Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease

Abstract

Virus infections and autoimmune disease have long been linked. These infections often precede the occurrence of inflammation in the target organ. Several mechanisms often used to explain the association of autoimmunity and virus infection are molecular mimicry, bystander activation (with or without epitope spreading), and viral persistence. These mechanisms have been used separately or in various combinations to account for the immunopathology observed at the site of infection and/or sites of autoimmune disease, such as the brain, heart, and pancreas. These mechanisms are discussed in the context of multiple sclerosis, myocarditis, and diabetes, three immune-medicated diseases often linked with virus infections.

Figures

FIG. 1.

Virus-infected APCs present viral peptides in the context of MHC class I or II to naive CD8+ T cells or CD4+ T cells, respectively. Activation of T cells leads to IFN-γ production, which will further activate APCs, leading to IL-12 production, a potent T-cell-differentiating cytokine. Effector CD4+ T cells release proinflammatory cytokines such as IFN-γ and IL-2, stimulating T cells to differentiate into effector T cells. Activated T cells can also secrete IFN-γ and TNF, which can lead to macrophage activation. The activated macrophages in turn release TNF, nitric oxide, and reactive oxygen intermediates (ROI), which can kill infected cells and uninfected cells. The dead and dying cells are then phagocytosed by macrophages and dendritic cells that can present self antigens to autoreactive CD4+ T cells. Similarly, effector CD8+ T cells can kill infected cells via perforin and granzyme granules. Cell debris is taken up by APCs, which can present self antigens to autoreactive CD8+ T cells. The generation of such cells could lead to autoimmune responses with enhanced inflammation if not modulated by regulatory T cells releasing IL-10 and/or TGF-β. Bracketed squares, costimulatory molecules and ligand. Bracketed ovals, MHC class II peptide complex and T-cell receptor. Arrow-Y, MHC class I peptide complex and T-cell receptor. Double open circle, perforin. Shaded circle, granzyme.

FIG. 2.

(A) Three-week-old female SJL/J mice were primed with a cDNA encoding ubiquitin in frame with PLP (three times). Two weeks after the last injection, mice were challenged with CFA. Some of these animals developed CNS inflammatory lesions typical of EAE. (B) Three- to 4-week-old female SJL/J mice were primed with recombinant vaccinia virus encoding self CNS proteins. The vaccinia virus is cleared by about 2 weeks postinfection. After 5 weeks mice were challenged with CFA. Most of the animals primed with the recombinant vaccinia viruses encoding self CNS proteins developed CNS inflammatory lesions, while those infected with a recombinant virus encoding β-galactosidase and challenged with CFA did not.

FIG. 3.

Virus infection can initiate or accelerate autoimmune disease via epitope spreading and molecular mimicry, leading to the development of an inflammatory region with activated APCs and possible presentation of self antigens. On the other side of the coin, virus infection could lead to immunosuppression and chemokine gradients of anti-inflammatory cytokines such as IL-10 or TGF-β with activation-induced cell death of autoreactive cells.