Search

Background Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that associates with aberrant activation of B lymphocytes and excessive autoantibodies. Interleukin 10 (IL-10)/interleukin 35 (IL-35) and IL-10/IL-35-producing regulatory B cells have been demonstrated to possess immunosuppressive functions during systemic lupus erythematosus. Here, we detected the proportion of CD19+CD24highCD27+ B cells as well as IL-10 and IL-35 levels in peripheral blood of SLE patients and healthy individuals, and investigated their relations with clinical features of SLE. Methods 41 SLE patients and 25 healthy controls were recruited. The patients were divided into groups based on SLEDAI score, anti-dsDNA antibody, rash, nephritis and hematological disorder. Flow cytometry was used to detect the proportion of CD24hiCD27+ B cells. ELISA was used to detect serum levels of IL-10 and IL-35. Results Our results showed that the CD19+CD24highCD27+ B population was decreased in active SLE patients, and anti-correlated with the disease activity. Of note, we found significant increase of IL-10 and decrease of IL-35 in SLE patients with disease activity score > 4, lupus nephritis or hematological disorders compared to those without related clinical features. Conclusions Reduced CD19+CD24highCD27+ B cells expression may be involved in the pathogenesis of SLE. Moreover, we supposed that IL-35 instead of IL-10 played a crucial role in immune regulation during SLE disease.

is missing (Quiz)

We present three Chinese male patients with similar complaints of recurrent episodes of vesicles, blisters, erosion/ulcers predominantly on sun-exposed areas. They were diagnosed as having porphyria cutanea tarda after a clinical investigation. Of note, all patients had a history of alcohol abuse with or without apparent liver function damage.

Bile acids (BAs), produced in the liver and further transformed in the gut, are cholesterol-derived molecules involved in essential physiological processes. Recent studies suggest that BAs regulate T helper 17 cell function, but the underlying mechanism of this action and their therapeutic value in disease models remains unclear. Using an IL-23 minicircle DNA-based murine model of psoriasiform dermatitis, we showed that oral administration of secondary BAs, including lithocholic acid (LCA), deoxycholic acid, and 3-oxoLCA, significantly improved psoriasiform dermatitis without inducing apparent hepatotoxicity. Of the BAs tested, LCA possessed the greatest potency in treating psoriasiform dermatitis. Intravenous administration of LCA at a much lower dosage (compared with oral treatment) showed a comparable antipsoriatic effect and markedly suppressed the IL-17A response. Exvivo experiments revealed that LCA reduced IL-17A production in IL-23-stimulated murine T cells in the absence of BA receptors TGR5 or FXR. Strikingly, BAs inhibited CCL20 expression in keratinocytes, which led to reduced migration of CCR6-expressing Jurkat cells cultured in the conditioned medium of stimulated keratinocytes. Thus, BAs improve psoriasiform dermatitis with minimal toxicity via direct inhibition of IL-17A production and blockade of CCL20-mediated trafficking, supporting the potential use of BAs in psoriasis.

Cytokines like IL-17A have been consistently found to be elevated in psoriatic lesional skin, and therapeutic antibodies to IL-17 have demonstrated efficacy in treating psoriatic skin and joint disease. However, results about the circulating cytokines in psoriasis patients remained controversial. Anticytokine autoantibodies (ACAAs) were detected in various autoimmune diseases but remained largely unknown in psoriasis. We aimed to investigate the serum levels of cytokines and ACAAs in psoriasis patients. The study included 44 biologics-naive psoriasis patients and 40 healthy controls. Serum cytokines and the corresponding autoantibodies were measured by multiplex bead-based technology. The bioactivity of serum IL-17A was determined by IL-8 production in primary keratinocytes. Herein, we found serum levels of IL-12B (median: 6.16 vs. 9.03, p = 0.0194 ) and Th17 cytokines (IL-17A: median: 0.32 vs. 1.05, p = 0.0026 ; IL-22: median: 4.41 vs. 4.41, p = 0.0120 ) were increased in psoriasis patients. More interestingly, bioactive IL-17A was identified in a proportion of patients and positively correlated with disease severity. A few of cytokines were closely associated with each other and formed into a distinct panel in psoriasis. Of 13 anticytokine antibodies, anti-IL-22 was moderately lower (median: 262.8 vs.190.5, p = 0.0418 ), and anti-IL-15 was slightly higher (median: 25.5 vs. 30.5, p = 0.0069 ) in psoriasis than controls. None of ACAAs was related to disease severity. Consequently, the ratios of antibodies to cytokines varied with the pattern of cytokines. In summary, our finding suggested that the levels of circulating bioactive IL-17A were associated with disease activity in psoriasis patients. In contrast, the titers of ACAAs were not significantly altered nor correlated with disease severity. However, the functionality of ACAAs remains to be further demonstrated in vitro in future studies.

