The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease of humans and is characterized by eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. The noncollagenous 16A domain (NC16A) of BP180 has been found to contain major epitopes recognized by autoantibodies in BP. We recently established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice that express the human high-affinity IgE receptor, FcεRI, and human NC16A domain (FcεRI/NC16A). In this model, anti-NC16A IgEs recruit eosinophils to mediate tissue injury and clinical disease in FcεRI/NC16A mice. The objective of this study was to characterize the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury in anti-NC16A IgE-induced BP. We show that anti-NC16A IgEs significantly increase levels of key eosinophil chemoattractants, eotaxin-1 and eotaxin-2, as well as the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) in the lesional skin of FcεRI/NC16A mice. Importantly, neutralization of eotaxin-1, but not eotaxin-2, and blockade of the main eotaxin receptor, CCR3, drastically reduce anti-NC16A IgE-induced disease activity. We further show that anti-NC16A IgE/NC16A immune complexes induce the release of MMP-9 from eosinophils, and that MMP-9-deficient mice are resistant to anti-NC16A IgE-induced BP. Lastly, we find significantly increased levels of eotaxin-1, eotaxin-2, and MMP-9 in blister fluids of BP patients. Taken together, this study establishes the eotaxin-1/CCR3 axis and MMP-9 as key players in anti-NC16A IgE-induced BP and candidate therapeutic targets for future drug development and testing.

Exosomes from hypoxic pretreated ADSCs attenuate ultraviolet light-induced skin injury via GLRX5 delivery and ferroptosis inhibition.

Accumulation studies have found that adipose-derived stem cell (ADSC) exosomes have anti-oxidant and anti-inflammatory characteristics. The current study verified their therapeutic potential to elucidate mechanisms of ADSC exosome actions in ultraviolet B (UVB) light-induced skin injury. Exosomes were isolated from ADSCs and hypoxic pretreated ADSCs. Next-generation sequencing (NGS) was applied to characterize differential mRNA expression. A UV-induced mice skin injury model was generated to investigate therapeutic effects regarding the exosomes via immunofluorescence and ELISA analysis. Regulatory mechanisms were illustrated using luciferase report analysis and in vitro experiments. The results demonstrated that exosomes from hypoxic pretreated ADSCs (HExos) inhibited UVB light-induced vascular injury by reversing reactive oxygen species, inflammatory factor expression and excessive collagen degradation. NGS showed that HExos inhibits UV-induced skin damage via GLRX5 delivery, while GLRX5 downregulation inhibited the therapeutic effect of HExos on UV-induced skin damage. GLRX5 upregulation increased the protective Exo effect on UV-induced skin and EPC damage by inhibiting ferroptosis, inflammatory cytokine expression and excessive collagen degradation. Therefore, the data indicate that HExos attenuate UV light-induced skin injury via GLRX5 delivery and ferroptosis inhibition.

Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer.

Diabetes is a complex metabolic syndrome that is characterized by prolonged high blood glucose levels and frequently associated with life-threatening complications1,2. Epidemiological studies have suggested that diabetes is also linked to an increased risk of cancer3-5. High glucose levels may be a prevailing factor that contributes to the link between diabetes and cancer, but little is known about the molecular basis of this link and how the high glucose state may drive genetic and/or epigenetic alterations that result in a cancer phenotype. Here we show that hyperglycaemic conditions have an adverse effect on the DNA 5-hydroxymethylome. We identify the tumour suppressor TET2 as a substrate of the AMP-activated kinase (AMPK), which phosphorylates TET2 at serine 99, thereby stabilizing the tumour suppressor. Increased glucose levels impede AMPK-mediated phosphorylation at serine 99, which results in the destabilization of TET2 followed by dysregulation of both 5-hydroxymethylcytosine (5hmC) and the tumour suppressive function of TET2 in vitro and in vivo. Treatment with the anti-diabetic drug metformin protects AMPK-mediated phosphorylation of serine 99, thereby increasing TET2 stability and 5hmC levels. These findings define a novel 'phospho-switch' that regulates TET2 stability and a regulatory pathway that links glucose and AMPK to TET2 and 5hmC, which connects diabetes to cancer. Our data also unravel an epigenetic pathway by which metformin mediates tumour suppression. Thus, this study presents a new model for how a pernicious environment can directly reprogram the epigenome towards an oncogenic state, offering a potential strategy for cancer prevention and treatment.

