Naked DNA in cells: An inducer of major histocompatibility complex molecules to evoke autoimmune responses?

Abstract

The major histocompatibility complex (MHC) is the exclusive chaperone that presents intracellular antigens, either self or foreign to T cells. Interestingly, aberrant expression of MHC molecules has been reported in various autoimmune target tissues such as thyroid follicular cells in Grave’s disease. Herein, we review the discovery of an unexpected effect of cytosolic double-stranded DNA (dsDNA), despite its origins, to induce antigen processing and presenting genes, including MHC molecules, in non-immune cells. Moreover, we highlight several recent studies that suggest cell injury endows thyroid epithelial cells with a phenotype of mature antigen presenting cells by inducing multiple antigen processing and presenting genes via releasing genomic DNA fragments into the cytosol. We discuss the possibility that such cytosolic dsDNA, in naked form without binding to histone proteins, might be involved in the development of cell damage-triggered autoimmune responses. We also discuss the possible molecular mechanism by which cytosolic dsDNA can induce MHC molecules. It is reasonable to speculate that cytosolic dsDNA-induced MHC class I is partially due to an autocrine/paracrine effect of type I interferon (IFN). While the mechanism of cytosolic dsDNA-induced MHC class II expression appears, at least partially, distinct from that mediated by IFN-γ. Further in-depth are required to clarify this picture.

Keywords: Cytosolic double-stranded DNA, Major histocompatibility complex molecules, Autoimmune response, Antigen presentation, Tissue injury

Core tip: We reviewed the discovery of an unexpected effect of cytosolic double-stranded DNA (dsDNA) to induce antigen processing and presenting genes including major histocompatibility complex (MHC) molecules in non-immune cells. We also focus on the current status quo of the overall research in the field with highlight on our recent findings that suggest cell injury-induced self-cytosolic dsDNA is a potential trigger in the development of autoimmunity. Meanwhile, we provide in-depth discussion of the molecular signals responsible for the effect of dsDNA to induce MHC molecules, based on the current opinion of dsDNA-mediated signal pathways.