Cross-Comparison of Inflammatory Skin Disease Transcriptomics Identifies PTEN as a Pathogenic Disease Classifier in Cutaneous Lupus Erythematosus.

Tissue transcriptomics is used to uncover molecular dysregulations underlying diseases. However, the majority of transcriptomics studies focus on single diseases with limited relevance for understanding the molecular relationship between diseases or for identifying disease-specific markers. In this study, we used a normalization approach to compare gene expression across nine inflammatory skin diseases. The normalized datasets were found to retain differential expression signals that allowed unsupervised disease clustering and identification of disease-specific gene signatures. Using the NS-Forest algorithm, we identified a minimal set of biomarkers and validated their use as diagnostic disease classifier. Among them, PTEN was identified as being a specific marker for cutaneous lupus erythematosus and found to be strongly expressed by lesional keratinocytes in association with pathogenic type I IFNs. In fact, PTEN facilitated the expression of IFN-ß and IFN-κ in keratinocytes by promoting activation and nuclear translocation of IRF3. Thus, cross-comparison of tissue transcriptomics is a valid strategy to establish a molecular disease classification and to identify pathogenic disease biomarkers.

Immunohistochemical Study of the PD-1/PD-L1 Pathway in Cutaneous Lupus Erythematosus.

The pathomechanism of various autoimmune diseases is known to be associated with the altered function of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) axis. We aimed to investigate the role of this pathway and inflammatory cell markers in subtypes of cutaneous lupus erythematosus (CLE): discoid lupus erythematosus (DLE), subacute CLE (SCLE) and toxic epidermal necrolysis (TEN)-like lupus, a hyperacute form of acute CLE (ACLE). Ten skin biopsy samples from 9 patients were analyzed with immunohistochemistry regarding the following markers: CD3, CD4, CD8, Granzyme B, CD123, CD163, PD-1, PD-L1. Our group consisted of 4 SCLE (2 idiopathic (I-SCLE) and 2 PD-1 inhibitor-induced (DI-SCLE)), 4 DLE and 1 TEN-like lupus cases. From the latter patient two consecutive biopsies were obtained 1 week apart. Marker expression patterns were compared through descriptive analysis. Higher median keratinocyte (KC) PD-L1 expression was observed in the SCLE group compared to the DLE group (65% and 5%, respectively). Medians of dermal CD4, Granzyme B (GB), PD-1 positive cell numbers and GB+/CD8+ ratio were higher in the DLE group than in the SCLE group. The I-SCLE and DI-SCLE cases showed many similarities, however KC PD-L1 expression and dermal GB positive cell number was higher in the former. The consecutive samples of the TEN-like lupus patient showed an increase by time within the number of infiltrating GB+ cytotoxic T-cells and KC PD-L1 expression (from 22 to 43 and 30%-70%, respectively). Alterations of the PD-1/PD-L1 axis seems to play a role in the pathogenesis of CLE.

IL-33/ST2 Activation Is involved in Ro60-Regulated Photosensitivity in Cutaneous Lupus Erythematosus.

Interleukin- (IL-) 33 contributes to various inflammatory processes. IL-33/ST2 activation participates in systemic lupus erythematous via binding to the receptor of Suppression of Tumorigenicity 2 protein (ST2). However, whether IL-33/ST2 interferes with the nosogenesis of cutaneous lupus erythematosus (CLE) has not been reported so far. Herein, we proposed to disclose the impacts on IL-33/ST2 activation and Ro60 on CLE and their potential implications in the photosensitization of CLE cells. IL-33, ST2, and Ro60 in CLE patients' skin lesions were detected. Murine keratinocytes stimulated with or without IL-33 were irradiated by ultraviolet B (UVB), and the levels of Ro60 and inflammation markers were determined. Keratinocytes were cocultured with J774.2 macrophages and stimulated with IL-33 for analysis of chemostasis. The results identified that IL-33, ST2, and downstream inflammation markers were significantly upregulated in CLE lesions with Ro60 overexpression. Additionally, IL-33 treatment promoted the upregulation of Ro60 induced by UVB treatment in murine keratinocytes. Moreover, IL-33 stimulates keratinocytes to induce macrophage migration via enhancing the generation of the chemokine (C-C motif) ligands 17 and 22. Meanwhile, the silencing of ST2 or nuclear factor-kappa B (NF-κB) suppression abolished IL-33-induced upregulation of Ro60 in keratinocytes. Similarly, the inhibition of SOX17 expression was followed by downregulation of Ro60 in keratinocytes following IL-33 stimulation. In addition, UVB irradiation upregulated SOX17 in keratinocytes. Conclusively, the IL-33/ST2 axis interferes with Ro60-regulated photosensitization via activating the NF-κB- and PI3K/Akt- and SOX17-related pathways.

