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Innate sensors for nucleic acids and lupus pathogenesis
Arthritis Research & Therapy volume 14, Article number: A37 (2012)
We continue our efforts to define the pathogenesis of systemic lupus-like autoimmunity in predisposed mouse models by focusing on the role of endosomal nucleic acid-sensing TLRs.
We reported that NZB mice deficient for the common receptor for type I IFNs showed significant reductions in all disease parameters. To differentiate whether the pathogenic effects were mediated by the multiple IFNα subtypes and/or the single IFNβ, we created congenic NZB mice lacking Ifnb and found that disease severity was unaltered, strongly implicating IFNα subtypes as the principal effectors. We then documented that long-term treatment of male BXSB mice with an anti-IFNAR antibody of mouse origin reduced serologic, cellular and histologic disease manifestations and extended survival, suggesting that disease acceleration by the Tlr7 gene duplication in this model is mediated by type I IFN signaling. The efficacy of this treatment was greater when applied relatively early in the disease process, but reductions in some disease characteristics, especially kidney pathology, were evident even when treatment was initiated at later stages, and a transient therapeutic effect was also noted in the MRL-Faslpr model. The combined findings suggest that antibody-mediated IFNAR blockade may be a useful treatment approach in human SLE and probably other autoimmune syndromes in which these cytokines appear to play a pathogenic role.
We have also hypothesized that engagement of nucleic acid-sensing TLRs may be responsible for spreading the aberrant response beyond ANAs to encompass the broader spectrum of disease-associated autoantibody specificities. Using MRL-Faslpr mice congenic for the 3d mutation of the Unc93b1 gene, in which signaling by all endosomal TLRs (TLR3, TLR7, TLR9) is extinguished, we indeed found reductions not only in autoantibodies against nucleic acids and associated proteins (anti-chromatin, anti-RNP, anti-Sm), but also in a broad panel of autoantibody specificities, particularly against antigens known to contain or bind to nucleic acids, such as cardiolipin, β2-glycoprotein 1 and myeloperoxidase. Surprisingly, even anti-erythrocyte autoantibodies and hemolytic anemia were significantly reduced in NZB mice congenic for the 3d mutation compared with wild-type controls. Thus, almost the entire gamut of autoantibodies in lupus can be traced to the initial engagement of nucleic acid-sensing TLRs.
To examine whether engagement of B-cell intrinsic nucleic acid-sensing TLRs is required for autoantibody production in vivo, we generated mixed bone marrow chimeras of B6-Faslpr mice that were either 3d/IgHb or WT/IgHa and measured allotype-specific IgM RF and IgG2a anti-chromatin responses. Strikingly, both autoantibodies were derived almost exclusively from the wild-type donor B cells. This finding underscores the essential significance of B-cell nucleic acid sensors in loss of tolerance and production of autoantibodies in lupus and provides a specific target for intervention.
Evidence suggests that plasmacyotoid dendritic cells (pDC), the major producers of type I IFNs, are likely to be involved in the pathogenesis of lupus. One ENU phenovariant identified by Beutler and colleagues, named feeble, showed abrogation of both TLR7-induces and TLR9-induced type I IFN and proinflammatory cytokine production by pDCs, while leaving intact pDC development and TLR responses by other cells. The feeble phenotype was mapped to a mutation in Slc15a4, which encodes the peptide/histidine transporter 1 (PHT1), one of the four members of the solute carrier 15 (Slc15) family of proteins. In preliminary collaborative studies with Beutler and colleagues, lupus-prone B6Faslpr mice congenic for the feeble mutation showed significant reduction in hypergammaglobulinemia, lymphadenopathy and mortality. These findings provide direct evidence for the role of pDC in the pathogenesis of systemic autoimmunity and suggests that pharmacologic agents that interfere with Sle15a4 function may be useful in treating lupus and other diseases in which these cells appear to be involved.
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Theofilopoulos, A., Gonzalez-Quintial, R., Koh, Y. et al. Innate sensors for nucleic acids and lupus pathogenesis. Arthritis Res Ther 14, A37 (2012) doi:10.1186/ar3971
- Bone Marrow Chimera
- BXSB Mouse
- Endosomal TLRs
- Mixed Bone Marrow
- Unc93b1 Gene