Cutting Edge: Plasmacytoid Dendritic Cells in Late-Stage Lupus Mice Defective in Producing IFN-α

Abstract

Plasmacytoid dendritic cells (pDCs) are professional type I IFN producers believed to promote lupus. However, questions exist about whether they function at the same level throughout the course of lupus disease. We analyzed high-purity pDCs sorted from lupus mice. Although pDCs produced a large amount of IFN-α during disease initiation, those sorted from late-stage lupus mice were found to be defective in producing IFN-α. These pDCs expressed an increased level of MHC, suggesting a functional drift to Ag presentation. We examined the potential mechanism behind the defect and identified a novel transcriptional factor, Foxj2, which repressed the expression of several genes in pDCs, but not IFN-α. Dysregulation in pDCs appears to be predisposed, because they exhibited an altered transcriptional profile before the onset of clinical signs. Our results suggest that pDCs do not function the same throughout the disease course and lose the ability to produce IFN-α in late-stage lupus mice.

Plasmacytoid dendritic cells are functionally exhausted while non-haematopoietic sources of type I interferon dominate human autoimmunity

“…This has been shown to initiate in non-haematopoietic cells, similarly to our findings in humans (54). Moreover, experimental work on lupus-prone mice reported a gradual loss of pDC capacity to produce IFN-α at late stage of disease course (55,56). Importantly, murine models of chronic viral infection maintained a pool of functionally exhausted pDCs -a similar state to what we describe in chronic autoimmunity in humans (57).…”

Breakdown of Immune Tolerance in Systemic Lupus Erythematosus by Dendritic Cells

“…The expression of three inhibitory receptors, BDCA2, leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), and ILT3, on human pDC is reduced in SLE patients compared to HC [ 94 , 106 , 107 ]. On the contrary, MHC-II and costimulatory molecules are increased on pDC of both SLE patients and lupus-prone mice, suggesting an increased ability to present self-antigens and activate autoreactive T cells [ 28 , 37 , 38 , 101 , 108 , 109 ].…”

“…Similar results have been obtained from lupus-prone mice [ 101 ]. We have shown in our recent study that pDC isolated from older MRL/lpr mice in the late stage of lupus development produced significantly less IFN α upon CpG stimulation in vitro compared to pDC purified from younger mice in the early stage [ 109 ]. The reduced IFN α -producing ability may be due to continuous exposure to nucleic acid self-antigens, as pDC from HC produced much less IFN α after repeated stimulation with CpG or DNA-containing ICs [ 159 ].…”

Ethnicity-specific transcriptomic variation in immune cells and correlation with disease activity in systemic lupus erythematosus

“…Some of the shared genes across the four cells were involved in SLE or autoimmune related pathways such as: AFAP1, which was studied in Plasmacytoid dendritic cells in lupus mice. 24 , USP32P1 which is an Immune-Induced gene speci c of Caucasians only 25 , and RPL3P2 which is a gene mapping in the HLA class I region and in the autosomal dominant polycystic kidney disease gene region 26 . The top three up-regulated genes in the CD4 + T cells for the White cohort were AFAP1, a gene shown to have an expression pattern similar to the interferon alpha in SLE mice 24 , USP32P1, a ubiquitinase speci c of the White population 25 , and NAP1L3, Nucleosome Assembly Protein 1 Like 3, which has been recently listed as one of the 93-SLE gene signature (SLE MetaSignature) that is differentially expressed in the blood of patients with SLE compared with healthy volunteers 27 .…”