Skin CD4+ Trm cells distinguish acute cutaneous lupus erythematosus from localized discoid lupus erythematosus/subacute cutaneous lupus erythematosus and other skin diseases.

BACKGROUND: Although the contribution of aberrant CD4+ T cell signaling to systemic lupus erythematosus (SLE) is well established, its role in cutaneous lupus erythematosus (CLE) skin is largely unknown. Because the rate of systemic manifestations varies in each subtype, resident memory CD4+ T cells in lesions that are responsible for only skin-associated tissue responses may vary in each subtype. However, the role of CD4+ tissue-resident memory T (CD4+ Trm) cells in each CLE subtype remains unclear. OBJECTIVES: To analyze and compare CD4+ Trm cells and absent in melanoma 2 (AIM2) identified by smart RNA sequencing (Smart-seq) in CD4+ Trm cells from patients with acute CLE (ACLE), subacute CLE (SCLE), and localized discoid lupus erythematosus (localized DLE) lesions. METHODS: We performed Smart-seq to investigate differences in dermal CD4+ Trm cells between patients with ACLE and normal controls (NCs). Multicolor immunohistochemistry was utilized to measure the levels of AIM2 in CD4+ Trm cells present in the skin of 134 clinical patients, which included patients with localized DLE (n = 19), ACLE (n = 19), SCLE (n = 16), psoriasis (n = 12), rosacea (n = 17), lichen planus (n = 18), and annular granuloma (n = 15), as well as NCs (n = 18). RESULTS: The Smart-seq data showed higher AIM2 expression in skin CD4+ Trm cells from ACLE lesions than NCs (fold change >10, adjusted P < 0.05). AIM2 expression in CD4+ Trm cells did not vary according to age or sex. AIM2 expression in CD4+ Trm cells was significantly lower in patients with ACLE (6.38 ± 5.22) than localized DLE (179.41 ± 160.98, P < 0.0001) and SCLE (63.43 ± 62.27, P < 0.05). In an overall comparison of ACLE with localized DLE and SCLE, the receiver operating characteristic curve for AIM2 expression in CD4+ Trm cells had a sensitivity of 100.00% and a specificity of 82.86% at a cutoff value of 18.26. In a comparison of ACLE with localized DLE, the sensitivity was 89.47%, and the specificity was 100.00% at a cutoff value of 12.26. In a comparison of ACLE with SCLE, the sensitivity was 100.00%, and the specificity was 75.00% at a cutoff value of 18.26. CONCLUSIONS: The number of CD4+ Trm cells is increased in lesions of SCLE and localized DLE compared to ACLE, suggesting that CD4+ Trm cells may have a more crucial role in persistent lesions of SCLE and localized DLE. In addition, AIM2 expression in CD4+ Trm cells discriminates patients with ACLE from those with localized DLE and SCLE.

NKG2D and its ligands as cytotoxic factors in cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disorder that is characterized by an anti-epidermal lymphocytic infiltrate invading the dermo-epidermal junction, causing an interface dermatitis (ID). Pathogenesis of CLE has been linked to activation of innate immunity. NKG2D is an innate immune receptor on NK cells and distinct T-cell populations. The NKG2D ligands MHC class I polypeptide-related sequence A and B (MICA, MICB) have been associated to CLE susceptibility. Our gene microarray analyses of chronic discoid lupus erythematosus (CDLE) skin lesions, separated in epidermal, junctional and dermal skin areas via laser microdissection, revealed a high expression of NKG2D in the lymphocytic infiltrate and led us to further investigate the role of NKG2D in CLE. Pathway analyses showed a strong "interferon (IFN) signature" and vast activation of innate immune response pathways (TLR, RIG-I, cytosolic DNA sensing, JAK/STAT) in CDLE, that expressed the high NKG2D signal. Immunohistochemistry (IHC) confirmed the presence of NKG2D and its ligand MICB in CDLE and subacute cutaneous lupus erythematosus (SCLE) lesions. Finally, HaCaT cells were stimulated with nucleic acids and extracted RNA was sequenced with Illumina HiSeq and showed that stressed keratinocytes express typical NKG2D ligands MICA/B and ULBP2. This study provides first evidence that NKG2D is present in CDLE and SCLE skin lesions and could be relevant for cytotoxicity in IFN-driven skin lesions with upregulated innate immune response pathways present in CLE. It could furthermore play a role in CLE inflammation promoted by keratinocytes under cell stress.

