Myeloid Dendritic Cells from B6.NZM Sle1/Sle2/Sle3 Lupus-Prone Mice Express an IFN Signature That Precedes Disease Onset

Abstract

Patients with systemic lupus erythematosus (SLE) show an over-expression of Type I Interferon (IFN) responsive genes called “Interferon Signature”. We found that the B6.NZMSle1/Sle2/Sle3 (Sle1,2,3) lupus-prone mice also express an Interferon Signature compared to non autoimmune C57BL/6 mice. In vitro, myeloid dendritic cells (mDCs)(GM-CSF bone marrow-derived BMDCs) from Sle1,2,3 mice constitutively over-expressed IFN responsive genes such as IFNb, Oas-3, Mx-1, ISG-15 and CXCL10, and the members of IFN signaling pathway STAT1, STAT2, and IRF7. The Interferon Signature was similar in Sle1,2,3 BMDCs from young, pre-autoimmune mice and from mice with high titers of autoantibodies, suggesting that the Interferon Signature in mDCs precedes disease onset and it is independent from the autoantibodies. Sle1,2,3 BMDCs hyper-responded to stimulation with IFNa and the TLR7 and TLR9 agonists R848 and CpGs. We propose that this hyper-response is induced by the Interferon Signature and only partially contributes to the Signature, since oligonucleotides inhibitory for TLR7 and TLR9 only partially suppressed the constitutive Interferon Signature and pre-exposure to IFNa induced the same hyper-response in wild type BMDCs than in Sle1,2,3 BMDCs. In vivo, mDCs and with lesser extent T and B cells from young pre-diseased Sle1,2,3 mice also expressed the Interferon Signature, although they lacked the strength that BMDCs showed in vitro. Sle1,2,3 plasmacytoid DCs expressed the Interferon Signature in vitro but not in vivo, suggesting that mDCs may be more relevant before disease onset. We propose that Sle1,2,3 mice are useful tools to study the role of the Interferon Signature in lupus pathogenesis.

VISTA Deficiency Accelerates the Development of Fatal Murine Lupus Nephritis

“…Lupus patients have high levels of IFN α in their serum (31,32) and increased expression of IFN-responsive genes (29). The IFN signature has been reported in Sle1.Sle2.Sle3 mice (23). We found that IFN α levels were significantly increased in Sle1.Sle3 VISTA −/− mice compared with Sle1.Sle3 or B6 VISTA −/− mice (Figure 6A).…”

Estrogen Receptor α Deficiency Modulates TLR Ligand–Mediated PDC-TREM Expression in Plasmacytoid Dendritic Cells in Lupus-Prone Mice

“…To assess endogenous type I IFN activity, we measured expression of type I IFN signature genes in the spleens of NZM mice. We compared expression of type I IFN signature genes that were previously shown to be elevated in the lymphocytes of pre-disease lupus-prone mice compared to B6 mice (30). Using this previously validated assay, we found the absence of ERα significantly reduced the expression of the Type I IFN signature genes Cxcl-10 and Mx-1 in the NZM spleens (Figure 4E).…”

Amyloid-DNA Composites of Bacterial Biofilms Stimulate Autoimmunity

“…A Type I IFN Signature is up-regulated in PBMCs of SLE patients (Baechler et al, 2003; Bennett et al, 2003; Crow et al, 2003; Feng et al, 2006; Han et al, 2003) and in DCs from lupus prone mice (Sriram et al, 2012), and administration of exogenous Type I IFNs accelerates autoimmunity in lupus prone mice (Mathian et al, 2005). Therefore, the results that curli-DNA composites accelerate the onset of autoimmunity in lupus-prone mice can be partially explained by the strong induction of Type I IFNs in DCs as well as by the polyclonal activation of the adaptive immune system, as curli up-regulated activation markers in splenic T and B cells.…”

“…The more frequent outcome of Salmonella infection in bacteremia and complications in soft tissues in SLE patients (Lim et al, 2001; Pablos et al, 1994; Tsao et al, 2002) and the recent identification of increased levels of circulating endotoxin in SLE patients (Shi et al, 2014), support this hypothesis. In addition, since inflammatory cytokines can decrease intestinal mucosal barrier function (Turner, 2009), the high levels of cytokines present in pre-disease stages of lupus (Connolly and Hakonarson, 2012; Sriram et al, 2012), might compromise mucosal barrier function and allow the biofilm material produced by microbiota at mucosal sites to access the immune system, act as danger signals and trigger lupus onset.…”