Type I interferon-associated cytotoxic inflammation in cutaneous lupus erythematosus

2008 ◽  
Vol 301 (1) ◽  
pp. 83-86 ◽  
Author(s):  
Joerg Wenzel ◽  
Sabine Zahn ◽  
Thomas Bieber ◽  
Thomas Tüting
2005 ◽  
Vol 205 (4) ◽  
pp. 435-442 ◽  
Author(s):  
Joerg Wenzel ◽  
Eva Wörenkämper ◽  
Silke Freutel ◽  
Stefanie Henze ◽  
Otto Haller ◽  
...  

2018 ◽  
Vol 5 (1) ◽  
pp. e000284 ◽  
Author(s):  
Joan T Merrill ◽  
Richard Furie ◽  
Victoria P Werth ◽  
Munther Khamashta ◽  
Jorn Drappa ◽  
...  

ObjectiveThis post hoc analysis compared anifrolumab 300 mg every 4 weeks with placebo on rash and arthritis measures with different stringency in patients with moderate to severe SLE (phase IIb; MUSE; NCT01438489). Subgroups were analysed by type I interferon gene signature (IFNGS test–high or test–low).MethodsRash was measured with the SLE Disease Activity Index 2000 (SLEDAI-2K), British Isles Lupus Assessment Group (BILAG) Index and modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI). Arthritis was evaluated using SLEDAI-2K, BILAG and swollen and tender joint counts. Outcomes were measured at week 52.ResultsMore anifrolumab-treated patients demonstrated resolution of rash by SLEDAI-2K versus placebo: 39/88 (44.3%) versus 13/88 (14.8%), OR (90% CI) 4.56 (2.48 to 8.39), p<0.001; improvement of BILAG: 48/82 (58.5%) versus 24/85 (28.2%), OR (90% CI) 3.59 (2.08 to 6.19), p<0.001; and ≥50% improvement by mCLASI: 57/92 (62.0%) versus 30/89 (33.7%), OR (90% CI) 3.31 (1.97 to 5.55), p<0.001. More anifrolumab-treated patients had improved arthritis by SLEDAI-2K versus placebo: 55/97 (56.7%) versus 42/99 (42.4%), OR (90%  CI) 1.88 (1.16 to 3.04), p=0.032;  and BILAG: 65/94 (69.1%) versus 47/95 (49.5%), OR (90% CI) 2.47 (1.48 to 4.12), p=0.003; and mean (SD) swollen and tender joint reductions: –5.5 (6.3) versus –3.4 (5.9), p=0.004. Comparable results were demonstrated in IFNGS test–high patients (n=151). In IFNGS test–low patients (n=50), substantial numerical differences in partial rash and arthritis responses were observed in anifrolumab-treated patients versus placebo, with statistical significance only for rash by BILAG in this small population.ConclusionsAnifrolumab treatment was associated with improvements versus placebo in specific SLE features of arthritis and rash using measures of different stringency. Although driven by robust data in the prevalent IFNGS test–high population, further evaluation in IFNGS test–low patients is warranted.


2016 ◽  
Vol 64 (4) ◽  
pp. 976.2-977
Author(s):  
JN Stannard ◽  
TJ Reed ◽  
JM Kahlenberg ◽  
EM Myers ◽  
L Lowe ◽  
...  

