| First Author | Pau E | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 5 | Pages | e36761 |
| PubMed ID | 22574220 | Mgi Jnum | J:187254 |
| Mgi Id | MGI:5435984 | Doi | 10.1371/journal.pone.0036761 |
| Citation | Pau E, et al. (2012) TLR tolerance reduces IFN-alpha production despite plasmacytoid dendritic cell expansion and anti-nuclear antibodies in NZB bicongenic mice. PLoS One 7(5):e36761 |
| abstractText | 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-alpha mRNA in their spleens, the levels of IFN-alpha-induced gene expression were reduced. Splenocytes from bicongenic mice also demonstrated reduced secretion of IFN-alpha following TLR stimulation in vitro. This reduction was not due to inhibition by TNF-alpha 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-alpha production, a phenomenon termed TLR tolerance. Bone marrow pDC from both B6 and bicongenic mice demonstrated markedly inhibited secretion of IFN-alpha 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-alpha production and severe kidney disease, revealing additional complexity in the regulation of autoimmunity in systemic lupus erythematosus. |