IL18-containing 5-gene signature distinguishes histologically identical dermatomyositis and lupus erythematosus skin lesions.

Skin lesions in dermatomyositis (DM) are common, are frequently refractory, and have prognostic significance. Histologically, DM lesions appear similar to cutaneous lupus erythematosus (CLE) lesions and frequently cannot be differentiated. We thus compared the transcriptional profile of DM biopsies with CLE lesions to identify unique features. Type I IFN signaling, including IFN-κ upregulation, was a common pathway in both DM and CLE; however, CLE also exhibited other inflammatory pathways. Notably, DM lesions could be distinguished from CLE by a 5-gene biomarker panel that included IL18 upregulation. Using single-cell RNA-sequencing, we further identified keratinocytes as the main source of increased IL-18 in DM skin. This study identifies a potentially novel molecular signature, with significant clinical implications for differentiating DM from CLE lesions, and highlights the potential role for IL-18 in the pathophysiology of DM skin disease.

MicroRNA Expression in Cutaneous Lupus: A New Window to Understand Its Pathogenesis.

BACKGROUND: The role of miRNAs in the pathogenesis of cutaneous lupus has not been studied. OBJECTIVE: It was to assess the levels of a selected panel of circulating miRNAs that could be involved in the regulation of the immune response, inflammation, and fibrosis in cutaneous lupus. METHODS: It was a cross-sectional study. We included 22 patients with subacute (SCLE) and 20 with discoid (DLE) lesions, and 19 healthy donors (HD). qRT-PCR for miRNA analysis, flow cytometry in peripheral blood, and skin immunohistochemistry were performed to determine the distribution of CD4 T cells and regulatory cells and their correlation with circulating miRNAs. RESULTS: miR-150, miR-1246, miR-21, miR-23b, and miR-146 levels were downregulated in SCLE vs. HD. miR-150, miR-1246, and miR-21 levels were downregulated in DLE vs. HD. miR-150, miR-1246, and miR-21 levels were downregulated in DLE γ + with miR-1246 in SCLE, whereas CD123+/CD196+/IDO+ cells were positively associated with miR-150 in DLE. In the tissue, CD4+/IL-4+ and CD20+/IL-10+ cells were positively associated with miR-21 and CD4+/IFN-γ + with miR-1246 in SCLE, whereas CD123+/CD196+/IDO+ cells were positively associated with miR-150 in DLE. In the tissue, CD4+/IL-4+ and CD20+/IL-10+ cells were positively associated with miR-21 and CD4+/IFN-ß, thyroid hormone, and cancer signaling pathways were shared between miR-21, miR-31, miR-23b, miR-146a, miR-1246, and miR-150. CONCLUSIONS: A downregulation of miR-150, miR-1246, and miR-21 in both CLE varieties vs. HD. miR-150, miR-1246, and miR-21 levels were downregulated in DLE.

Fas ligand promotes an inducible TLR-dependent model of cutaneous lupus-like inflammation.

Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.

High expression of B lymphocyte stimulator in lesional keratinocytes of patients with cutaneous lupus erythematosus.

Belimumab, an anti-B lymphocyte stimulator (BLyS) monoclonal antibody, is approved for systemic lupus erythematosus; however, it is unclear if it can be used to treat specific skin lesions in this disease. In this analysis, we investigated the expression of BLyS and its receptors in skin lesions of different subtypes of cutaneous lupus erythematosus (CLE) using immunohistochemistry and gene expression analyses. Compared to healthy controls, the expression of BLyS was significantly higher in skin lesions of all included CLE subtypes. Similar results were seen for the BLyS receptors BAFF-R and BCMA. Moreover, CLE-typical pro-inflammatory mediators (immunostimulatory DNAs) significantly enhanced the BLyS expression of keratinocytes in vitro. This study suggests a potential role for BLyS as therapeutic target in the treatment of CLE skin lesions.

