The molecular basis for the lack of immunostimulatory activity of vertebrate DNA

Stacey, Katryn J., Young, Greg R., Clark, Francis, Sester, David P., Roberts, Tara L., Naik, Shalin, Sweet, Matthew J. and Hume, David A. (2003) The molecular basis for the lack of immunostimulatory activity of vertebrate DNA. Journal of Immunology, 170 7: 3614-3620.


Author Stacey, Katryn J.
Young, Greg R.
Clark, Francis
Sester, David P.
Roberts, Tara L.
Naik, Shalin
Sweet, Matthew J.
Hume, David A.
Title The molecular basis for the lack of immunostimulatory activity of vertebrate DNA
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2003-04-01
Sub-type Article (original research)
Volume 170
Issue 7
Start page 3614
End page 3620
Total pages 7
Editor Rich
Robert R
Place of publication Bethesda, USA
Publisher American Association of Immunologists
Language eng
Subject C1
320202 Cellular Immunology
730102 Immune system and allergy
Abstract Macrophages and B cells are activated by unmethylated CpG-containing sequences in bacterial DNA. The lack of activity of self DNA has generally been attributed to CpG suppression and methylation, although the role of methylation is in doubt. The frequency of CpG in the mouse genome is 12.5% of Escherichia coli, with unmethylated CpG occurring at similar to3% the frequency of E. coli. This suppression of CpG alone is insufficient to explain the inactivity of self DNA; vertebrate DNA was inactive at 100 mug/ml, 3000 times the concentration at which E. coli DNA activity was observed. We sought to resolve why self DNA does not activate macrophages. Known active CpG motifs occurred in the mouse genome at 18% of random occurrence, similar to general CpG suppression. To examine the contribution of methylation, genomic DNAs were PCR amplified. Removal of methylation from the mouse genome revealed activity that was 23-fold lower than E. coli DNA, although there is only a 7-fold lower frequency of known active CpG motifs in the mouse genome. This discrepancy may be explained by G-rich sequences such as GGAGGGG, which potently inhibited activation and are found in greater frequency in the mouse than the E. coli genome. In summary, general CpG suppression, CpG methylation, inhibitory motifs, and saturable DNA uptake combined to explain the inactivity of self DNA. The immunostimulatory activity of DNA is determined by the frequency of unmethylated stimulatory sequences within an individual DNA strand and the ratio of stimulatory to inhibitory sequences.
Keyword Immunology
Stimulatory Cpg Motifs
Murine B-cells
Bacterial-dna
Immune Activation
Scavenger Receptors
Oligonucleotides
Oligodeoxynucleotides
Sequence
Methylation
Inhibition
Q-Index Code C1
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Created: Wed, 15 Aug 2007, 12:51:50 EST