Background An ever-increasing number of cancer patients are being treated with checkpoint inhibitors such as anti-PD-1 antibodies, and a small percentage of these patients develop a psoriasis-like skin eruption or severe flares of prior psoriasis. Objective We investigated the role of obesity in immune checkpoint inhibitors-exacerbated psoriasiform eruption. Methods We fed female C57BL/6 mice a so-called Western diet (WD) or a control diet (CD). Imiquimod (IMQ) was applied topically on ears for 5 consecutive days to induce psoriasiform dermatitis (PsD). Psoriasis-related markers were examined by quantitative real-time PCR. Then we induced PsD in WD- and CD-fed mice in the presence or absence of systemic treatment of anti-PD-1 antibodies to examine if obese mice are more susceptible to anti-PD-1 related PsD than lean mice. Results WD-fed mice showed higher baseline mRNA expression levels of psoriasis-associated cytokines such as IL-17, S100A8, and S100A9 compared to mice fed with CD. Furthermore, WD-fed mice had more γδ low (GDL) T cells in the whole skin and higher expression of PD-1 on GDL T cells than CD-fed mice. WD-fed mice receiving anti-PD-1 had more prominent ear swelling than lean mice receiving anti-PD-1 during the 5-day IMQ course (2-fold increase, P Conclusion WD-induced obesity enhances IMQ-induced psoriasiform inflammation. The finding that WD-fed mice have a more dramatic response to anti-PD-1 than lean mice in terms of IMQ-induced ear swelling suggests that obesity could be a risk factor in the development of psoriasiform eruption during anti-PD-1 therapy.

is missing (Quiz)

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that associates with aberrant activation of B lymphocytes and excessive autoantibodies. Interleukin 10 (IL-10)/interleukin 35 (IL-35) and IL-10/IL-35-producing regulatory B cells have been demonstrated to possess immunosuppressive functions during systemic lupus erythematosus. Here, we detected the proportion of CD1941 SLE patients and 25 healthy controls were recruited. The patients were divided into groups based on SLEDAI score, anti-dsDNA antibody, rash, nephritis and hematological disorder. Flow cytometry was used to detect the proportion of CD24Our results showed that the CD19Reduced CD19

Vascular inflammation could occur in all organs and tissues in patients with systematic lupus erythematosus (SLE), of which skin is the most frequent one. Our previous research identified anti-galectin-3 (Gal3) antibodies (Abs) as an important mediator of lupus cutaneous vasculopathy. Herein, we showed that anti-Gal3 Abs dysregulated the function of vascular endothelial cells with higher transcript levels of IL-1β and increased expression of mature IL-1β. The enhanced production of IL-1β secreted by endothelial cells was dependent on NLRP3 inflammasome. Intradermal injection of anti-Gal3 Abs in mice induced local inflammation with perivascular infiltration of T cells and neutrophils, which was inhibited by IL-1β blockade. Induction of anti-Gal3 Abs in circulation by immunization of Gal3 antigen not only led to histopathologic changes in the skin, including focal keratinocytes vacuolization and thickening of blood vessels, but also a systemic autoimmune phenotype that involves autoantibody production and kidney damage. Intriguingly, local overexpression of IL-1β was primarily associated with skin lesions but not with other internal organs in mice. Finally, we showed that the serum levels of IL-1β were comparable between SLE patients and healthy donors. Whilst the expression of IL-1β was enriched in local area with perivascular inflammation in lupus skin lesion compared to healthy normal skin. The results strongly suggest that IL-1β plays an important role in mediating anti-Gal3 Ab-induced skin vascular inflammation and raised the prospect for using IL-1β blocking therapies to treat lupus cutaneous damage.

Artesunate, one of the derivatives of artemisinin (“qinghaosu” in Chinese), is known as an antimalarial drug with high efficiency and low toxicity. Of interest, emerging evidences suggest that artesunate also possesses an immunomodulatory effect during innate and adaptive immune responses in cell types and context-dependent manner. Although it shows promising application in many diseases, such as inflammatory diseases, hypersensitivity, autoimmune diseases, and cancers, little is known about underlying molecular. In this review, we summarize recent advances of how artesunate regulates innate and adaptive immune cells. In addition, its potential application in immune-related diseases is also highlighted.

Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about the role of autophagy-related proteins in the cutaneous immune response. Herein, we showed that ULK1, the key autophagic initiator, and its phosphorylation at Ser556 were distinctively decreased in the epidermis from lesional skin of psoriasis patients. Topical application of SBI0206965, a selective ULK1 inhibitor, significantly attenuated epidermal hyperplasia, infiltration of neutrophils, and transcripts of the psoriasis-related markers in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD). In vitro, ULK1 impairment by siRNA and SBI0206965 arrested cell proliferation and promoted apoptosis of keratinocytes but had a marginal effect on the expression of proinflammatory mediators under steady status. Surprisingly, SBI0206965 blocked the production of chemokines and cytokines in keratinocytes stimulated by neutrophils. Of interest, the pro-apoptotic and anti-inflammatory effects of ULK1 inhibition cannot be fully replicated by autophagic inhibitors. Our findings suggest a self-regulatory process by downregulating ULK1 to maintain the immune homeostasis of psoriatic skin via regulating keratinocytes and their crosstalk with neutrophils, possibly through both autophagy-dependent and independent mechanisms. ULK1 might be a potential target for preventing or treating psoriasis.

is missing (Quiz)

Oncolytic virus can selectively recognize cancer cells, target tumors, and stimulate an oncolytic and immune response. Recombinant armed oncolytic vaccinia virus has emerged as an attractive tool in oncolytic virotherapy because it has tumor-specific cytotoxicity and serves as a vector to express immune genes. A novel thymidine kinase (TK) gene–deleted oncolytic vaccinia virus (named ΔTK-Armed-VACV) armed with anti-human-programed cell death-1 protein (PD-1) antibody and anti-human-tumor necrosis factor receptor superfamily, member 9 (4-1BB) antibody genes was constructed based on Western Reserve in our previous study. The present study evaluated the ability of this virus for cancer-targeted therapy both in vitro and in vivo. A complete morphological structure of ΔTK-Armed-VACV was verified using transmission electron microscopy. The antibody was co-expressed with the replication of ΔTK-Armed-VACV in vitro assessed by Western blot analysis, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-rboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay showed that the ΔTK-Armed-VACV exhibited significant tumor-specific cytotoxicity in vitro. The ΔTK-Armed-VACV inhibited the tumor growth in a 4T1 or A549 tumor-bearing mouse model. ELISpot assay showed that ΔTK-Armed-VACV-treated mice induced the expression of interferon-gamma, and lactate dehydrogenase–dependent cytotoxicity assay revealed that the ΔTK-Armed-VACV treatment activated tumor-specific cytotoxic T lymphocytes. The results indicated that oncolytic VACV with Western Reserve–mediated anti-human-PD-1 and anti-human-4-1BB antibody co-expression exerted a significant antitumor effect, indicating that the combination of oncolytic virotherapy and immunotherapy by the oncolytic VACV expressing one or more immune checkpoint genes might have satisfactory clinical expectations.

Objective To investigate the profiles of anti-RPLP0, anti-galectin3 antibodies, interferon-α (IFN-α), interferon-λ1(IFN-λ1) and interleukin-17A/F(IL-17A/F) in the subtypes of cutaneous lupus erythematosus (CLE) including acute CLE (ACLE), subacute CLE (SCLE) and discoid lupus erythematosus (DLE). Methods Serum levels of autoantibodies and cytokines were determined by enzyme-linked immunoabsorbent assay (ELISA). Lupus lesions were evaluated by cutaneous lupus erythematosus disease area and severity index (CLASI). Results Serum anti-RPLP0, anti-galectin3 antibodies and IFN-λ1 were higher in systemic lupus erythematosus (SLE) patients with skin lesions than those without skin lesions, compared to healthy controls. IFN-α, IL-17A and IL-17F was elevated in all patients regardless of skin lesions. The two antibodies, IFN-α and IL-17A were positively correlated with the CLASI score in all patients with CLE. In addition, serum IL-17A was positively correlated to the CLASI score of ACLE, SCLE and DLE, while anti-RPLP0 and anti-galectin3 antibodies were only correlated to the score of SCLE and IL-17F to DLE. Conclusion Serum anti-RPLP0, anti-galectin3 antibodies, IFN-α, IFN-λ1 and IL-17A/F are associated with the occurrence of lupus skin lesions regardless of the systemic complications, whereas the profiles of these inflammatory mediators vary with the subtypes of lupus skin lesions.

