title: TLR tolerance reduces IFN-alpha production despite plasmacytoid dendritic cell expansion and anti-nuclear antibodies in NZB bicongenic mice.
abstract: 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.
authors.affiliation: Arthritis Centre of Excellence, Toronto Western Research Institute, Toronto, Ontario, Canada.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Pau
authors.forename: Yui-Ho
authors.initials: YH
authors.lastname: Cheung
authors.forename: Christina
authors.initials: C
authors.lastname: Loh
authors.forename: Ginette
authors.initials: G
authors.lastname: Lajoie
authors.forename: Joan E
authors.initials: JE
authors.lastname: Wither
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D002452:Cell Count; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D013154:Spleen / Q000166:cytology; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D016898:Interferon-alpha; D051193:Toll-Like Receptors