Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides

Abnormal expression of major histocompatibility complex (MHC) class I and c lass II in various tissues is associated with autoimmune disease. Autoimmun e responses can be triggered by viral infections or tissue injuries. We sho w that the ability of a virus or a tissue injury to increase MHC gene expre ssion is duplicated by any fragment of double-stranded (ds) DNA or dsRNA in troduced into the cytoplasm of nonimmune cells. Activation is sequence-inde pendent, is induced by ds polynucleotides as small as 25 bp in length, and is not duplicated by single-stranded polynucleotides. In addition to causin g abnormal MHC expression, the ds nucleic acids increase the expression of genes necessary for antigen processing and presentation: proteasome protein s (e.g., LMP2), transporters of antigen peptides; invariant chain, HLA-DM, and the costimulatory molecule B7.1. The mechanism is different from and ad ditive to that of gamma-interferon (gamma IFN), i.e., ds polynucleotides in crease class I much more than class II, whereas gamma IFN increases class I I more than class I. The ds nucleic acids also induce or activate Stat1, St at3, mitogen-activated protein kinase, NF-kappa B, the class II transactiva tor, RPX5, and the IFN regulatory factor 1 differently from gamma IFN. CpG residues are not responsible for this effect, and the action of the ds poly nucleotides could be shown in a variety of cell types in addition to thyroc ytes. We suggest that this phenomenon is a plausible mechanism that might e xplain how viral infection of tissues or tissue injury triggers autoimmune disease; it is potentially relevant to host immune responses induced during gene therapy.