A Western diet (WD)-characterized by its high fat and simple sugar content-is thought to predispose individuals to inflammatory skin diseases such as psoriasis through the development of obesity. This scenario, however, is being challenged by emerging data suggesting that dietary components, rather than obesity itself, may exacerbate psoriasis. We herein show that short-term feeding with a diet analogous to the WD in mice leads to T helper type 1-/T helper type 17-biased skin inflammation before significant body weight gain. Feeding for as little as 4 weeks with a WD promoted mild dermatitis and accumulation of IL-17A-producing γδ T cells in the skin. Strikingly, γδ T cells from WD-fed mice exhibited enriched IL-23 receptor expression and increased the potential to produce IL-17A after IL-23 stimulation. In contrast to wild-type mice, WD-fed TCRδ-deficient and CCR6-deficient mice had reduced skin inflammation and IL-17A expression. Supplementation with a bile acid sequestrant, cholestyramine, prevented WD-induced skin inflammation along with a reduction in the infiltration of γδ T cells and the expression of proinflammatory mediators. In summary, our data revealed dietary influences in inflammatory signaling in the skin. The dysregulation of IL-23 pathways and bile acid pathways may be key to the development of WD-associated psoriasiform dermatitis.

Although psoriasis and psoriatic arthritis (PsA) have been classically considered to be diseases of the skin and joints, respectively, emerging evidence suggests that a combination of innate and environmental factors creates widespread immune dysfunction, affecting multiple organ systems. A greater understanding of the pathogenesis of psoriasis and the systemic effects of psoriatic inflammation has allowed for the development of new, more effective treatments. The second portion of this two-part review series examines the comorbidities associated with psoriasis and PsA as well as the most recent advances in targeted systemic therapies for these conditions.

We previously showed that exposure to a high-sugar and moderate-fat diet (i.e., Western diet [WD]) in mice induces appreciable skin inflammation and enhances the susceptibility to imiquimod-induced psoriasiform dermatitis, suggesting that dietary components may render the skin susceptible to psoriatic inflammation. In this study, utilizing an IL-23 minicircle-based model with features of both psoriasiform dermatitis and psoriatic arthritis, we showed that intake of WD for 10 weeks predisposed mice not only to skin but also to joint inflammation. Both WD-induced skin and joint injuries were associated with an expansion of IL-17A‒producing γδ T cells and increased expression of T helper type 17 cytokines. After IL-23 minicircle delivery, WD-fed mice had reduced microbial diversity and pronounced dysbiosis. Treatment with broad-spectrum antibiotics suppressed IL-23‒mediated skin and joint inflammation in the WD-fed mice. Strikingly, reduced skin and joint inflammation with a partial reversion of the gut microbiota were noted when mice switched from a WD to a standard diet after IL-23 minicircle delivery. These findings reveal that a short-term WD intake‒induced dysbiosis is accompanied by enhanced psoriasis-like skin and joint inflammation. Modifications toward a healthier dietary pattern should be considered in patients with psoriatic skin and/or joint disease.

OBJECTIVE To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target. METHODS First, we quantified CCL20 levels in peripheral blood and synovial fluid from PsA patients and examined the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an interleukin-23 minicircle DNA (IL-23 MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression as well as the preventive and therapeutic effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1β to assess the production of CCL20 by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated using a Transwell system. RESULTS We observed an up-regulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsy specimens. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and, accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD. CONCLUSION Our study highlights the pathogenic role of the CCR6/CCL20 axis in enthesitis and introduces the prospect of a novel therapeutic approach for treating patients with PsO and PsA.

Background Bromodomain and extra-terminal (BET) proteins perform key roles in epigenetic control of gene expression that is involved in inflammatory conditions, including psoriasiform dermatitis (PsD). Predicting which (of many potential available BET inhibitors) will be effective in vivo is challenging. Objective We determine if a novel in vitro assay that includes two critical cell types involved in human psoriasis can predict the therapeutic potential of specific BET inhibitors in vivo. Methods An in vitro model consisting of U-937 and HaCaT cell co-culture was created to screen small molecule BET antagonists for inhibition of cutaneous inflammatory genes. Efficacious BET inhibitors were tested in a mouse imiquimod (IMQ)-induced PsD model. Results In the co-culture system, HaCaT cells exhibited a marked increase in the secretion of a characteristic set of proinflammatory and Th17-associated cytokines. Of the ten commercially-available small molecules targeting BET proteins assayed, most compounds exhibited inhibitory functions at 1 μM against inflammatory activation, but responded variably at lower concentrations. OTX015, a typical representative for most of the compounds, barely inhibited the inflammatory reactions at 0.1 μM. By contrast, ABBV075 was effective in concentrations as low as 0.01 μM. While oral administration OTX015 in IMQ-treated mice reduced disease severity, ABBV075 equally decreased the symptoms and molecular and cellular severity markers at one-tenth of the minimal dosing required for OTX015. Conclusion In vitro screening system combined with an in vivo animal model, can serve as a convenient pre-clinical screening tool for the selection of BET inhibitors (and possibly other drugs) that may have clinical potential in psoriasis therapy.

