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关键词： Spesolimab   anit-IL36R   pyoderma gangrenosum   IL-17   undifferentiated oligoarthritis   Ixekizumab   case report  

摘要： Pyoderma gangrenosum (PG) is a classic neutrophilic dermatosis often associated with inflammatory conditions, frequently leading to misdiagnosis and delayed treatment. Drug-induced and postoperative are two potential triggers of PG. A 70-year-old woman, who had been treated with Ixekizumab for undifferentiated oligoarthritis, presented with cribriform violaceous ulcers on her right posterior ankle after 8 months of debridement. A skin biopsy revealed a predominant neutrophilic infiltrate with no signs of infection after extensive microbiology investigation. The patient was diagnosed with pyoderma gangrenosum (PG) and achieved remission after receiving three doses of 900 mg intravenous Spesolimab every 4 weeks, along with discontinuation of Ixekizumab. The case highlights the successful use of Spesolimab (anti-IL36R) in treating PG and explores the potential "paradoxical phenomenon" linked to anti-IL-17 therapy, providing novel insights into immune dysregulation and therapeutic strategies.

关键词： NADPH oxidase   epithelial sodium channel   capillary endothelium   alveolar-capillary barrier function   pneumonia   TNF   TIP peptide  

摘要： The endothelium represents a crucial regulator of vascular homeostasis. Since endothelial cells mainly rely on glycolysis rather than on oxidative phosphorylation for their ATP generation, this allows capillaries to transport the maximum amount of oxygen to oxygen-starved tissues, where it can be used for energy generation. However, the occasionally high levels of oxygen and of reactive oxygen species (ROS) in the blood vessels requires a balancing act between pro- and anti-oxidative mechanisms in the endothelium. When this balance is disturbed by excessive oxidative stress, as can occur in bacterial and viral pneumonia, endothelial barrier function can be compromised. This review will discuss some of the recently discovered barrier-protective mechanisms during bacterial and viral pneumonia, mediated through the reduction of oxidative stress in lung capillaries by the epithelial sodium channel (ENaC).

关键词： Heart Failure   Transverse aortic constricition   Interleukin-22   Inflammation   Fibrosis  

摘要： Heart failure (HF) due to left ventricular (LV) dysfunction remains a major global health challenge, with inflammation driving its progression under chronic pressure overload, such as hypertension. This study explored the role of interleukin-22 (IL-22), a cytokine associated with tissue protection, in HF induced by transverse aortic constriction (TAC). IL-22 knockout (KO) mice exhibited exacerbated HF, marked by worsened LV hypertrophy, heightened inflammation, and impaired cardiac function compared to wild-type controls. Conversely, treatment with recombinant IL-22Fc improved LV function, reduced inflammatory cell infiltration, and alleviated cardiac remodeling and inflammation. These findings demonstrate that IL-22 plays a critical role in regulating inflammation and cardiac remodeling in pressure overload-induced HF. Targeting IL-22 may represent a promising therapeutic strategy to alleviate HF progression and associated pulmonary complications.

关键词： Immortalized human minor salivary gland cell line   Human telomerase reverse transcriptase   SV40 large T antigen   Inflammatory cytokines   Chemokines  

摘要： The role of inflammatory response by salivary gland cells is considered to be important in the pathogenesis of salivary gland chronic inflammation, as seen in Sj & ouml;gren's syndrome patients. The primary salivary gland cell cultures are required to investigate such inflammatory responses, though primary cells exhibit a limited replicative short lifespan with only a few passages. An immortalized human minor salivary gland cell line, NSG cells, was established by transfection with human telomerase reverse transcriptase (hTERT) and SV40 large T antigen (SV40LT). The effects of IFN-gamma, TNF-alpha, and IL-1 beta on chemokine expression in those cells were then examined. Following hTERT expression vector and SV40LT vector transfections into minor salivary gland cells with a non-viral method, real-time PCR was employed to examine the effects of IFN-gamma, TNF-alpha, and IL-1 beta on chemokine mRNA expression. Additionally, ELISA was used to examine the effects of combinations of IFN-gamma, TNF-alpha, and IL-1 beta on CXCL10 and CXCL1 protein expressions. NSG cell growth was found to continue for more than 100 population doublings and the cells constitutively expressed immortalized-related and salivary gland-associated genes. IFN-gamma, TNF-alpha, and IL-1 beta each increased the examined chemokines by various levels. Both TNF-alpha and IL-1 beta separately increased IFN-gamma-induced CXCL10 in the NSG cells, whereas IFN-gamma decreased CXCL1 induced by TNF-alpha or IL-1 beta. An immortalized human minor salivary gland cell line was established by hTERT and SV40LT transfection. The examinations showed that IFN-gamma, TNF-alpha, and IL-1 beta have important roles for development of salivary gland inflammation, such as Sj & ouml;gren's syndrome.

