Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

Abstract

Several studies have described a role for type I interferons (IFNab) in the initiation and/or prolongation of autoimmune diseases. Most pronounced has been the association of disease activity with what is now known as 'the interferon signature' of gene expression in peripheral blood mononuclear cells from lupus patients. In correlation, studies have shown that inhibition of IFNab signaling abrogates disease in various mouse models of lupus. New Zealand black (NZB) and B6.Nba2 congenic mice spontaneously develop elevated levels of serum anti-nuclear autoantibodies (ANAs). Nevertheless, neither of these strains develop fatal renal disease. The female F1 offspring of NZB or B6.Nba2 crossed with New Zealand white (NZW) mice do, however, develop kidney disease. We have previously shown that increases in endogenous IFNab levels in (B6.Nba2 Â NZW)F1 mice leads to accelerated development of renal disease in an IFNab-dependent manner. We now show that B6.Nba2 and (B6.Nba2 Â NZW)F1 mice deficient for the IFNab-receptor fail to develop ANA and renal disease, although the mice have substantial immune complex deposition in the glomeruli. Thus, endogenous IFNab might influence disease by affecting B-cell activation and differentiation, as well as the kidneys' susceptibility to damage, the latter perhaps through induction of a local inflammatory milieu.

Viral RNA Induces Type I Interferon-Dependent Cytokine Release and Cell Death in Mesangial Cells via Melanoma-Differentiation-Associated Gene-5

“…In this process, IFN-␤ induces innate viral RNA recognition receptors in primary mesangial cells just like Tnf/IFN-␥ previously shown for cell lines of murine and human mesangial cells. 14,29 The pathogenic relevance of this mechanism for glomerulonephritis was recently demonstrated by Jørgensen et al 30 autoimmune B6.Nba2 mice and (B6Nba2 ϫ NZW)F 1 mice deficient for the type I IFNR failed to develop glomerulonephritis, although the mice had substantial glomerular immune complex deposits. 29 In summary, poly I:C RNA stimulates glomerular mesangial cells to produce large amounts of type I IFN, especially when being delivered into the intracellular cytosol where it can interact with Mda5.…”

Toll-like receptor 7 (TLR7)–driven accumulation of a novel CD11c+ B-cell population is important for the development of autoimmunity

“…[20][21][22] Evidence also suggests that the onset of autoimmunity is often associated with disregulation of TLRs, key players of innate immunity involved in the recognition of pathogen-associated molecular structures. 23,24 Young and old female mice deficient in the receptor for IFN␣␤, IFN␣R, or deficient in TLR7 were screened for the presence of ABCs in their spleens ( Figure 5A).…”

Disruption of Type I-IFN Signaling Decreases Autoimmune Development and Kidney Damage, But Not Anxiety-Like Behaviors in Lupus NZB Mice

“…Nonetheless, there were no significant differences between the two groups of mice in measurements of the general locomotor activity, the total number of arms entries and total number of beam breaks (Figure 2A To confirm the critical effect of type I-IFN on autoimmune development and kidney damage reported in previous studies [6,7], (Ambion, Austin, TX, USA) method and analyzed for expression of IFN-stimulated genes by RNase protection assay (RPA) as described in our previous studies [13].…”

“…For example, gene chip analyses reveal a significantly enhanced transcriptional profile in the cells prepared from SLE patients in response to IFN-α (a major form of type I IFN) [4,5]. Meanwhile, suppression of type I-IFN signaling led to a marked attenuation of autoimmune development and kidney damages in lupus-prone NZB mice [6,7].…”