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Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease
- Source :
- Journal of immunology (Baltimore, Md. : 1950). 183(9)
- Publication Year :
- 2009
-
Abstract
- Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR−/− mice. Numbers of activated CD40high plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR−/− mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR−/− spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR−/− DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR−/− DC produced less IL-12p40/70 and TNF-α than did NZM DC. The limited IFNAR−/− DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.
- Subjects :
- Mice, Inbred MRL lpr
Immunology
Lupus nephritis
Cell Count
Receptor, Interferon alpha-beta
Biology
Article
Immune tolerance
Mice
medicine
Immune Tolerance
Immunology and Allergy
Animals
Humans
Lupus Erythematosus, Systemic
Genetic Predisposition to Disease
Autoantibodies
CD86
Mice, Knockout
Antigen Presentation
Systemic lupus erythematosus
Lupus erythematosus
CD40
Mice, Inbred NZB
TLR9
Interferon-alpha
Dendritic cell
Dendritic Cells
medicine.disease
biology.protein
Female
Inflammation Mediators
Subjects
Details
- ISSN :
- 15506606
- Volume :
- 183
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....143b9430aeefd61a9821f96eabf8d7d7