title: Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus.
abstract: In vitro evidence suggests that plasmacytoid dendritic cells (pDCs) are intimately involved in the pathogenesis of lupus. However, it remains to be determined whether these cells are required in vivo for disease development, and whether their contribution is restricted to hyperproduction of type I IFNs. To address these issues, we created lupus-predisposed mice lacking the IFN regulatory factor 8 (IRF8) or carrying a mutation that impairs the peptide/histidine transporter solute carrier family 15, member 4 (SLC15A4). IRF8-deficient NZB mice, lacking pDCs, showed almost complete absence of anti-nuclear, anti-chromatin, and anti-erythrocyte autoantibodies, along with reduced kidney disease. These effects were observed despite normal B-cell responses to Toll-like receptor (TLR) 7 and TLR9 stimuli and intact humoral responses to conventional T-dependent and -independent antigens. Moreover, Slc15a4 mutant C57BL/6-Fas(lpr) mice, in which pDCs are present but unable to produce type I IFNs in response to endosomal TLR ligands, also showed an absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. Taken together, our results demonstrate that pDCs and the production of type I IFNs by these cells are critical contributors to the pathogenesis of lupus-like autoimmunity in these models. Thus, IRF8 and SLC15A4 may provide important targets for therapeutic intervention in human lupus.
authors: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. rbaccala@scripps.edu
authors: Roberto
authors: R
authors: Baccala
authors: Rosana
authors: R
authors: Gonzalez-Quintial
authors: Amanda L
authors: AL
authors: Blasius
authors: Ivo
authors: I
authors: Rimann
authors: Keiko
authors: K
authors: Ozato
authors: Dwight H
authors: DH
authors: Kono
authors: Bruce
authors: B
authors: Beutler
authors: Argyrios N
authors: AN
authors: Theofilopoulos
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D008024:Ligands; D026901:Membrane Transport Proteins; D000099185:Interferon Regulatory Factor-8; C554281:Slc15a4 protein, mouse
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