TLR tolerance reduces IFN-alpha production despite plasmacytoid dendritic cell expansion and anti-nuclear antibodies in NZB bicongenic mice

PLoS One. 2012;7(5):e36761. doi: 10.1371/journal.pone.0036761. Epub 2012 May 4.


Genetic loci on New Zealand Black (NZB) chromosomes 1 and 13 play a significant role in the development of lupus-like autoimmune disease. We have previously shown that C57BL/6 (B6) congenic mice with homozygous NZB chromosome 1 (B6.NZBc1) or 13 (B6.NZBc13) intervals develop anti-nuclear antibodies and mild glomerulonephritis (GN), together with increased T and B cell activation. Here, we produced B6.NZBc1c13 bicongenic mice with both intervals, and demonstrate several novel phenotypes including: marked plasmacytoid and myeloid dendritic cell expansion, and elevated IgA production. Despite these changes, only minor increases in anti-nuclear antibody production were seen, and the severity of GN was reduced as compared to B6.NZBc1 mice. Although bicongenic mice had increased levels of baff and tnf-α mRNA in their spleens, the levels of IFN-α-induced gene expression were reduced. Splenocytes from bicongenic mice also demonstrated reduced secretion of IFN-α following TLR stimulation in vitro. This reduction was not due to inhibition by TNF-α and IL-10, or regulation by other cellular populations. Because pDC in bicongenic mice are chronically exposed to nuclear antigen-containing immune complexes in vivo, we examined whether repeated stimulation of mouse pDC with TLR ligands leads to impaired IFN-α production, a phenomenon termed TLR tolerance. Bone marrow pDC from both B6 and bicongenic mice demonstrated markedly inhibited secretion of IFN-α following repeated stimulation with a TLR9 ligand. Our findings suggest that the expansion of pDC and production of anti-nuclear antibodies need not be associated with increased IFN-α production and severe kidney disease, revealing additional complexity in the regulation of autoimmunity in systemic lupus erythematosus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / blood
  • Antibodies, Antinuclear / immunology*
  • Bone Marrow Cells / cytology
  • Cell Count
  • Dendritic Cells / cytology*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Female
  • Humans
  • Immunoglobulin G / blood
  • Immunoglobulin G / immunology
  • Interferon-alpha / biosynthesis*
  • Interferon-alpha / metabolism
  • Lupus Erythematosus, Systemic / immunology
  • Mice
  • Mice, Congenic
  • Spleen / cytology
  • Toll-Like Receptors / metabolism*


  • Antibodies, Antinuclear
  • Immunoglobulin G
  • Interferon-alpha
  • Toll-Like Receptors