Activation of target-tissue immune-recognition molecules by double-stranded polynucleotides.
Abnormal expression of major histocompatibility complex (MHC) class I and class II in various tissues is associated with autoimmune disease. Autoimmune responses can be triggered by viral infections or tissue injuries. We show that the ability of a virus or a tissue injury to increase MHC gene expression is duplicated by any fragment of double-stranded (ds) DNA or dsRNA introduced into the cytoplasm of nonimmune cells. Activation is sequence-independent, is induced by ds polynucleotides as small as 25 bp in length, and is not duplicated by single-stranded polynucleotides. In addition to causing abnormal MHC expression, the ds nucleic acids increase the expression of genes necessary for antigen processing and presentation: proteasome proteins (e.g., LMP2), transporters of antigen peptides; invariant chain, HLA-DM, and the costimulatory molecule B7.1. The mechanism is different from and additive to that of gamma-interferon (gammaIFN), i.e., ds polynucleotides increase class I much more than class II, whereas gammaIFN increases class II more than class I. The ds nucleic acids also induce or activate Stat1, Stat3, mitogen-activated protein kinase, NF-kappaB, the class II transactivator, RFX5, and the IFN regulatory factor 1 differently from gammaIFN. CpG residues are not responsible for this effect, and the action of the ds polynucleotides could be shown in a variety of cell types in addition to thyrocytes. We suggest that this phenomenon is a plausible mechanism that might explain how viral infection of tissues or tissue injury triggers autoimmune disease; it is potentially relevant to host immune responses induced during gene therapy.
Suzuki
K
K
Cell Regulation Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Mori
A
A
Ishii
K J
KJ
Saito
J
J
Singer
D S
DS
Klinman
D M
DM
Krause
P R
PR
Kohn
L D
LD
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D004279:DNA, Viral / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D007371:Interferon-gamma / Q000276:immunology; D008285:Major Histocompatibility Complex; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000276:immunology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D018139:Simplexvirus / Q000276:immunology*; D013961:Thyroid Gland; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014763:Viral Matrix Proteins / Q000276:immunology
D004279:DNA, Viral; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D012330:RNA, Double-Stranded; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494081:Stat1 protein, rat; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; D014763:Viral Matrix Proteins; D007371:Interferon-gamma; D017871:Calcium-Calmodulin-Dependent Protein Kinases