BackgroundCutaneous lupus erythematosus (CLE) is a disfiguring disease that can affect up to 70% of patients with systemic lupus. Treatment modalities are often ineffective and flares are frequent. Interleukin-6 (IL-6) is a pro-inflammatory cytokine which has gotten recent attention in SLE as IL-6 is increased in the serum of active patients and blockade of IL-6 is therapeutic in murine lupus models and phase I human trials. The source of IL-6 in CLE remains unclear.MethodsAll studies were approved by the University of Michigan Internal Review Board (IRB# 72843 and 66116 to JMK). RNA was isolated from formalin fixed, paraffin-embedded biopsies of CLE rashes, which were obtained from the University of Michigan Pathology database. Real-time PCR was used to determine the expression level of the myxovirus (influenza virus) resistance 1 (MX-1) and interleukin-6 (IL6) genes. Biopsies were stained for IL-6 using immunohistochemistry. Skin biopsies were obtained from uninvolved skin of SLE patients with a history of cutaneous involvement or healthy controls followed by isolation and culture of keratinocytes. At confluence, cultures were treated with various concentrations of TLR ligands or UVB and IL-6 release was measured via ELISA. Blockade of type I IFN signaling was completed via monoclonal antibody to the type I IFN receptor.ResultsReal-time PCR analysis of subacute cutaneous lupus erythematosus (sCLE) (n=21) and discoid (DLE) (n=22) rashes demonstrated a significant upregulation of both the IFN-regulated gene, MX1, and the pro-inflammatory cytokine IL-6 when compared with control samples (n=9). Immunohistochemical analysis of skin biopsies confirmed upregulation of IL-6 in the epidermis when compared to control. Keratinocytes from healthy skin of lupus patients produced significantly more IL-6 when stimulated by TLR2, 3 or 4 agonists or exposed to UVB radiation when compared to identical passage keratinocytes from healthy controls. Treatment of control keratinocytes with IFNα increased their IL-6 production and blockade of type I IFNs in the culture media of SKE keratinocytes downregulated the secretion of IL-6.ConclusionsIL-6 is increased at the RNA and protein level within cutaneous lupus biopsies when compared to healthy control skin. Keratinocytes are a major producer of IL-6 in the skin and lupus keratinocytes have enhanced production of IL-6 in response to TLR ligands and UV radiation. Exposure to type I IFN can increase IL-6 production in keratinocytes. SLE-derived keratinocytes downregulate IL-6 production in the presence of tonic blockade of the type I IFN receptor. These data suggest that the epidermis, which is an important barrier for environmental insults, is primed for IL-6 production by autocrine type I IFN production and that this may be one mechanism by which factors such as UV exposure may trigger rash development. Further investigations should focus on the pathogenic significance of IL-6 upregulation in the skin and whether targeting this pathway will have an impact on cutaneous disease activity.


Lupus ◽  
2021 ◽  
pp. 096120332110172
Author(s):  
Hyeon-Jung Gu ◽  
Shinyoung Song ◽  
Joo Young Roh ◽  
YunJae Jung ◽  
Hee Joo Kim

Background Tissue resident memory T cells (TRMs) persist long-term in peripheral tissues without recirculation, triggering an immediate protective inflammatory state upon the re-recognition of the antigen. Despite evidence incriminating the dysregulation of TRMs in autoimmune diseases, few studies have examined their expression in cutaneous lupus erythematosus (CLE). Objectives We aimed to examine whether there are differences among TRM populations in CLE depending on different clinical conditions, such as the CLE subtype or association with systemic lupus erythematosus, and to determine the effect of type I interferon (IFN) on the development of TRMs in CLE. Methods CLE disease activity was evaluated using the Cutaneous Lupus Erythematosus Disease Area and Severity Index. The expression of the TRM markers CD69 and CD103 in CLE lesions was evaluated by immunofluorescence. Flow cytometry was performed on peripheral blood mononuclear cells after IFNα treatment. Results The number of TRMs expressing either CD69 or CD103 was significantly higher in CLE lesions than in control skin; however, it was not significantly different between discoid lupus erythematosus and subacute CLE, or dependent on the presence of concomitant systemic lupus. Lesional severity was not correlated with an increase in TRMs in CLE. IFNα treatment induced a conspicuous increase in CD69 expression in skin-homing T cells, more profoundly in CD4+ T cells than in CD8+ T cells. Conclusions Skin TRMs, either CD69 or CD103-positive cells, showed increased levels in the lesional skin of CLE, and IFNα increased the expression of CD69 in T cells.


2021 ◽  
Vol 12 ◽  
Author(s):  
Lisa Abernathy-Close ◽  
Stephanie Lazar ◽  
Jasmine Stannard ◽  
Lam C. Tsoi ◽  
Sean Eddy ◽  
...  

Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin disease characterized by a diverse cadre of clinical presentations. CLE commonly occurs in patients with systemic lupus erythematosus (SLE), and CLE can also develop in the absence of systemic disease. Although CLE is a complex and heterogeneous disease, several studies have identified common signaling pathways, including those of type I interferons (IFNs), that play a key role in driving cutaneous inflammation across all CLE subsets. However, discriminating factors that drive different phenotypes of skin lesions remain to be determined. Thus, we sought to understand the skin-associated cellular and transcriptional differences in CLE subsets and how the different types of cutaneous inflammation relate to the presence of systemic lupus disease. In this study, we utilized two distinct cohorts comprising a total of 150 CLE lesional biopsies to compare discoid lupus erythematosus (DLE), subacute cutaneous lupus erythematosus (SCLE), and acute cutaneous lupus erythematosus (ACLE) in patients with and without associated SLE. Using an unbiased approach, we demonstrated a CLE subtype-dependent gradient of B cell enrichment in the skin, with DLE lesions harboring a more dominant skin B cell transcriptional signature and enrichment of B cells on immunostaining compared to ACLE and SCLE. Additionally, we observed a significant increase in B cell signatures in the lesional skin from patients with isolated CLE compared with similar lesions from patients with systemic lupus. This trend was driven primarily by differences in the DLE subgroup. Our work thus shows that skin-associated B cell responses distinguish CLE subtypes in patients with and without associated SLE, suggesting that B cell function in skin may be an important link between cutaneous lupus and systemic disease activity.


2018 ◽  
Vol 77 (11) ◽  
pp. 1653-1664 ◽  
Author(s):  
Mrinal K Sarkar ◽  
Grace A Hile ◽  
Lam C Tsoi ◽  
Xianying Xing ◽  
Jianhua Liu ◽  
...  

ObjectiveSkin inflammation and photosensitivity are common in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), yet little is known about the mechanisms that regulate these traits. Here we investigate the role of interferon kappa (IFN-κ) in regulation of type I interferon (IFN) and photosensitive responses and examine its dysregulation in lupus skin.MethodsmRNA expression of type I IFN genes was analysed from microarray data of CLE lesions and healthy control skin. Similar expression in cultured primary keratinocytes, fibroblasts and endothelial cells was analysed via RNA-seq. IFNK knock-out (KO) keratinocytes were generated using CRISPR/Cas9. Keratinocytes stably overexpressing IFN-κ were created via G418 selection of transfected cells. IFN responses were assessed via phosphorylation of STAT1 and STAT2 and qRT-PCR for IFN-regulated genes. Ultraviolet B-mediated apoptosis was analysed via TUNEL staining. In vivo protein expression was assessed via immunofluorescent staining of normal and CLE lesional skin.ResultsIFNK is one of two type I IFNs significantly increased (1.5-fold change, false discovery rate (FDR) q<0.001) in lesional CLE skin. Gene ontology (GO) analysis showed that type I IFN responses were enriched (FDR=6.8×10−04) in keratinocytes not in fibroblast and endothelial cells, and this epithelial-derived IFN-κ is responsible for maintaining baseline type I IFN responses in healthy skin. Increased levels of IFN-κ, such as seen in SLE, amplify and accelerate responsiveness of epithelia to IFN-α and increase keratinocyte sensitivity to UV irradiation. Notably, KO of IFN-κ or inhibition of IFN signalling with baricitinib abrogates UVB-induced apoptosis.ConclusionCollectively, our data identify IFN-κ as a critical IFN in CLE pathology via promotion of enhanced IFN responses and photosensitivity. IFN-κ is a potential novel target for UVB prophylaxis and CLE-directed therapy.


2019 ◽  
Vol 8 (8) ◽  
pp. 1244 ◽  
Author(s):  
Celine C. Berthier ◽  
Lam C. Tsoi ◽  
Tamra J. Reed ◽  
Jasmine N. Stannard ◽  
Emily M. Myers ◽  
...  

Cutaneous lupus erythematosus (CLE) is a common manifestation of systemic lupus erythematosus (SLE), and CLE can also develop without systemic involvement. CLE can be difficult to treat and negatively contributes to quality of life. Despite the importance of CLE, our knowledge of what differentiates cutaneous lupus subtypes is limited. Here, we utilized a large cohort of 90 CLE lesional biopsies to compare discoid lupus erythematosus (DLE) and subacute cutaneous lupus (SCLE) in patients with and without associated SLE in order to discern the drivers of disease activity and possibly uncover better treatment targets. Overall, we found that DLE and SCLE share many differentially expressed genes (DEG) reflecting type I interferon (IFN) signaling and repression of EGFR pathways. No differences between CLE only and SLE-associated CLE lesions were found. Of note, DLE uniquely expresses an IFN-γ node. Unbiased cluster analysis of the DEGs identified two groups separated by neutrophilic vs. monocytic signatures that did not sort the patients based on clinical phenotype or disease activity. This suggests that unbiased analysis of the pathobiology of CLE lesions may be important for personalized medicine and targeted therapeutic decision making.


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