Microarray study reveals a transforming growth factor-ß-dependent mechanism of fibrosis in discoid lupus erythematosus.

BACKGROUND: Discoid lupus erythematosus (DLE) is characterized by scarring lesions that develop and perpetuate fibrotic lesions. These are not observed in subacute cutaneous lupus erythematosus (SCLE). The pathophysiological basis of this is currently unknown. OBJECTIVES: To identify contradistinctive signalling pathways and cellular signatures between the two type of lupus, with a focus on the molecular mechanisms leading to fibrosis. METHODS: We conducted a gene expression microarray analysis in lesional and nonlesional skin biopsy specimens of patients with DLE (n = 10) and SCLE (n = 10). Confirmatory reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were performed on selected transcripts in a new cohort of paraffin-embedded skin biopsies (n = 20). Changes over time of a group of selected inflammatory and fibrotic genes were also evaluated in a second biopsy taken 12 weeks later. In vitro functional studies were performed in primary isolated fibroblasts. RESULTS: Compared with nonlesional skin, DLE samples expressed a distinctive T-cell gene signature. DLE samples displayed a significant CD4 T-cell enrichment with an imbalance towards T helper 1 cytokine predominance and a relative increased forkhead box (FOX)P3 response. RT-qPCR and immunochemical analysis over time showed a progressive increment of fibrotic markers and persistent FOXP3 recruitment. Ex vivo upregulation of SERPINE1, MMP9, TGFBR1, phosphorylated SMAD3 and TGFB1 suggested a transforming growth factor (TGF)-ß-dependent mechanism of fibrosis in DLE, also confirmed by the results observed following in vitro stimulation with TGF-ß. CONCLUSIONS: These results highlight major pathogenic pathways in DLE and provide novel molecular targets for the development of new therapies. The data suggest the existence of a TGF-ß-dependent pathway inducing fibrosis in DLE.

Tumor-forming plasmacytoid dendritic cells associated with myeloid neoplasms. Report of a peculiar case with histopathologic features masquerading as lupus erythematosus.

Plasmacytoid dendritic cells (PDC) belong to a subtype of dendritic cells that are normally absent in healthy skin. In some inflammatory diseases of the skin, especially lupus erythematosus (LE), these cells are occasionally recruited in great amounts, which can be used as a helpful clue for diagnosis. Rarely, PDC may also accumulate in the skin of patients with myeloid leukemia, a yet poorly known condition currently called 'tumor-forming PDC associated with myeloid neoplasms'. In this study, we describe a patient with unsuspected chronic myelomonocytic leukemia who developed cutaneous lesions characterized by a dermal infiltrate rich in PDC. Similarly to LE, such neoplastic PDC were accompanied by interface dermatitis-like changes, but displayed an aberrant phenotype and shared the same chromosomal abnormality with the leukemic cells identified in the bone marrow, thus revealing the neoplastic nature of the process. This observation illustrates that tumor-forming PDC associated with myeloid neoplasms may microscopically mimic LE in some patients. Accordingly, a hematologic workup is recommended in any skin lesion featuring excessive numbers of PDC, even if morphological alterations suggestive of interface dermatitis are found.

Pathophysiology of cutaneous lupus erythematosus.

The pathophysiology of cutaneous lupus erythematosus (CLE) encompasses the complex interactions between genetics, the environment, and cells and their products. Recent data have provided enhanced understanding of these interactions and the mechanism by which they cause disease. A number of candidate genes have been identified which increase the risk of developing CLE. Ultraviolet radiation, the predominant environmental exposure associated with CLE, appears to initiate CLE lesion formation by inducing apoptosis, precipitating autoantigen presentation, and promoting cellular production of specific cytokines. Autoantibodies are a well-known entity in CLE, but their exact role remains unclear. Finally, cells ranging from native skin cells to innate and adaptive immune cells produce cytokines and other molecules and play specific roles in lesion formation and perpetuation. Native skin cells implicated in CLE include keratinocytes and endothelial cells. Innate immune cells crucial to CLE pathophysiology include dendritic cells and neutrophils. The primary adaptive immune cells thought to be involved include Th1 cells, Th17 cells, cytotoxic T cells, and invariant natural killer T cells. Though the pathophysiology of CLE has yet to be fully characterized, current research provides direction for future research and therapies.

