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J Exp Med. 2014 Sep 22;211(10):1969-76. doi: 10.1084/jem.20132522. Epub 2014 Sep 1.

Genetic evidence for the role of plasmacytoid dendritic cells in systemic lupus erythematosus.

Author information

1
Department of Microbiology and Immunology and Department of Pathology, Columbia University Medical Center, New York, NY 10032.
2
Department of Medicine, University of Washington, Seattle, WA 98195.
3
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, Rockville, MD 20852.
4
Department of Microbiology and Immunology and Department of Pathology, Columbia University Medical Center, New York, NY 10032 bvr2101@columbia.edu.

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.

PMID:
25180061
PMCID:
PMC4172218
DOI:
10.1084/jem.20132522
[Indexed for MEDLINE]
Free PMC Article

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