Background Anti-ribosomal P (anti-Rib-P) antibody is a specific serological marker for systemic lupus erythematosus (SLE) and routinely tested by targeting the common epitope of three ribosomal proteins of P0, P1 and P2. This study aimed to investigate if testing antibodies against individual ribosomal protein, but not the common epitope, is required to achieve the best diagnostic benefit in SLE. Methods The study included 82 patients with SLE and 22 healthy donors. Serum antibodies were determined by ELISA and immunoblot. Results The prevalence of each antibody determined by ELISA was 35.4% (anti-Rib-P), 45.1% (anti-Rib-P0), 32.9% (anti-Rib-P1) and 40.2% (anti-Rib-P2) at 99% specificity, respectively. Of 53 patients with negative anti-Rib-P antibody, 21 (39.6%) were positive for anti-Rib-P0, 9 (17.0%) for anti-Rib-P1 and 12 (22.6%) for anti-Rib-P2 antibody. The positive rate of anti-Rib-P antibody detected by ELISA was close to the results by immunoblot (33.4%). Patients with any of these antibodies were featured by higher disease activity and prevalence of skin rashes than those with negative antibodies. Moreover, each antibody was particularly related to some clinical and laboratory disorders. The distribution of subclasses of IgG1–4 was varied with each antibody. Anti-Rib-P0 IgG1 and IgG3 were strongly correlated with disease activity and lower serum complement components 3 and 4. Conclusions Anti-Rib-P antibody is not adequate to predict the existence of antibodies against ribosomal P0, P1 and P2 protein. The examination of antibodies against each ribosomal protein is required to achieve additional diagnostic benefit and to evaluate the association with clinical and serological disorders as well.

Psoriasis-specific proteins dysregulated in keratinocytes and involved in the pathophysiological process of psoriasis remains elusive. We report here that epidermal galectin-3 expression is significantly downregulated in lesional skin, but not in non-lesional skin in psoriasis patients, nor in a group of diseases known as psoriasiform dermatitis clinically and histologically similar to psoriasis. The deficiency of epidermal galectin-3 is sufficient to promote development of psoriatic lesions, as evidenced by more severe skin inflammation in galectin-3 knockout (gal3-/-) mice, compared to wild-type mice, after imiquimod treatment, and in skin from gal3-/- mice grafted onto wildtype mice. The development of psoriatic-like lesions is attributable to 1) the spontaneously tuning up of psoriasis signatures in keratinocytes through JNK pathway; and 2) neutrophil accumulation caused by the enhanced leukocyte-recruiting capacity associated with overexpression of S100A7-9 and CXCL-1, 8 in keratinocytes with impaired galectin-3 expression. Psoriasis-like skin inflammation is significantly improved in gal-3-/- mice both by inhibition of neutrophils accumulation with a selective CXCR2 antagonist of SB225002, and by intracutaneous injection of recombinant galectin-3. Overall, these findings offer promising galectin-3-related diagnostic and therapeutic resolutions of psoriasis.

CCR6 is important for the trafficking of IL-17A–producing γδ T cells and required for the development of psoriasiform dermatitis in an IL-23 intradermal injection model. The role of CCR6, however, in IL-23–mediated joint inflammation is unclear. We herein hydrodynamically delivered IL-23 minicircle DNA into wild-type and CCR6-deficient (CCR6-knockout) mice to induce overexpression of IL-23 systemically. After IL-23 gene transfer, wild-type mice exhibited concurrent skin and joint changes that recapitulate some features found in human psoriatic skin and joints. CCR6-knockout mice were resistant to IL-23–induced skin inflammation but exhibited no changes in joint inflammation compared with wild-type mice. Depletion of neutrophils protected wild-type mice from skin and joint disease without suppressing T helper type 17 cytokine expression. In contrast, mice lacking γδ T cells showed a partial reduction in neutrophilic recruitment and a significant decrease in IL-17A expression in skin and paw tissue. Thus, in an IL-23–mediated model that allows concurrent assessment of both skin and joint disease, we showed that CCR6 is critical for inflammation in the skin but not in the joint. Furthermore, our data suggest that neutrophils and γδ T cells are key effector cells in IL-23–mediated skin and joint inflammation in mice.

