Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 211, Issue 10, Pages 1977-1991Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20132620
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Funding
- Ruth L. Kirschstein National Research Service Award [5T32AI007163-35]
- AIRC (Associazione Italiana per la Ricerca sul Cancro) [IG 11924]
- Fondazione Beretta (Brescia, Italy)
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Plasmacytoid dendritic cells (pDCs) have long been implicated in the pathogenesis of lupus. However, this conclusion has been largely based on a correlative link between the copious production of IFN-alpha/beta by pDCs and the IFN-alpha/beta signature often seen in human lupus patients. The specific contribution of pDCs to disease in vivo has not been investigated in detail. For this reason, we generated a strain of BXSB lupus-prone mice in which pDCs can be selectively depleted in vivo. Early, transient ablation of pDCs before disease initiation resulted in reduced splenomegaly and lymphadenopathy, impaired expansion and activation of T and B cells, reduced antibodies against nuclear autoantigens and improved kidney pathology. Amelioration of pathology coincided with decreased transcription of IFN-alpha/beta induced genes in tissues. PDC depletion had an immediate impact on the activation of immune cells, and importantly, the beneficial effects on pathology were sustained even though pDCs later recovered, indicating an early pDC contribution to disease. Together, our findings demonstrate a critical function for pDCs during the IFN-alpha/beta-dependent initiation of autoimmune lupus and point to pDCs as an attractive therapeutic target for the treatment of SLE.
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