Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease

H Agrawal, N Jacob, E Carreras, S Bajana… - The journal of …, 2009 - journals.aai.org
H Agrawal, N Jacob, E Carreras, S Bajana, C Putterman, S Turner, B Neas, A Mathian
The journal of immunology, 2009journals.aai.org
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 …
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 CD40 high 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.
journals.aai.org