scholarly journals Non-lesional and Lesional Lupus Skin Share Inflammatory Phenotypes that Drive Activation of CD16+ Dendritic Cells

2021 ◽  
Author(s):  
Allison C. Billi ◽  
Feiyang Ma ◽  
Olesya Plazyo ◽  
Mehrnaz Gharaee-Kermani ◽  
Rachael Wasikowski ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Lupus Erythematosus ◽  
Cutaneous Lupus Erythematosus ◽  
Cell Communication ◽  
Cell Types ◽  
Type I ◽  
Lesional Skin ◽  
Skin Cell ◽  
Disease Predisposition ◽  
Inflammatory Phenotypes

Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Studies to date suggest that non-lesional keratinocytes play a role in disease predisposition, but this has not been investigated in a comprehensive manner or in the context of other cell populations. To investigate CLE immunopathogenesis, normal-appearing skin, lesional skin, and circulating immune cells from lupus patients were analyzed via integrated single-cell RNA-sequencing and spatial-seq. We demonstrate that normal-appearing skin of lupus patients represents a type I interferon-rich, 'prelesional' environment that skews gene transcription in all major skin cell types and dramatically distorts cell-cell communication. Further, we show that lupus-enriched CD16+ dendritic cells undergo robust interferon education in the skin, thereby gaining pro-inflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and non-lesional skin in lupus and identify a role for skin education of CD16+ dendritic cells in CLE pathogenesis.

scholarly journals Mycophenolic acid, the active form of mycophenolate mofetil, interferes with IRF7 nuclear translocation and type I IFN production by plasmacytoid dendritic cells

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Minoru Shigesaka ◽  
Tomoki Ito ◽  
Muneo Inaba ◽  
Kai Imai ◽  
Hideki Yamanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycophenolate Mofetil ◽  
Mycophenolic Acid ◽  
Lupus Erythematosus ◽  
Nuclear Translocation ◽  
Active Form ◽  
Autoimmune Disorders ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Alternative Treatment Strategy

Abstract Background Both humoral and cellular immune mechanisms are involved in the onset and progression of autoimmune responses in systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) play a central role in the pathogenesis of SLE via the dysregulation of type I interferon (IFN) production; these cells act together with activated myeloid DCs (mDCs) to amplify the vicious pathogenic spiral of autoimmune disorders. Therefore, control of aberrant DC activation in SLE may provide an alternative treatment strategy against this disease. Mycophenolate mofetil (MMF), which has been used to treat lupus nephritis, specifically blocks the proliferation of B and T lymphocytes via inhibition of inosine-5-monophosphate dehydrogenase. Here, we focus on the effects of MMF in targeting DC functions, especially the IFN response of pDCs. Methods We isolated human blood pDCs and mDCs by flow cytometry and examined the effect of mycophenolic acid (MPA), which is a metabolic product of MMF, on the toll-like receptor (TLR) ligand response of DC subsets. Additionally, we cultured pDCs with serum from SLE patients in the presence or absence of MPA and then examined the inhibitory function of MPA on SLE serum-induced IFN-α production. Results We found that treatment with 1−10 μM of MPA (covering the clinical trough plasma concentration range) dose-dependently downregulated the expression of CD80 and CD86 on mDCs (but not pDCs) without inducing apoptosis, in response to R848 or CpG-ODN, respectively. Notably, in pDCs, MPA significantly suppressed IFN-α production with IRF7 nuclear translocation and repressed the AKT activity. In addition, MPA inhibited IL-12 production with STAT4 expression in mDCs. We further identified that MPA had an inhibitory effect on SLE serum-induced IFN-α production by pDCs. Conclusions Our data suggest that MPA can interrupt the vicious pathogenic spiral of autoimmune disorders by regulating the function of DC subsets. This work unveiled a novel mechanism for the therapeutic ability of MMF against SLE.

Familial chilblain lupus due to a gain-of-function mutation in STING

2016 ◽  
Vol 76 (2) ◽  
pp. 468-472 ◽  
Author(s):  
Nadja König ◽  
Christoph Fiehn ◽  
Christine Wolf ◽  
Max Schuster ◽  
Emanuel Cura Costa ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Homology Modelling ◽  
Cutaneous Lupus Erythematosus ◽  
Janus Kinase ◽  
Heterozygous Mutation ◽  
Type I ◽  
Type I Ifn ◽  
Gain Of Function ◽  
Familial Chilblain Lupus ◽  
Chilblain Lupus

ObjectivesFamilial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology.MethodsExome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-β reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes.ResultsIn a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature.ConclusionsA heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.

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