How viral infections trigger autoimmunity is poorly understood. A role for Toll-like receptor 3 (TLR3) was hypothesized in this context as viral double-stranded RNA (dsRNA) activates dendritic cells to secrete type I interferons and cytokines that are known to be associated with the disease activity in systemic lupus erythematosus (SLE). Immunostaining of nephritic kidney sections of autoimmune MRL lpr/lpr mice revealed TLR3 expression in infiltrating antigen-presenting cells as well as in glomerular mesangial cells. TLR3-positive cultured mesangial cells that were exposed to synthetic polyinosinic-cytidylic acid (pI:C) RNA in vitro produced CCL2 and IL-6. pI:C RNA activated macrophages and dendritic cells, both isolated from MRL lpr/lpr mice, to secrete multiple proinflammatory factors. In vivo, a single injection of pI:C RNA increased serum IL-12p70, IL-6, and IFN-␣ levels. A course of 50 g of pI:C RNA given every other day from weeks 16 to 18 of age aggravated lupus nephritis in pI:C-treated MRL lpr/lpr mice. Serum DNA autoantibody levels were unaltered upon systemic exposure to pI:C RNA in MRL lpr/lpr mice, as pI:C RNA, in contrast to CpG-DNA, failed to induce B cell activation. It therefore was concluded that viral dsRNA triggers disease activity of lupus nephritis by mechanisms that are different from those of bacterial DNA. In contrast to CpG-DNA/TLR9 interaction, pI:C RNA/TLR3-mediated disease activity is B cell independent, but activated intrinsic renal cells, e.g., glomerular mesangial cells, to produce cytokines and chemokines, factors that can aggravate autoimmune tissue injury, e.g., lupus nephritis.

Objective. Peripheral blood cells (PBMCs) from some patients with systemic sclerosis (SSc) express an interferon-␣ (IFN␣) signature. The aim of this study was to determine whether SSc patient sera could induce IFN␣ and whether IFN␣ induction was associated with specific autoantibodies and/or clinical features of the disease.Methods. SSc sera containing autoantibodies against either topoisomerase I (anti-topo I; n ‫؍‬ 12), nucleolar protein (ANoA; n ‫؍‬ 12), or centromeric protein (ACA; n ‫؍‬ 13) were cultured with a HeLa nuclear extract and normal PBMCs. In some experiments, different cell extracts or inhibitors of plasmacytoid dendritic cell (DC) activation, Fc␥ receptor II (Fc␥RII), endocytosis, or nucleases were used. IFN␣ was measured by enzyme-linked immunosorbent assay.Results. Topo I-containing sera induced significantly higher levels of IFN␣ as compared with all other groups. IFN␣ induction was inhibited by anti-blood dendritic cell antigen 2 (90%), anti-CD32 (76%), bafilomycin (99%), and RNase (82%). In contrast, ACAs induced low levels of IFN␣ even when necrotic, apoptotic, or demethylated extracts were used, despite the fact that CENP-B-binding oligonucleotide containing 2 CpG motifs effectively stimulated IFN␣. IFN␣ production was significantly higher in patients with diffuse SSc (mean ؎ SEM 641 ؎ 174 pg/ml) than in those with limited SSc (215 ؎ 66 pg/ml) as well as in patients with lung fibrosis than in those without. Conclusion. Autoantibody subsets in SSc sera differentially induce IFN␣ and may explain the IFN␣ signature observed in SSc. IFN␣ is induced by plasmacytoid DCs and required uptake of immune complexes through Fc␥RII, endosomal transport, and the presence of RNA, presumably for interaction with Toll-like receptor 7. The higher IFN␣ induction in sera from patients with diffuse SSc than in those with limited SSc as well as in sera from patients with lung fibrosis suggests that IFN␣ may contribute to tissue injury.

Thus, cell-type-specific expression and regulation of TLRs may be involved in infection-associated exacerbation of immune complex glomerulonephritis of MRLlpr/lpr mice.

Viral infections may trigger immune complex glomerulonephritis via

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