Efficacy and safety of topical minocycline foam (FMX101 4%) in treatment of Chinese subjects with moderate-to-severe facial acne vulgaris: A phase 3, multi-centre, randomized, double-blind, vehicle-controlled study.

BACKGROUND: FMX101 4%, as a topical foam formulation of minocycline, has been approved by US Food and Drug Administration for the treatment of moderate-to-severe acne vulgaris (AV). OBJECTIVE: To evaluate the efficacy and safety of FMX101 4% in treating Chinese subjects with moderate-to-severe facial AV. METHODS: This was a multi-centre, randomized, double-blind, vehicle-controlled phase 3 study in Chinese subjects with moderate-to-severe AV. Eligible subjects were randomized 2:1 to receive either FMX101 4% or vehicle foam treatment for 12 weeks. The primary efficacy endpoint was the change in inflammation lesion count (ILC) from baseline at week 12. The key secondary endpoint was the treatment success rate according to Investigator's Global Assessment (IGA) at week 12. RESULTS: In total, 372 subjects were randomized into two groups (FMX101 4% group, n = 248; vehicle group, n = 124). After 12 weeks treatment, the reduction in ILC from baseline was statistically significant in favour of FMX101 4%, compared with vehicle foam (-21.0 [0.08] vs. -12.3 [1.14]; LSM [SE] difference, -8.7 [1.34]; 95% CI [-11.3, -6.0]; p < 0.001). FMX101 4% treatment yielded significantly higher IGA treatment success rate at week 12 as compared to the control treatment (8.06% vs. 0%). Applying FMX101 4% also resulted in significant reduction in noninflammatory lesion count (nILC) versus vehicle foam at week 12 (-19.4 [1.03] vs. -14.9 [1.47]; LSM [SE] difference, -4.5 [1.74]; 95% CI [-8.0, -1.1]; p = 0.009). Most treatment-emergent adverse events (TEAEs) were mild-to-moderate in severity, and no treatment-related treatment-emergent serious adverse event (TESAE) occurred. Thus, FMX101 4% was considered to be a safe and well-tolerated product during the 12-week treatment period. CONCLUSION: FMX101 4% treatment for 12 weeks could lead to significantly reduced ILC and nILC, and improved IGA treatment success rate in Chinese subjects with moderate-to-severe facial AV. It also showed a well acceptable safe and tolerability profile.

A transcriptome-wide association study identifies novel susceptibility genes for psoriasis.

Although >80 psoriasis genetic risk loci have been reported through genome-wide association studies (GWASs), the genetic mechanism of psoriasis remains unclear. To identify novel candidate genes associated with psoriasis and reveal the potential effects of genetic factors in the development of psoriasis, we conducted a transcriptome-wide association study (TWAS) based on summary statistics from GWAS of psoriasis (5175 cases and 447 089 controls) and gene expression levels from six tissues datasets (blood and skin). We identified 11 conditionally independent genes for psoriasis after Bonferroni corrections, such as the most significant genes UBLCP1 (PYFS = 2.98 × 10-16) and LCE3C (PSNSE = 9.72 × 10-12, PSSE = 6.24 × 10-12). The omnibus test identified additional five genes associated with psoriasis via the joint association model from multiple reference tissues. Among the 16 identified genes, 5 genes (CTSW, E1F1AD, KLRC3, FIBP and EFEMP2) were regarded as novel genes for psoriasis. We evaluated the 16 candidate genes by querying public databases and identified 11 differentially expressed genes and 8 genes proved by the knockout mice models. Through GO enrichment analyses, we found that TWAS genes were enriched in the known GO terms associated with skin development, such as cornified envelope (P = 4.80 × 10-8) and peptide cross-linking (P = 1.50 × 10-7). Taken together, our results detected multiple novel candidate genes for psoriasis, providing clues for understanding the genetic mechanism of psoriasis.