Transient receptor potential ankyrin 1 (TRPA1), a membrane protein ion channel, is known to mediate itch and pain in skin. The function of TRPA1, however, in psoriasiform dermatitis (PsD) is uncertain. Herein, we found that expression of TRPA1 is highly up‐regulated in human psoriatic lesional skin. To study the role of TRPA1 in PsD, we assessed Psoriasis Severity Index (PSI) scores, transepidermal water loss (TEWL), skin thickness and pathology, and examined dermal inflammatory infiltrates, Th17‐related genes and itch‐related genes in c57BL/6 as wild‐type (WT) and TRPA1 gene knockout (KO) mice following daily application of topical IMQ cream for 5 days. Compared with WT mice, clinical scores, skin thickness change and TEWL scores were similar on day 3, but were significantly decreased on day 5 in IMQ‐treated TRPA1 KO mice (vs WT mice), suggesting reduced inflammation and skin barrier defects. Additionally, the relative area of epidermal Munro's microabscesses and mRNA levels of neutrophil inducible chemokines (S100A8, S100A9 and CXCL1) were decreased in the treated skin of TRPA1 KO mice, suggesting that neutrophil recruitment was impaired in the KO mice. Furthermore, mast cells, CD31+ blood vascular cells, CD45+ leukocytes and CD3+ T cells were all reduced in the treated skin of TRPA1 KO mice. Lastly, mRNA expression levels of IL‐1β, IL‐6, IL‐23, IL‐17A, IL‐17F and IL‐22 were decreased in TRPA1 KO mice. In summary, these results suggest a key role for TRPA1 in psoriasiform inflammation and raising its potential as a target for therapeutic intervention.

Tumor-associated macrophages (TAMs) recruited from blood monocytes are key in establishing an immunosuppressive tumor microenvironment (TME) for the support of tumor growth. We hypothesize that blocking monocyte trafficking (through the inhibition of specific chemokine receptors) into skin can positively affect tumor development. Herein, the authors examined the effects of oral administration of a small molecule inhibitor for CCR2, CCR2i, which blocks CCR2-mediated chemotaxis of monocytes in a syngeneic mouse T-cell lymphoma in skin. Following CCR2i administration, the depletion of macrophages was achieved as early as 2 days after tumor initiation in ear TME. Quantitative real-time PCR detected an increase in the levels of immune stimulatory inflammatory cytokines, for example, IFN-γ and IL-12, in CCR2i- versus vehicle-treated mice. Within 2 weeks, the tumors from the control groups attained the maximum size, whereas CCR2i-treated mice exhibited much smaller tumor sizes and weights. Immunohistochemistry revealed that CCR2i-treated tumors possessed considerably more CD8+ T cells, which demonstrated their essential role in CCR2i-induced tumor inhibition. Finally, the combination of anti-programmed cell death protein 1 with CCR2i considerably increased the efficacy of tumor eradication related to the activation of IFN-γ–producing CD8 T cells. Our findings provide strong evidence that the CCR2i, particularly in combination with an immune checkpoint inhibitor, reduces tumor growth and is a potential future treatment option for cutaneous T-cell lymphomas.

Background Transient Receptor Potential Vanilloid 1 (TRPV1) is known to mediate itch and neurogenic inflammation, but the role of TRPV1 in psoriasiform dermal inflammation is poorly understood. Objective To investigate the function of TRPV1 in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) in mice. Methods Following daily treatment of topical IMQ cream for consecutive 5 days in C57BL/6 wide-type (WT) and TRPV1 gene knockout (KO) mice, we assessed the psoriasis severity index (PSI) scores, transepidermal water loss (TEWL), dermal inflammatory infiltrates, as well as gene expression levels for psoriasis related genes in mouse skin lesions. Results Compared with WT mice, the clinical and TEWL scores, the extent of skin hyperplasia, the area of Munro microabscesses (MM) and angiogenesis of psoriasis were all significantly decreased in TRPV1 KO mice triggered with IMQ, suggesting a reduction in skin inflammation and barrier defects. In addition, the infiltration of CD45+ leukocytes, mast cells as well as CD3+ T cells was all reduced in the IMQ-treated skin of TRPV1 KO mice. Quantitative Real-time PCR (RT-qPCR) revealed that expression levels of IL-1β, IL-6, IL-23, S100A8 were decreased while IL-10 was increased in TRPV1 KO mice. Conclusions In summary, key markers of psoriatic inflammation and epidermal hyperplasia are reduced in TRPV1 KO mice, indicating the involvement of TRPV1 in the psoriasiform inflammation and suggesting its potential as a therapeutic target.

