title: Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the production of antibodies to self-nucleic acids, immune complex deposition, and tissue inflammation such as glomerulonephritis. Innate recognition of self-DNA and -RNA and the ensuing production of cytokines such as type I interferons (IFNs) contribute to SLE development. Plasmacytoid dendritic cells (pDCs) have been proposed as a source of pathogenic IFN in SLE; however, their net contribution to the disease remains unclear. We addressed this question by reducing gene dosage of the pDC-specific transcription factor E2-2 (Tcf4), which causes a specific impairment of pDC function in otherwise normal animals. We report that global or DC-specific Tcf4 haplodeficiency ameliorated SLE-like disease caused by the overexpression of the endosomal RNA sensor Tlr7. Furthermore, Tcf4 haplodeficiency in the B6.Sle1.Sle3 multigenic model of SLE nearly abolished key disease manifestations including anti-DNA antibody production and glomerulonephritis. Tcf4-haplodeficient SLE-prone animals showed a reduction of the spontaneous germinal center reaction and its associated gene expression signature. These results provide genetic evidence that pDCs are critically involved in SLE pathogenesis and autoantibody production, confirming their potential utility as therapeutic targets in the disease.
authors.affiliation: Department of Microbiology and Immunology and Department of Pathology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Vanja
authors.initials: V
authors.lastname: Sisirak
authors.affiliation: Department of Microbiology and Immunology and Department of Pathology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Dipyaman
authors.initials: D
authors.lastname: Ganguly
authors.affiliation: Department of Microbiology and Immunology and Department of Pathology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Kanako L
authors.initials: KL
authors.lastname: Lewis
authors.affiliation: Department of Microbiology and Immunology and Department of Pathology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Coline
authors.initials: C
authors.lastname: Couillault
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195.
authors.forename: Lena
authors.initials: L
authors.lastname: Tanaka
authors.affiliation: Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD 20852.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolland
authors.affiliation: Department of Microbiology and Immunology and Department of Pathology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195.
authors.forename: Keith B
authors.initials: KB
authors.lastname: Elkon
authors.affiliation: Department of Microbiology and Immunology and Department of Pathology, Columbia University Medical Center, New York, NY 10032 bvr2101@columbia.edu.
authors.forename: Boris
authors.initials: B
authors.lastname: Reizis
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018628:Gene Dosage / Q000235:genetics; D007370:Interferon Type I / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D051199:Toll-Like Receptor 7 / Q000378:metabolism; D000073940:Transcription Factor 4
chemical_list: D000974:Antibodies, Antinuclear; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D007370:Interferon Type I; D008562:Membrane Glycoproteins; C090743:Tcf4 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D000073940:Transcription Factor 4