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

Hydroquinone-induced skin irritant reaction could be achieved by activating mast cells via mas-related G protein-coupled receptor X2.

Hydroquinone (HQ) is one of the most effective drugs to treat hyperpigmentary disorders, but often causes skin irritation in clinic. Mast cell plays an important role in contact dermatitis and triggering pseudo-allergic reactions via MRGPRX2. Whether HQ-induced skin irritant reaction through activating mast cells via MRGPRX2 remains unknown. To investigate the role of mast cells in HQ-induced skin irritant reaction and verify whether MRGPRX2 participated in the HQ effect on mast cells which contributed to the pathogenesis of skin irritant reaction, a mouse model of HQ-induced skin irritation was established to observe the local and systemic inflammation associated with mast cell receptor MrgprB2. Human mast cell LAD2 was used to verify the effect of HQ on mast cells via MRGPRX2 by knocking down with siRNA. As a result, mast cells were involved in the development of HQ-induced irritant reaction, and local inflammation is closely related to mast cell receptor MrgprB2. HQ could activate mast cells via MRGPRX2, causing changes in calcium concentration, degranulation and release of inflammatory cytokines which lead to skin irritant reaction. In conclusion, HQ-induced skin irritant reaction could be skin pseudo-allergic reactions achieved by activating mast cells via MRGPRX2.

Diversity in the clinical presentation of generalized pustular psoriasis (GPP): A series of case vignettes from around the world.

A key principle of clinical studies and case reports is that they should reflect the demographics and epidemiology of the patient population concerned. Here, we have compiled a diverse group of clinical cases of generalized pustular psoriasis (GPP) to showcase the differences in GPP presentation in patients worldwide. We attempt to capture the broad spectrum of clinical presentations of GPP and showcase the diversity of the patient population. The patients included in this series are diverse in age, genetic background, skin phototype and medical history. Moreover, they present with a variety of clinical courses of GPP and different degrees of systemic involvement, and experience flares triggered by different inciting factors. The key learnings from this case series may support physicians in identifying and managing patients with this rare and multifaceted disease that can affect patients both physically and psychologically.

Neuroblast Differentiation-Associated Protein Derived Polypeptides: AHNAK(5758-5775) Induces Inflammation by Activating Mast Cells via ST2.

Psoriasis is a chronic inflammatory skin disease. Mast cells are significantly increased and activated in psoriatic lesions and are involved in psoriatic inflammation. Some endogenous substances can interact with the surface receptors of mast cells and initiate the release of downstream cytokines that participate in inflammatory reactions. Neuroblast differentiation-associated protein (AHNAK) is mainly expressed in the skin, esophagus, kidney, and other organs and participates in various biological processes in the human body. AHNAK and its derived peptides have been reported to be involved in the activation of mast cells and other immune processes. This study aimed to investigate whether AHNAK (5758-5775), a neuroblast differentiation-associated protein-derived polypeptide, could be considered a new endogenous substance in psoriasis patients, which activates mast cells and induces the skin inflammatory response contributing to psoriasis. Wild-type mice were treated with AHNAK(5758-5775) to observe the infiltration of inflammatory cells in the skin and cytokine release in vivo. The release of inflammatory mediators by mouse primary mast cells and the laboratory of allergic disease 2 (LAD2) human mast cells was measured in vitro. Molecular docking analysis, molecular dynamics simulation, and siRNA transfection were used to identify the receptor of AHNAK(5758-5775). AHNAK(5758-5775) could cause skin inflammation and cytokine release in wild-type mice and activated mast cells in vitro. Moreover, suppression of tumorigenicity 2 (ST2) might be a key receptor mediating AHNAK(5758-5775)'s effect on mast cells and cytokine release. We propose a novel polypeptide, AHNAK(5758-5775), which induces an inflammatory reaction and participates in the occurrence and development of psoriasis by activating mast cells.

