help explain why autoimmunity is relatively infrequent in the general population.…”

Double-Stranded RNA—Dependent Protein Kinase Is Not Required for Double-Stranded RNA—Induced Nitric Oxide Synthase Expression or Nuclear Factor-κB Activation by Islets

“…Viral infection has been implicated as one environmental factor that may trigger the initial autoimmune reaction that targets and destroys ␤-cells in genetically susceptible individuals (2)(3)(4)(5). Viruses have been isolated from the pancreata of acutely diabetic deceased patients, and viral-specific IgM responses have been identified in newly diagnosed diabetic patients (2,5).…”

Role of Interferon Regulatory Factor-1 in Double-stranded RNA-induced iNOS Expression by Mouse Islets

“…Viruses have been isolated from the pancreata of acutely diabetic deceased patients, and viral-specific IgM antibodies have been isolated from newly diagnosed diabetic patients (8,10,11). Autoimmune diabetes can also be induced in genetically susceptible strains of rats and mice by viral infection (8,10,12). Kilham rat virus-induced diabetes in diabetesresistant BioBreeding rats is dependent on the presence of macrophages and associated with the increased expression of the macrophage-derived cytokines IL-12, IL-1␤, and TNF-␣, as well as the T-cell cytokine IFN-␥ (13).…”