Objective The objective of this paper is to investigate the association of clinical manifestations and laboratory parameters between familial systemic lupus erythematosus (SLE) and sporadic SLE. Methods All relevant literature was retrieved from the PubMed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) databases. The qualities of these studies were evaluated using a modified version of the Newcastle-Ottawa scale. The characteristics and clinical manifestations of involved individuals were extracted from each study. Pooled odds ratio (OR) was calculated using the random effects-method, and the heterogeneity between studies was quantified using the I2 statistic. Results Of 330 studies identified by the search strategy, six were included in this review. In total, 733 cases were familial SLE and 1405 were sporadic SLE. Analysis revealed that photosensitivity, nephritis and thrombocytopenia were negatively associated with familial SLE, with OR (95% CI) values of 0.73 (0.60-0.89), 0.72 (0.59-0.88) and 0.75 (0.57-0.98), respectively. Conclusions Photosensitivity, thrombocytopenia and renal involvement could be more common in non-familial SLE, which should be further confirmed by well-designed studies with large populations.

Cutaneous lupus erythematosus (CLE) can be an individual disease only involving skin, or presents as part of the manifestations of SLE. A small proportion of CLE may progress into SLE, however, the underlying pathogenic mediators remain elusive. By only including researches that clearly described if the subtypes of CLE presented by enrolled subjects was associated with or without SLE, we provided an overview of antibodies, inflammatory cells and inflammatory molecular mediators identified in blood and skin that were possibly involved in lupus skin damages. IgG autoantibodies are crucial for the development of CLE associated with SLE, but the circulating inflammatory cells and molecular mediators require further studies to provide definitive proof for their association with skin damages. Discoid lupus erythematosus (DLE) is the most common subtype of CLE. For DLE without associated with SLE (CDLE), it is lack of evidences if autoantibodies and circulating inflammatory cells are involved in the pathogenesis or not, but is clear that the cutaneous inflammatory infiltrates are dominated by Th1, but not Th17 cells in contrast to the various complex profile in SLE. As the major target cells in skin, keratinocytes may participate the pathophysiological process by increase cell apoptosis and the production of proinflammatory cytokines in SLE and CDLE. Insights into the similarities and differences of the pathogenesis of CLE and CLE associated with SLE will also improve our therapeutic strategies for CLE that is currently adopted from SLE, and prevent the progression of CLE to SLE by providing interventions within an appropriate window of disease development.

Objective The specific autoantibodies and antigens that mediate systemic lupus erythematosus (SLE)–related organ injuries remain largely unknown. This study was undertaken to investigate the antibody-mediated immune response that leads to SLE skin lesions. Methods The study included 85 SLE patients with lupus-specific skin lesions and 31 without skin lesions. The reactivity of serum antibody with skin antigens was determined by immunoblotting using human foreskin as the substrate. Skin antigens were identified using mass spectrometry. Serum antibody was isolated by affinity purification and was injected intracutaneously into mouse skin to determine pathogenicity. Serum antibody levels were monitored by enzyme-linked immunosorbent assay. Results We determined that 78% of the patients with skin lesions had serum antibodies reactive with 35-kd and/or 25-kd skin antigens, which was significantly higher than the percentage of patients without skin lesions (P < 0.0001), suggesting a correlation between immune response and skin lesions. Acidic ribosomal protein P0 (RPLP0) and galectin 3 were 2 target antigens identified from 35-kd and 25-kd proteins, respectively. Purified serum anti-RPLP0 and anti–galectin 3 antibodies induced lupus-like histologic changes after intracutaneous injection. Anti-RPLP0 and anti–galectin 3 antibody levels were significantly higher in SLE patients than in healthy controls and decreased with skin recovery. Anti–galectin 3 antibody levels were not significantly higher in SLE patients than in patients with dermatomyositis or scleroderma, but strongly related to lupus cutaneous vasculitis. Additionally, levels of the 2 antibodies were positively correlated with leukopenia and C3 deficiency, and the anti-RPLP0 antibody level was also positively correlated with arthritis and SLE disease activity. Conclusion Our findings indicate that the immune response mediated by serum anti-RPLP0 and anti–galectin 3 antibodies plays a key role in the pathogenesis of SLE skin lesions. These findings provide new insights into the mechanism of SLE-related organ disorders.

To investigate whether serum anti-high mobility group box 1 (anti-HMGB1) antibodies are related to the development of skin lesions in systemic lupus erythematosus (SLE).This study involved 21 SLE patients with skin lesions, 18 without skin lesions, and 22 healthy controls. The presence and serum levels of anti-HMGB1-IgG and -IgM were measured by western blot and enzyme-linked immunosorbent assay (ELISA), respectively. HMGB1 expression and serum antibodies deposited in the skin were visualized by immunofluorescence staining.Using western blot analysis, we detected anti-HMGB1-IgG antibodies in 13 out of 21 SLE patients with skin lesions and 11 out of 18 SLE patients without skin lesions (p0.05). Serum levels of anti-HMGB1-IgG measured by ELISA were also comparable between the two groups of SLE patients (p0.05) but were higher in patients than in healthy controls (p0.05). Similar results were found with serum anti-HMGB1-IgM antibodies. HMGB1 accumulated under the stratum corneum in lupus cutaneous lesions without forming immune complexes with IgG or IgM, which were mainly observed along the epidermal-dermal junction. Furthermore, serum anti-HMGB1-IgM was higher in the group of patients with arthritis than in those without arthritis.Based on the findings of the current study, it is unlikely that anti-HMGB1 antibodies play a role in the development of SLE cutaneous lesions.