关键词： Biological therapy   Clinical remission   Recurrence   Rheumatoid arthritis   Withdrawing treatment  

摘要： BackgroundThis study evaluates the long-term effectiveness and safety of methotrexate-tacrolimus combination therapy compared to methotrexate monotherapy in maintaining successful tumor necrosis factor (TNF) inhibitor discontinuation in rheumatoid arthritis (RA) *** retrospectively analyzed consecutive RA patients who discontinued TNF inhibitors after achieving disease control by October 2022 and received either methotrexate monotherapy or methotrexate-tacrolimus combination therapy for up to 10 years. Per-observation time-to-event analyses assessed treatment failure, treatment intensification, first disease flare, and irreversible functional deterioration. Mixed-effects Cox models, time-dependent Cox models without random effects, and Kaplan-Meier estimates with inverse probability weighting were applied. Safety assessment included treatment-limiting adverse events and renal function *** total of 147 treatment lines (96 methotrexate monotherapy and 51 combination therapy) in 116 patients were analyzed. The combination therapy significantly reduced treatment failure (hazard ratio [HR], 0.42;95% confidence interval [CI], 0.24-0.72), treatment intensification with the index drugs (HR, 0.38;95% CI, 0.22-0.67) and with biologics or Janus kinase inhibitors (HR, 0.39;95% CI, 0.22-0.71), and first flare (HR, 0.55;95%CI 0.36-0.84), with consistent findings across models. The benefit was most pronounced in patients with prior flares during methotrexate monotherapy after TNF inhibitor discontinuation, with HRs as low as 0.04-0.12 across outcomes. No significant differences in treatment-limiting adverse events were observed. The annual increase in serum creatinine for tacrolimus users was 0.0032 mg/dL, suggesting minimal long-term renal ***-tacrolimus combination therapy significantly reduces relapse risk following TNF inhibitor discontinuation without compromising safety, offering a potentially sustainable treatment altern

关键词： liver fibrosis   IFNAR-1   Kupffer Cells   stat3   tissue repair  

摘要： Liver macrophages play a role in the development of liver fibrosis progression via the regulation of inflammatory signaling. However, the precise mechanisms of macrophages contributing to liver fibrosis progression remain unclear. Using a preclinical model of CCl4-treated mice, we determined the composition of immune cells and the alteration of inflammatory gene expression. Our findings revealed a significant increase in liver macrophages, particularly those derived from infiltrating blood monocytes, in fibrotic mice. Moreover, the expression levels of type I IFN signature genes such as IFN alpha, IFN beta, ISG15, USP18, Ifi44, Ifit1, Ifit2, IRF3, and IRF7 were elevated in fibrotic mice. To determine the role of type I IFN signaling in liver fibrosis, we administered an IFNAR-1 antibody to block this pathway for 3 days prior to harvesting the liver. Notably, IFNAR-1 blockade reduced macrophage numbers compared to control mice and alleviated liver fibrosis in mice with increased hepatocyte proliferation and apoptosis. The ratio of P-STAT3/P-STAT1 in monocyte-derived macrophages was increased in the IFNAR-1 blockade group compared to fibrotic mice, and this was related to the appearance of M2 macrophage differentiation. Additionally, single-cell RNA-seq analysis indicated that IFNAR blockade affected inflammatory pathways involved in hepatocyte regeneration and fibrosis prevention. Taken together, IFNAR-1 blockade alleviates liver fibrosis progression by modulating macrophage inflammatory responses. These results provide insights for developing anti-fibrotic therapies against type I IFN signaling.

