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J Immunol. 2019 Apr 1. pii: ji1801267. doi: 10.4049/jimmunol.1801267. [Epub ahead of print]

Cutting Edge: BCAP Promotes Lupus-like Disease and TLR-Mediated Type I IFN Induction in Plasmacytoid Dendritic Cells.

Author information

1
Immunology Program, Benaroya Research Institute, Seattle, WA 98109.
2
Department of Immunology, University of Washington, Seattle, WA 98109; and.
3
Department of Pathology, University of Washington, Seattle, WA 98195.
4
Immunology Program, Benaroya Research Institute, Seattle, WA 98109; jhamerman@benaroyaresearch.org.

Abstract

Systemic lupus erythematosus severity correlates with elevated serum levels of type I IFNs, cytokines produced in large quantities by plasmacytoid dendritic cells (pDC) in response to engagement of TLR7 and TLR9 with endocytosed nucleic acids. B cell adaptor for PI3K (BCAP) promoted many aspects of TLR7-driven lupus-like disease, including Isg15 and Ifit1 expression in blood and an immature pDC phenotype associated with higher IFN production. BCAP-/- mice produced significantly less serum IFN-α than wild-type mice after injection of TLR9 agonist, and BCAP promoted TLR7 and TLR9-induced IFN-α production specifically in pDC. TLR-induced IFN-α production in pDC requires DOCK2-mediated activation of Rac1 leading to activation of IKKα, a mechanism we show was dependent on BCAP. BCAP-/- pDC had decreased actin polymerization and Rac1 activation and reduced IKKα phosphorylation upon TLR9 stimulation. We show a novel role for BCAP in promoting TLR-induced IFN-α production in pDC and in systemic lupus erythematosus pathogenesis.

PMID:
30936294
DOI:
10.4049/jimmunol.1801267

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