Apoptosis in chronic cutaneous lupus erythematosus, discoid lupus, and lupus profundus.

INTRODUCTION: Lupus erythematosus is a multisystemic disease that is characterized by autoantibody production and immune complex deposition in such tissues as the mucosa, joints, the central nervous system, and skin. Cutaneous lupus erythematosus is categorized as acute, subacute, and chronic. Chronic cutaneous lupus erythematosus comprises discoid lupus erythematosus (DLE) and lupus profundus (LP). AIM: To analyze the expression of proapoptotic molecules in patients with lupus erythematosus discoid and lupus profundus. MATERIAL AND METHODS: Descriptive study, the study groups comprised 10 cases of LP and 10 cases of DLE, and a control. Skin samples of cases and controls were processed for immunohistochemistry and by TUNEL technique. The database and statistical analysis was performed (statistical test X(2)) SPSS (Chicago, IL, USA). RESULTS: Apoptotic features were broadly distributed along the skin biopsies in epidermal keratinocytes as well as at dermis. By immunohistochemistry the expression of Fas receptor and Fas-L was higher in the skin of lupus patients compared with controls. We also noted differences in Fas-L, -Fas, and -Bax proteins expression intensity in discoid lupus erythematosus patients in the epidermis, and hair follicles. CONCLUSIONS: Fas and Fas-L are expressed similarly in LP and DLE.

A multicenter photoprovocation study to identify potential biomarkers by global peptide profiling in cutaneous lupus erythematosus.

Cutaneous lupus erythematosus (CLE) is an inflammatory autoimmune skin disease in which abnormal photosensitivity is an important pathogenetic factor but is difficult to predict, creating a challenge in determining treatment efficacy. Although photosensitivity in CLE patients may change over time, photoprovocation testing with ultraviolet (UV) A and UVB irradiation can be a helpful tool to explore differences between responders and nonresponders during photoprovocation. To identify biomarkers that could substitute for the clinical endpoint lesion development, we performed a global peptidomics profiling analysis of CLE subjects in a controlled photoprovocation study. Plasma and skin biopsy samples were collected before and after UV-irradiation from 13 healthy volunteers and 47 CLE subjects. Twenty-two of the 47 CLE subjects developed skin lesions. The samples were analyzed using a label-free quantitative peptidomics workflow combined with univariate and multivariate statistical analyses. The primary finding was identification of a specific plasma peptide signature separating responders versus nonresponders at baseline. The peptide signature consisted of beta 2-microglobulin (B2MG), human beta-defensin-1, and peptides derived from CD99, polymeric immunoglobulin receptor, and immunoglobulin kappa light chains. In skin, elevated B2MG levels correlated with lesion formation. Our results show that the peptidome is a rich source of potential biomarkers for predicting photosensitivity in CLE.

TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus.

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.

Reticular erythematous mucinosis: histopathological and immunohistochemical features of 25 patients compared with 25 cases of lupus erythematosus tumidus.

BACKGROUND AND OBJECTIVES: Reticular erythematous mucinosis (REM) and lupus erythematosus tumidus (LET) share similarities. However, to our knowledge no study extensively compared the histological features of these two conditions. The aim of this study is to compare the histological and immunohistochemical features of REM and LET. METHODS: We evaluated epidermal thickness, hyperkeratosis, dermo-epidermal junction changes, interstitial mucin deposition, vessel dilatation and pattern, type and density of the inflammatory infiltrate in 25 cases of REM and LET. Anti-CD3, anti-CD20, anti-CD68, anti-CD4, anti-CD8, anti-CD123, anti-CD2AP, anti-IgG and anti-C3 antibodies were tested in a subset of patients. RESULTS: Both diseases are characterized by perivascular dermal infiltrates of lymphocytes mainly CD4+ positive and increased dermal mucin. However, REM tended to show more scattered and more superficial lymphocytes with more superficial mucin and to have less frequent immunoglobulin and complement depositions along the dermo-epidermal junction. Plasmacytoid dendritic cells (PDCs) were less represented in REM, and were mainly found as single cells differently from LET. CONCLUSIONS: REM and LET present some differences in the infiltrate, including PDCs, the mucin deposition and the immunoreactant deposition at the dermo-epidermal junction that justify the distinction of the two diseases and suggest different pathogenetic mechanisms.

Ultraviolet light protection by a sunscreen prevents interferon-driven skin inflammation in cutaneous lupus erythematosus.