Suprabasin-derived polypeptides: SBSN(50-63) induces inflammatory response via TLR4-mediated mast cell activation.

Psoriasis is a chronic, relapsing, immune-mediated, and papulosquamous skin disorder. Excessive mast cell activation, in psoriatic lesions, contributes to inflammation. Various endogenous peptides can participate in the pathogenesis of inflammatory diseases by activating mast cells. Suprabasin (SBSN) is expressed in multiple epithelial tissues and it regulates the normal epidermal barrier function. We have recently shown that suprabasin-derived polypeptides, SBSN(50-63), are significantly increased in psoriatic lesions, through differential peptide analysis. This study was conducted to clarify whether SBSN(50-63) plays a pivotal role in activating mast cells and mediating proinflammatory cytokines and chemokines production in psoriasis. The increased expression of SBSN in psoriatic lesions was confirmed by bioinformatics analysis, PCR and ELISA. Wild-type mice injected subcutaneously with SBSN(50-63) exhibited infiltration of inflammatory cells and the release of cytokines in vivo. SBSN(50-63) stimulated mouse primary mast cells (MPMC) and the laboratory of allergic disease 2 (LAD2) human mast cells to produce more inflammatory mediators than the control group, which were measured ex vivo and in vitro. Toll-like receptor 4 was identified as the receptor of SBSN on mast cells by molecular docking analysis, molecular dynamics simulation, and siRNA transfection. Collectively, SBSN(50-63) could activate mast cells through TLR4, which may increase the inflammatory response in psoriasis.

Effectiveness and safety of Adalimumab in psoriasis and its influence on gut microbiome.

Psoriasis is an inflammatory immune-mediated skin disease that significantly impacts physical and psychological well-being. Adalimumab (ADA), a tumor necrosis factor (TNF)-α antagonist, is used to treat psoriasis. This study was performed to assess the efficacy and safety of ADA, identify the fecal microbial composition of psoriasis patients, and explore the effect of ADA on the gut bacteria in psoriasis. Clinical characteristics of the 13 psoriasis patients before (BT) and after ADA treatment (AT) were collected. And total 39 fecal samples from 13 psoriasis patients (BT and AT) and 13 healthy controls were sequenced by 16S rRNA and analyzed by informatics methods. After three months' ADA treatment, physician global assessment (PGA), psoriasis area and severity index (PASI), dermatology life quality index (DLQI), state-trait anxiety inventory (STAI), and itch numeric rating scale (NRS) scores all decreased, and there were no severe adverse effects. Besides, the microbiota of the psoriasis group differed from that of the healthy group, but no microbial diversity and composition alteration were observed between psoriasis patients BT and AT. We suggested that the gut microbiome may change more slowly than skin lesions. Long-term follow-up of patients treated with ADA and further study of psoriasis based on microbiota may provide more evidence for the treatment of psoriasis.

Lipopolysaccharide reduces melanin synthesis in vitiligo melanocytes by regulating autophagy.

Vitiligo is an autoimmune-related disease with a complex aetiology that involves innate immunity. Toll-like receptors (TLRs) are important parts of innate immunity and are related to a variety of autoimmune diseases, including vitiligo, through an unknown mechanism. In this study, we found that the TLR4 gene expression was increased in blood samples of patients with advanced stage vitiligo, and then, we evaluated the effect of TLR4 ligand lipopolysaccharide (LPS) on melanin synthesis in a vitiligo melanocyte cell line PIG3V and along with its mechanism. LPS suppressed melanin synthesis, downregulated the expression of melanin synthesis-related proteins and activated autophagy in vitiligo melanocytes. Inhibiting autophagy with 3-methyladenine or chloroquine blocked these effects. This suggests that LPS inhibits skin pigmentation by modulating autophagy, thus providing novel insights into the pathogenesis of vitiligo.