Objective Anti-ribosomal P (anti-P) antibody is a serological specific marker of systemic lupus erythematosus (SLE). The aim of this study is to investigate the association of this antibody with clinical and serological disorders in SLE. Methods All relevant literature was retrieved from PubMed, EMBASE, Web of Science and CNKI databases. The qualities of these studies were evaluated using a modified version of the Newcastle–Ottawa scale. The associations of anti-P antibody with clinical and serological disorders were determined by the pooled odds ratio (OR) and the confidence interval (CI) calculated using meta-analysis with the Mantel–Haenszel method. Results Sixteen cohort studies with 2355 patients were included in this study. Malar rash, oral ulcer and photosensitivity were strongly associated with serum anti-P antibody, with OR (95% CI) values of 2.05 (1.42–2.92), 1.49 (1.05–2.13) and 1.44 (1.08–1.91), respectively. Arthritis and renal involvement were not associated with anti-P antibody, whereas a high heterogeneity was observed due to ethnicity and publication bias, respectively. Neuropsychiatric SLE (NPSLE), hepatic involvement, anti-dsDNA, anti-Sm and anti-cardiolipin antibodies (aCL) were observed more frequently in anti-P positive patients than in negative patients. Studies on hepatic involvement showed a low precision with substantially broad CI (2.56–11.2). A high heterogeneity presented among studies on NPSLE, anti-Sm and aCL. Conclusions Anti-P antibody is significantly associated with malar rash, oral ulcer, photosensitivity and serum anti-dsDNA antibody, and potentially associated with NPSLE, hepatic damage, serum anti-Sm and aCL.

Artesunate (ART), a derivative of artemisinin, is a medication to treat malaria. Beyond that, the anti-inflammatory and immunoregulatory activities of ART have been identified in autoimmune diseases. However, whether ART functions in psoriasis-like dermatitis induced by imiquimod (IMQ, a TLR7/8 agonist) is currently unkown. There, we found that the cumulative score, epidermal thickening and expression of Ki-67 of ART-treated BALB/c mice were significantly lower than those in the IMQ psoriatic model group. In addition, ART treatment ameliorated mice from systemic inflammation. Mechanistically, ART reduced γδ T cells in draining lymph nodes, which might be benefit the improvement of dermatitis. These findings suggested that ART could be a promising drug of psoriasis in clinic.

Galectin-3 has been suggested relative to tumor genesis, progression, and metastasis in basal cell carcinoma and squamous cell carcinoma that are the most common skin cancers characterized by malignant epidermal proliferation. In this study, we evaluated galectin-3 expression in seborrheic keratosis, keratoacanthoma, and infectious diseases including verruca vulgaris, condyloma acuminatum, and chromoblastomycosis that are pathologically featured by benign epidermal proliferation. Galectin-3 expression was shown by immunohistochemical staining and quantified using the Image Pro Plus V6.0. We found that galectin-3 distributed evenly in normal skin around the body decreased significantly in all selected diseases compared with healthy controls, but it was comparable among each disease. These findings imply that galectin-3 do not differentiate between benign and malignant proliferation of keratinocytes.

Anti-annexin1 antibodies are associated with the subtypes of cutaneous lupus and are elevated in systemic lupus erythematosus (SLE) patients. In this study, we investigated the correlation of this antibody with the incidence of SLE skin lesions. The presence of anti-annexin1-IgG and-IgM determined by Western blot was no different among healthy controls and SLE patients with and without skin lesions. Serum levels of anti-annexin1-IgG and -IgM measured by enzyme-linked immunosorbent assay were comparable between patients with and without skin lesions, whereas anti-annexin1-IgM was lower in SLE patients than in healthy controls. Annexin1 was abundantly detected in each epidermal layer in lupus lesional skin. Additionally, anti-annexin1-IgG was higher in SLE patients with arthritis and negatively correlated with white blood cells (WBC). Anti-annexin1-IgM was higher in patients with antinuclear antibody (ANA)-positive sera, and was positively related to hemoglobin and total serum IgM. Collectively, anti-annexin1 antibodies are not related to the incidence of skin lesions in SLE, and annexin1 abundantly distributes in epidermis in lesional skin.