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

K Suzuki, A Mori, KJ Ishii, J Saito… - Proceedings of the …, 1999 - National Acad Sciences
K Suzuki, A Mori, KJ Ishii, J Saito, DS Singer, DM Klinman, PR Krause, LD Kohn
Proceedings of the National Academy of Sciences, 1999National Acad Sciences
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 …
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 γ-interferon (γIFN), i.e., ds polynucleotides increase class I much more than class II, whereas γIFN increases class II more than class I. The ds nucleic acids also induce or activate Stat1, Stat3, mitogen-activated protein kinase, NF-κB, the class II transactivator, RFX5, and the IFN regulatory factor 1 differently from γIFN. 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.
National Acad Sciences