Dehydroandrographolide targets CD300f and negatively regulated MRGPRX2-induced pseudo-allergic reaction.

Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates mast cells (MCs) activation, which is a key target for the treatment of allergic diseases. However, there are few drugs targeting MRGPRX2. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) is a negative regulator of FcεRΙ-mediated MC activation. However, the regulatory effect of CD300f on MRGPRX2 remains unclear. Dehydroandrographolide (DA) is a main contributor of Andrographis paniculata (Burm.f.) Nees (family: Acanthaceae) have been shown to inhibit type I hypersensitivity. The aim of this study was to determine whether DA negatively regulated MRGPRX2-mediated MC activation via CD300f and showed therapeutic effect on pseudo-allergic reactions. Mouse allergic models and MC degranulation were detected in vivo and in vitro, and inflammatory mediators were detected. siRNA interference and Biacore were used to verify the target. DA inhibited pseudo-allergic reactions by reducing vasodilation and serum cytokine levels in mice and inhibited MRGPRX2-mediated MC activation. The regulatory effect of DA was significantly decreased after the knockdown of CD300f expression. Moreover, DA upregulated the phosphorylation level of Src homology region 2 domain-containing phosphatase (SHP)-1 and SHP-2, which are key kinases in the negative regulatory signaling pathways associated with CD300f. In conclusion, DA negatively regulates MRGPRX2-mediated MC activation via CD300f to inhibit pseudo-allergic reactions.

Luteolin inhibits FcεRΙ- and MRGPRX2-mediated mast cell activation by regulating calcium signaling pathways.

Luteolin is a flavonoid found in many fruits, vegetables, and herbs. The antiinflammatory effects of luteolin have been reported. In this study, the effect of luteolin on allergic diseases and the underlying molecular mechanism were investigated. We found that luteolin inhibits Fc epsilon RΙ (FcεRΙ)- and Mas-related G protein-coupled receptor X2 (MRGPRX2)-mediated mast cells (MCs) activation, including degranulation and release of cytokines in vitro. Moreover, luteolin reduces the degree of swelling and Evans blue exudation of mice paw in a dose-dependent manner. The concentrations of histamine, TNF-α, MCP-1, IL-8, and IL-13 in mice serum are also decreased by luteolin administration. Our study reveals that luteolin can inhibit FcεRΙ- and MRGPRX2-mediated allergic responses in vivo and in vitro, and our results discover luteolin inhibited mast cells mediated anaphylactic reaction by inhibiting the phosphorylation level of PLCγ.

Identification of a primary antigenic target of epitope spreading in endemic pemphigus foliaceus.

Epitope spreading is an important mechanism for the development of autoantibodies (autoAbs) in autoimmune diseases. The study of epitope spreading in human autoimmune diseases is limited due to the major challenge of identifying the initial/primary target epitopes on autoantigens in autoimmune diseases. We have been studying the development of autoAbs in an endemic human autoimmune disease, Brazilian pemphigus foliaceus (or Fogo Selvagem (FS)). Our previous findings demonstrated that patients before (i.e. preclinical) and at the onset of FS have antibody (Ab) responses against other keratinocyte adhesion molecules in addition to the main target autoantigen of FS, desmoglein 1 (Dsg1), and anti-Dsg1 monoclonal Abs (mAbs) cross-reacted with an environmental antigen LJM11, a sand fly saliva protein. Since sand fly is prevalent in FS endemic regions, individuals in these regions could develop Abs against LJM11. The anti-LJM11 Abs could recognize different epitopes on LJM11, including an epitope that shares the structure similarity with an epitope on Dsg1 autoantigen. Thus, Ab response against this epitope on LJM11 could be the initial autoAb response detected in individuals in FS endemic regions, including those who eventually developed FS. Accordingly, this LJM11 and Dsg1 cross-reactive epitope on Dsg1 could be the primary target of the autoimmune response in FS. This investigation aimed to determine whether the autoAb responses against keratinocyte adhesion molecules are linked and originate from the immune response to LJM11. The anti-Dsg1 mAbs from preclinical FS and FS individuals were employed to determine their specificity or cross-reactivity to LJM11 and keratinocyte adhesion molecules. The cross-reactive epitopes on autoantigens were mapped. Our results indicate that all tested mAbs cross-reacted with LJM11 and keratinocyte adhesion molecules, and we identified an epitope on these keratinocyte adhesion molecules which is mimicked by LJM11. Thus, the cross-reactivity could be the mechanism by which the immune response against an environmental antigen triggers the initial autoAb responses. Epitope spreading leads to the pathogenic autoAb development and ensuing FS among genetically susceptible individuals.

