OP0306 Downregulation of micrornas in plasmacytoid dendritic cells is associated with a type i interferon signature in systemic lupus erythematosus and antiphospholipid syndrome

AbstractAutoimmune connective tissue diseases arise in a stepwise fashion from asymptomatic preclinical autoimmunity. Type I interferons have a crucial role in the progression to established autoimmune diseases. The cellular source and regulation in disease initiation of these cytokines is not clear, but plasmacytoid dendritic cells have been thought to contribute to excessive type I interferon production. Here, we show that in preclinical autoimmunity and established systemic lupus erythematosus, plasmacytoid dendritic cells are not effector cells, have lost capacity for Toll-like-receptor-mediated cytokine production and do not induce T cell activation, independent of disease activity and the blood interferon signature. In addition, plasmacytoid dendritic cells have a transcriptional signature indicative of cellular stress and senescence accompanied by increased telomere erosion. In preclinical autoimmunity, we show a marked enrichment of an interferon signature in the skin without infiltrating immune cells, but with interferon-κ production by keratinocytes. In conclusion, non-hematopoietic cellular sources, rather than plasmacytoid dendritic cells, are responsible for interferon production prior to clinical autoimmunity.

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

Journal of Experimental Medicine ◽

10.1084/jem.20132522 ◽

2014 ◽

Vol 211 (10) ◽

pp. 1969-1976 ◽

Cited By ~ 138

Author(s):

Vanja Sisirak ◽

Dipyaman Ganguly ◽

Kanako L. Lewis ◽

Coline Couillault ◽

Lena Tanaka ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Lupus Erythematosus ◽

Gene Dosage ◽

Gene Expression Signature ◽

Plasmacytoid Dendritic Cells ◽

Genetic Evidence ◽

Type I ◽

Systemic Lupus ◽

Autoantibody Production

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.

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