Downregulation of microRNAs in Plasmacytoid Dendritic Cells Is Associated with a Type I Interferon Signature in Systemic Lupus Erythematosus and Antiphospholipid Syndrome

Lucas L. van den Hoogen¹, Joel A.G. van Roon^2,3, Ruth D.E. Fritsch-Stork⁴, Cornelis P.J. Bekker¹, Aridaman Pandit¹, Marzia Rossato⁵ and Timothy R.D.J. Radstake¹, ¹Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ²Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ³Laboratory for Translational immunology, University Medical Center Utrecht, Utrecht, Netherlands, ⁴Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ⁵Department of Rheumatology & Clinical Immunology, Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Antiphospholipid, Dendritic cells, Interferons and systemic lupus erythematosus (SLE), MicroRNA

Session Information

Date: Sunday, November 5, 2017

Title: Antiphospholipid Syndrome Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

The most prominent alteration in the immune system of patients with SLE is a type I interferon (IFN) signature, which we recently also reported in patients with primary APS (PAPS). In SLE and APS, this signature is related to disease activity and vascular disease. Plasmacytoid dendritic cells (pDC) are considered key players in the pathogenesis of SLE and APS as they are major producers of type I IFN. MicroRNAs (miRNAs) are short non-coding RNAs that modulate gene expression through RNA interference and have been implicated in the dysregulation of immune cells in autoimmune diseases. Here we investigated miRNA expression in pDC of patients with SLE and APS in relation to the IFN signature.

Methods:

RNA was extracted from pDCs isolated from the peripheral blood of patients with SLE (n=20), SLE+APS (n=10), PAPS (n=10) and HC (n=12). pDC miRNA and transcriptome profiles were assessed by RT-qPCR by OpenArray and RNA-sequencing (RNAseq) respectively. Patients were stratified by the presence (IFN-high) or absence (IFN-low) of an IFN signature on the basis of RNAseq. pDC stimulated with TLR7 agonists were analyzed for changes in miRNA expression. The frequency of circulating pDC was determined by flow cytometry in patients with SLE (n=49), SLE+APS (n=34) and PAPS (n=27) and healthy controls (HC, n=22)

Results:

Among 131 expressed miRNAs, 36, 17 and 21 miRNAs were differentially expressed (p<0.05) in patients with SLE, SLE+APS and PAPS, respectively, as compared with HC. All but one of these miRNAs were downregulated in the patients versus HC. Only 1 miRNA was differentially expressed when comparing between SLE and SLE+APS patients and between SLE+APS and PAPS patients. No changes in expression of genes related to the biogenesis of miRNAs were observed in the pDC of the patient groups. RNAseq data revealed an IFN signature in pDC, which was strongest in SLE and SLE+APS patients. IFN-high (n=23) patients showed a stronger downregulation of miRNAs as compared with IFN-low (n=17) patients. Activation of pDCs by TLR7 agonists induced a downregulation of miRNAs in pDC, resembling the miRNA expression pattern seen in patients, in particular those with a high type I IFN signature. Pathway enrichment on the overlap of the targets of the top three miRNA (p<0.001) and differentially expressed genes from RNAseq between IFN-high and –low patients indicated that these miRNAs are potentially regulating pathways relevant for pDC function such as TLR signaling, endocytosis and pDC survival. In line with that, the numbers of circulating pDC were reduced in peripheral blood of patients with SLE, SLE+APS and PAPS, in particular in patients with a high type I IFN signature.

Conclusion:

Reduced numbers of circulating pDC and downregulation of miRNAs in pDC are shared between SLE, SLE+APS and PAPS patients and are related to the IFN signature. Our data suggest that the reduced expression of a subset of miRNA underlies pDC dysregulation in SLE, SLE+APS and PAPS patients.

Disclosure: L. L. van den Hoogen, None; J. A. G. van Roon, None; R. D. E. Fritsch-Stork, None; C. P. J. Bekker, None; A. Pandit, None; M. Rossato, None; T. R. D. J. Radstake, None.

To cite this abstract in AMA style:

van den Hoogen LL, van Roon JAG, Fritsch-Stork RDE, Bekker CPJ, Pandit A, Rossato M, Radstake TRDJ. Downregulation of microRNAs in Plasmacytoid Dendritic Cells Is Associated with a Type I Interferon Signature in Systemic Lupus Erythematosus and Antiphospholipid Syndrome [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/downregulation-of-micrornas-in-plasmacytoid-dendritic-cells-is-associated-with-a-type-i-interferon-signature-in-systemic-lupus-erythematosus-and-antiphospholipid-syndrome/. Accessed .

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