Dysbiosis of gut microbiota and its correlation with dysregulation of cytokines in psoriasis patients.

BACKGROUND: Psoriasis is an inflammatory skin disease associated with multiple comorbidities and substantially diminishes patients' quality of life. The gut microbiome has become a hot topic in psoriasis as it has been shown to affect both allergy and autoimmunity diseases in recent studies. Our objective was to identify differences in the fecal microbial composition of patients with psoriasis compared with healthy individuals to unravel the microbiota profiling in this autoimmune disease. RESULTS: We collected fecal samples from 30 psoriasis patients and 30 healthy controls, sequenced them by 16S rRNA high-throughput sequencing, and identified the gut microbial composition using bioinformatic analyses including Quantitative Insights into Microbial Ecology (QIIME) and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). Our results showed that different relative abundance of certain bacterial taxa between psoriasis patients and healthy individuals, including Faecalibacterium and Megamonas, were increased in patients with psoriasis. It's also implicated that many cytokines act as main effect molecules in the pathology of psoriasis. We selected the inflammation-related indicators that were abnormal in psoriasis patients and found the microbiome variations were associated with the level of them, especially interleukin-2 receptor showed a positive relationship with Phascolarctobacterium and a negative relationship with the Dialister. The relative abundance of Phascolarctobacterium and Dialister can be regard as predictors of psoriasis activity. The correlation analysis based on microbiota and Inflammation-related indicators showed that microbiota dysbiosis might induce an abnormal immune response in psoriasis. CONCLUSIONS: We concluded that the gut microbiome composition in psoriasis patients has been altered markedly and provides evidence to understand the relationship between gut microbiota and psoriasis. More mechanistic experiments are needed to determine whether the differences observed in gut microbiota are the cause or consequences of psoriasis and whether the relationship between gut microbiota and cytokines was involved.

UHRF1 Knockdown Attenuates Cell Growth, Migration, and Invasion in Cutaneous Squamous Cell Carcinoma.

Ubiquitin like with PHD and ring finger domains 1 (UHRF1) contributes to the progression of many cancers. Here, we firstly observed UHRF1 was elevated in cutaneous squamous cell carcinoma (cSCC) and related to the differentiation stages. Knockdown of UHRF1 in A431 and Scl-1 attenuated cell proliferation, migration, and invasion, leading to G2/M cell cycle arrest and apoptosis. Through a mouse xenograft model, we found UHRF1 deficiency ameliorated tumor growth. These results may be associated with destruction of multiple signal pathways. In summary, our results suggest UHRF1 is involved in the pathogenesis of cSCC and may be a therapeutic target.

A Chinese case of Nakajo-Nishimura syndrome with novel compound heterozygous mutations of the PSMB8 gene.

BACKGROUND: Nakajo-Nishimura syndrome (NNS) is an autosomal recessive heredity disorder, one of a spectrum of autoinflammatory diseases named proteasome-associated autoinflammatory syndrome (PRAAS) caused by mutations of PSMB8 gene. NNS is characterized by pernio-like skin rashes, intermittent fever, and long clubbed fingers and toes with joint contractures, partially with progressive lipomuscular atrophy, emaciation, hepatosplenomegaly and basal ganglion calcification. CASE PRESENTATION: We presented a sporadic case of NNS with compound heterozygous mutations in the PSMB8 gene. The 4-year-old boy was affected by progressive erythematous plaques on his nose and gradually involved hands and feet later with characteristic appearance of long clubbed fingers. The repetitive periodic intermittent fever was recorded. By gene sequencing, novel compound heterozygous mutations c.373C > T (p.R125C) and c.355G > A (p.D119N) in the PSMB8 gene were found. The patient responded well to low dosage of oral methylprednisolone. CONCLUSIONS: We reported novel compound heterozygous mutations in PSMB8 in a sporadic Chinese NNS patient.

