Date: Monday, November 6, 2017
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Dendritic cells (DC) are the sentinel cells of the immune system that potently activate T-cells, making them important players in the pathophysiology of systemic autoimmune diseases. The most prominent alteration in the immune system of patients with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) is the upregulation of type I interferon (IFN) inducible genes, known as the IFN signature. This signature is related to disease activity and the occurrence of vascular disease and is considered a promising therapeutic target. Plasmacytoid DC (pDC) are held responsible for the increased type I IFN (IFNα) production in SLE and APS, however, little is known on the molecular mechanisms that underlie increased type I IFN production by pDC in SLE and APS. Here we investigated the causes and consequences of increased type I IFN signaling on the dysregulation of both pDC and myeloid DC (mDC) in patients with SLE and APS.
pDC and mDC were isolated from peripheral blood of patients with SLE (n=20), SLE+APS (n=10) and primary APS (PAPS, n=10) and healthy controls (n=12). RNA was extracted and used for RNA sequencing (RNAseq) to identify differentially expressed genes in pDC and mDC of SLE, SLE+APS and PAPS patients as compared with HC. Differential gene expression in pDC and mDC was compared between patients with (IFN-high) or without (IFN-low) a type I IFN signature. The effects of IFNα and TLR7 agonists on purified pDC were analyzed by RT-qPCR and flow cytometry. The effect of IFNα on cytokine production and the expression of T-cell stimulating molecules on pDC and mDC was measured by flow cytometry.
pDC and mDC shared an upregulation of type I IFN inducible genes in SLE, SLE+APS and PAPS as compared with HC. The expression of TLR7 and its downstream intermediates were increased in both pDC and mDC in all three patient groups as compared with HC. In pDC, not mDC, increased expression of TLR7 was confined to IFN-high patients (p<0.001). mDC of IFN-high patients showed an increased expression of genes involved in the activation of B- and T-cells (p<0.001). In vitro, IFNα upregulated TLR7 expression in pDC and augmented TLR7 mediated IFNα production. In contrast to pDC, in mDC IFNα priming enhanced TLR7 mediated TNFα production as well as the expression of T-cell stimulating molecules.
IFNα has different effects on pDC and mDC. pDC of IFN-high SLE and APS patients are primed for type I IFN production through upregulation of TLR7. This results in a pathogenic loop of IFNα production by pDC, sustaining an increased activation status of both pDC and mDC in SLE and APS. Intervening in this loop potentially attenuates the dysregulation of DC in SLE and APS.
To cite this abstract in AMA style:van den Hoogen LL, Pandit A, Palla G, Rossato M, Fritsch-Stork RDE, van Roon JAG, Radstake TRDJ. Type I Interferon Drives the Dysregulation of Plasmacytoid and Myeloid Dendritic Cells in Systemic Lupus Erythematosus and Antiphospholipid Syndrome [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/type-i-interferon-drives-the-dysregulation-of-plasmacytoid-and-myeloid-dendritic-cells-in-systemic-lupus-erythematosus-and-antiphospholipid-syndrome/. Accessed November 29, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/type-i-interferon-drives-the-dysregulation-of-plasmacytoid-and-myeloid-dendritic-cells-in-systemic-lupus-erythematosus-and-antiphospholipid-syndrome/