关键词： LILR   LIBAG   imputation   copy number   SNP   GWAS   CNV   HLA  

摘要： There are ten leukocyte immunoglobulin (Ig)-like receptor (LILR) genes, i.e., five genes encoding activating receptors (LILRA1, LILRA2, LILRA4, LILRA5, and LILRA6) characterized by their truncated cytoplasmic tails, and five genes encoding inhibitory receptors (LILRB1, LILRB2, LILRB3, LILRB4, and LILRB5) characterized by their extended cytoplasmic tails containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Among these, LILRB3, LILRA6, and LILRA3 are known for harboring high frequencies of copy number variations (CNVs). However, the presence of CNVs in the leukocyte receptor complex (LRC) region complicates single nucleotide polymorphism (SNP) association analysis within commercially available SNP microarray datasets. This study introduces LILR Genotype Imputation with Attribute Bagging (LIBAG), a novel method for determining CNVs in LILRB3, LILRA6, and LILRA3 from commercially available SNP genotyping array datasets. LILRA6 CNV imputation accuracy peaked at 98.0% for the Infinium Japanese Screening Array, followed by 97.4% for Axiom Japonica V2, 97.3% for Axiom Japonica Array NEO, and 94.3% for Axiom Japonica V1, with the lowest recorded accuracy of 93.6% for the Axiom Genome-wide ASI1 array. For the 1000 Genomes Project (1kGP) dataset, LILRA6 CNV imputation achieved peak accuracies of 94.5% for 1kGP-EAS (East Asian), 86.6% for 1kGP-AMR (Admixed American), 83.8% for 1kGP-EUR European), and 75.0% for 1kGP-AFR (African), particularly after the 20 kb flanking region. Similarly, imputation accuracy for LILRA3 CNV progressively increased, peaking at the 80 kb flanking region. Accuracy reached 1kGP-AMR, reaching 99.2% and 98.9% for 1kGP-AFR, 98.7% for 1kGP-EUR, and 97.5% for 1kGP-EAS. Investigating the LILR copy number (CN) in diseases associated with HLA class I molecules will provide further insights into disease pathogenesis.

关键词： tuberculosis   HN878   mouse model   B cell-derived IL-10   sex differences  

摘要： Introduction Due to the historical dogma that host defense against intracellular pathogens is primarily mediated by cell-mediated immunity, B cells have long been considered unimportant in providing protection against Mycobacterium tuberculosis (Mtb) and remained understudied for decades. However, emerging evidence highlights the multifaceted role of B cells in tuberculosis (TB) immunity. B cells accumulate at the site of infection in both animal models and human TB patients, suggesting a potential link to protective immunity. Still, the diverse roles of B cells in TB immunity are still being unraveled. In addition to producing antibodies, B cells secrete a wide range of cytokines that can influence the local immune response. In this study, we focused on the relevance of interleukin 10 (IL-10)-secreting B cells in the long-term control of the Mtb Beijing strain *** B cell-specific IL-10 expression was assessed in IL-10 transcriptional reporter (Vert-X) mice following Mtb infection. To investigate the role of B cell-derived IL-10 in TB immunity, both male and female mice with a targeted knockout of IL-10 in B cells (IL-10flox/CD19cre) were infected with Mtb HN878. Disease progression, control of bacterial replication, and immunological changes were monitored throughout the course of *** B cells contribute to IL-10 production in the Mtb-infected lung in both sexes, with CD138+ plasma cells serving as the primary source of B cell-derived IL-10. Mice lacking B cell-derived IL-10 exhibited increased resistance to aerosol Mtb infection, demonstrated by a delayed onset of clinical symptoms and prolonged survival. Notably, this effect was significantly more pronounced in males compared to females, and was associated with male-specific immune *** Our research highlights a previously unrecognized sex-specific regulatory role of B cell-derived IL-10 during Mtb infection.

摘要： Background:Sarcomas are a heterogeneous group of mesenchymal tumors frequently diagnosed in pediatric and young adult patients. These tumors respond poorly to conventional immunotherapy, though the precise reason for this is not known. We sought to characterize the systemic immune response to sarcomas by measuring the levels of circulating cytokines in the plasma of sarcoma patients, testing the hypothesis that the natures of a patient's immune response to their tumor directly affects outcome. Methods:Plasma was collected from newly diagnosed, treatment-naive pediatric sarcoma patients participating in an ongoing clinical trial, MCC20320. A panel of 18 cytokines was selected and cytokine levels were measured using the Luminex platform. Cytokine levels were analyzed based on clinicopathological parameters such as gender, age, stage, and survival. Results:We found that the cytokine profile in patients newly diagnosed with sarcoma is distinct from healthy controls, but different sarcomas were not distinguishable. Patients with osteosarcoma who had elevated levels of multiple cytokines had inferior overall survival compared to those with fewer or no elevated levels. Similarly, elevated levels of individual cytokines and chemokines, including IL-24, CXCL5, and CXCL10, were associated with inferior event-free or overall survival in patients with osteosarcoma. Perhaps most significantly, elevated IL-1β at diagnosis was associated with metastatic presentation and inferior event-free survival in patients with osteosarcoma. Conclusion:These findings suggest that pediatric sarcoma patients mount a systemic immune response that may affect event-free or overall survival. IL-1β in particular may be a valuable target for immunotherapy for osteosarcoma patients.