Walnut antigens can trigger autoantibody development in patients with pemphigus vulgaris through a "hit-and-run" mechanism.

BACKGROUND: Environmental factors, as well as genetic predisposition, are known to be critical for the development of autoimmunity. However, the environmental agents that trigger autoimmune responses have remained elusive. One possible explanation is the "hit-and-run" mechanism in which the inciting antigens that initiate autoimmune responses are not present at the time of overt autoimmune disease. OBJECTIVE: After our previous findings that some allergens can incite autoimmune responses, we investigated the potential role of environmental allergens in triggering autoantibody development in patients with an autoimmune skin disease, pemphigus vulgaris (PV). METHODS: Revertant/germline mAbs (with mutations on variable regions of heavy and light chains reverted to germline forms) of 8 anti-desmoglein (Dsg) 3 pathogenic mAbs from patients with PV were tested for reactivity against a panel of possible allergens, including insects, pollens, epithelia, fungi, and food antigens. RESULTS: All the PV germline mAbs were reactive to antigens from walnut, including the well-known allergen Jug r 2 and an uncharacterized 85-kDa protein component. Sera from patients with PV contained significantly greater levels of anti-Dsg3 autoantibodies than walnut-specific antibodies, suggesting that the autoreactive B-cell response in patients with PV might be initially triggered by walnut antigens but is subsequently driven by Dsg3. CONCLUSION: Our findings suggest that walnut antigens/allergens can initiate autoantibody development in patients with PV through a "hit-and-run" mechanism. The revertant/germline mAb approach might provide a paradigm for the etiological study of other allergic and autoimmune diseases.

Complement C3a promotes proliferation, migration and stemness in cutaneous squamous cell carcinoma.

BACKGROUND: Complement C3 has been shown to be highly expressed in cutaneous squamous cell carcinoma (cSCC) tumour tissues and is correlated with tumour cell growth. This study aimed to investigate the mechanism of C3 in cSCC malignant transformation. METHODS: C3 expression was analysed in cSCC cell lines A431, Tca8113, SCC13, HSC-5 and HSC-1 and in immortalized HaCaT keratinocytes. Proliferation and migration of cSCC were determined after C3a exposure. Expression of cyclin D1, cyclin E, vascular endothelial growth factor (VEGF), pro-matrix metalloproteinase 1 (pro-MMP1), pro-matrix metalloproteinase 2 (pro-MMP2), stemness factors, GSK-3ß, and ß-catenin were analyzed. Tumour growth was examined in a murine xenograft model. RESULTS: C3 expression was much more highly expressed in all cSCC cell lines than in HaCaT cells. C3a treatment significantly promoted cSCC cell proliferation and migration and upregulated cyclin D1, cyclin E, VEGF, pro-MMP1 and pro-MMP2 expression, which were impeded by the C3aR antagonist. Moreover, the expression of stemness factors Sox-2, Nanog, Oct-4, c-Myc and CD-44 was stimulated by C3a and slowed by C3aR disruption. Knockdown of Sox-2 by siRNA transfection suppressed cell proliferation and migration, constrained VEGF secretion and inhibited pro-MMP1 and pro-MMP2 expression. C3a also activated the Wnt and ß-catenin pathway in cSCC cells. Disruption of C3aR expression dampened tumour growth and the expression of Wnt-1, ß-catenin and Sox-2 in the xenograft model. CONCLUSIONS: C3a enhanced cell proliferation, migration and stemness in cSCC, and this activity was correlated with activation of the Wnt and ß-catenin pathway.