Requirement of toll‐like receptor 7 for pristane‐induced production of autoantibodies and development of murine lupus nephritis

Abstract

Objective. The detection of high titers of antibodies against small nuclear ribonucleoproteins (snRNP) is a diagnostic finding in patients in whom systemic lupus erythematosus (SLE) is suspected. Endogenous RNA molecules within snRNP trigger Toll-like receptor 7 (TLR-7) activation in B cells and dendritic cells, leading to anti-snRNP antibody production, which is associated with the development of immune complex nephritis in SLE. The purpose of this study was to investigate the role of TLR-7 in anti-snRNP antibody production and renal disease in SLE induced by an exogenous factor in the absence of genetic predisposition, using the pristane-induced murine lupus model.Methods. Serum autoantibodies, IgG isotypes, and cytokine levels in pristane-treated wild-type and TLR-7-deficient mice were analyzed by enzyme-linked immunosorbent assay. Histopathologic changes in mouse kidneys were determined by light immunofluorescence microscopy. Cell subsets in splenocytes and peritoneal lavage cells from the mice were examined by flow cytometry.Results. We found that anti-snRNP antibody production induced by pristane treatment was entirely dependent on the expression of TLR-7, whereas antidouble-stranded DNA antibody production was not affected by a lack of TLR-7. Impaired anti-snRNP antibody production in TLR-7-deficient mice was paralleled by lower levels of glomerular IgG and complement deposits, as well as less severe glomerulonephritis.Conclusion. TLR-7 is specifically required for the production of RNA-reactive autoantibodies and the development of glomerulonephritis in pristane-induced murine lupus, a model of environmentally triggered SLE in the absence of genetic susceptibility to autoimmunity. Specific interference with TLR-7 activation by endogenous TLR-7 ligands may therefore be a promising novel strategy for the treatment of SLE.The immunologic hallmark of systemic lupus erythematosus (SLE) is the presence of high levels of circulating antinuclear autoantibodies, which develop several years before manifestation of the disease and which are thought to be critically involved in its pathogenesis (1). Recent data indicate that Toll-like receptors (TLRs) recognizing self nucleic acids may be critically involved in breaking peripheral tolerance against nuclear antigens and allowing the generation of a destructive autoimmune response in SLE. By activating Tolllike receptor 9 (TLR-9) and TLR-7/8, endogenous DNA and RNA sequences contained within nuclear autoantigens in circulating autoimmune complexes act as "autoadjuvants" for efficient priming and boosting of the autoimmune response in SLE (2). By simultaneous

Suppression of systemic autoimmunity by the innate immune adaptor STING

“…STING-deficient MRL/lpr mice develop a dramatically accelerated disease profile characterized by the expansion and activation of both the lymphoid and myeloid compartments, increased numbers of type I IFN-producing cells, elevated autoantibody titers, and a shorter lifespan. Similar to our findings in the MRL/lpr model, STING deficiency exacerbated TMPD-induced inflammation, a condition also associated with type I IFNs and TLR-activated Ly6C hi monocytes (24,26). Nonautoimmune-prone STING-deficient mice do not exhibit any evidence of systemic autoimmunity.…”

“…These features include a type I IFN signature, ANAs, and glomerulonephritis (24,25). Importantly, TMPD-induced autoimmunity is dependent upon TLR7 and type I IFNs (26). Pristane injection of C57/Bl6 mice results in an early and persistent peritoneal inflammation and the recruitment of TLR7 hi Ly6C hi monocytes, a potential source of type I IFNs, in this model (25).…”

Molecular mimicry in innate immunity? The viral RNA recognition receptor TLR7 accelerates murine lupus

“…In addition, Christensen, et al [6] showed that lupus nephritis takes a significantly milder course in Tlr7-deficient MRLlpr/lpr mice. This was confirmed in pristane-induced lupus nephritis in C57BL/6 mice [8]. Both studies also observed a significant reduction in the plasma levels of IgG2a/2c isotype antibodies in Tlr7-deficient mice mice [6,8].…”

“…Both studies also observed a significant reduction in the plasma levels of IgG2a/2c isotype antibodies in Tlr7-deficient mice mice [6,8]. Lack of Tlr7 in MRLlpr/lpr mice was associated with a general reduction in immune activation affecting the proliferation and activation of splenic B and T lymphocytes [6], which was not observed in pristane-induced lupus in C57BL/6 mice [8].…”

“…In all three models studied so far, the MRLlpr/lpr mice and the 564 immunoglobulin transgenic mice, which develop lupus spontaneously, as well as the pristaneinduced lupus model, production of class switched autoantibodies recognizing the RNA-containing antigens snRNP, Sm, and ssRNA was specifically abrogated in the absence of Tlr7 [6][7][8]. In contrast the production of anti-chromatin and anti-dsDNA antibodies was found to be independent of Tlr7 in these models [6,8]. These results demonstrate an essential and specific function of Tlr7 for the generation of high affinity RNA-reactive autoantibodies in murine lupus.…”