Irradiation with ultraviolet (UV) light is an important exacerbating factor in cutaneous lupus erythematosus (CLE) and induces various effects in the skin of patients with the disease, such as cell death and inflammation. Recently, we demonstrated the ability of a broad-spectrum sunscreen to prevent UV-induced damage both in patients with CLE and healthy controls (HCs). The aim of this study was to evaluate whether the UV-dependent activation of interferon (IFN)-driven inflammation in CLE can also be prevented by application of the sunscreen. In 20 patients with different subtypes of CLE and 10 HCs, defined areas on the upper back were treated with a broad-spectrum liposomal sunscreen 20 min prior to a combined standardized UVA/UVB irradiation. Immunohistological analyses using antibodies directed against MxA, CD11c, CD123 and CD68 were performed from skin biopsies taken from areas before UV irradiation as well as from sunscreen-treated and sunscreen-untreated areas 24 and 72 h after UV irradiation. The expression of MxA was completely prevented by the sunscreen applied prior to UV irradiation in CLE patients and HCs. Additionally, sunscreen protection significantly diminished the number of the CD11c- and CD123-positive dendritic cells, which are suggested to be a major source of type I/III IFNs, in UV-irradiated skin of patients with CLE. Moreover, the application of the sunscreen prevented the increase in CD68-positive macrophages in both groups 72 h after UV irradiation. The data of this study demonstrate that UV protection reduces lesional tissue damage and inhibits the typical IFN-driven inflammatory response in CLE.

Comparative analysis of rosacea and cutaneous lupus erythematosus: histopathologic features, T-cell subsets, and plasmacytoid dendritic cells.

BACKGROUND: Distinction of rosacea and cutaneous lupus erythematosus (LE) can be challenging because of significant clinical and histologic overlap. A controlled study comparing these conditions is lacking. OBJECTIVE: We compared the histologic features, T-cell subsets, and plasmacytoid dendritic cells in rosacea and LE. METHODS: Biopsy specimens of rosacea (n = 27) and facial LE (n = 30) were retrospectively reviewed and reacted with Alcian blue and periodic acid-Schiff stains, and CD4, CD8, CD25, and CD123 immunostains. RESULTS: LE demonstrates a lower CD4:CD8 ratio (1.74 vs 2.80, P = .0064), fewer CD4(+)CD25(+) regulatory T cells (13% vs 31%, P < .0001), and more CD123(+) plasmacytoid dendritic cells (18% vs 6%, P = .0137) than rosacea. The plasmacytoid dendritic cells in LE are more likely to form clusters (P = .0137) and comprise at least 20% of the infiltrate (P = .0340). Also associated with LE are follicular plugging (P = .0039), perineural lymphocytic infiltrate (P = .0211), abundant mucin deposition (P = .0031), and conspicuous basement membrane thickening (P = .0073), whereas Demodex infestation (P = .0064) and sebaceous hyperplasia (P = .0029) are significantly associated with rosacea. LIMITATIONS: Although statistically significant, the immunophenotypic differences are rather small and limited for routine use. CONCLUSION: The infiltrates in rosacea and LE differ immunophenotypically, and may aid in their distinction in addition to conventional histologic examination.

Apoptotic signal molecules in skin biopsies of cutaneous lupus erythematosus: analysis using tissue microarray.

Cutaneous lupus erythematosus (CLE) is a heterogeneous autoimmune disease. Different pathogenetic mechanisms, including the accumulation of apoptotic keratinocytes in CLE, have been reported. Therefore, we investigated whether CLE and other inflammatory skin diseases differ with regard to the epidermal expression of molecules that are crucial for the initiation and regulation of apoptosis. In this study, 241 skin biopsies from patients with CLE, psoriasis (PSO), lichen planus (LP) and healthy controls (HCs) were analysed immunohistochemically using the tissue microarray (TMA) technique. The TUNEL assay and anti-activated caspase-3 antibodies revealed a significant increase of apoptotic keratinocytes in CLE lesions compared with HCs. Furthermore, we detected a significant increase in the epidermal expression of CD95 in CLE specimens compared with PSO, LP and HCs. These data suggest that the accumulation of apoptotic keratinocytes in CLE might be due to the increased epidermal expression of CD95, resulting in increased activity of the extrinsic apoptotic pathway in the disease.