Search

Chimeric antigen receptor T (CAR-T) cell therapy is a new treatment for cancers, but reports on curing immune-related skin diseases are limited. We report a case of successful CAR-T-cell therapy in a patient with refractory/relapsed diffuse large B-cell lymphoma (R/R DLBCL) who was incidentally cured of chronic generalized plaque psoriasis. The patient, a 65-year-old male who had a known history of psoriasis for 45 years, did not receive immunotherapy for psoriasis during this period. Imaging, molecular biology and immunology diagnostics confirmed DLBCL. After several weeks of standard-dose R-CHOP chemotherapy, the patient achieved partial remission, but according to CT, the patient relapsed, and there was no significant improvement in her psoriasis symptoms. Subsequently, the patient was enrolled in the CD19 CAR-T-cell therapy group. Four weeks after CAR-T-cell infusion, the patient’s abdominal pain disappeared, and there was a significant improvement in overall skin lesions. One year later, follow-up results indicated complete remission of R/R DLBCL (confirmed by PET-CT), with only minimal residual psoriatic skin lesions limited to the patient’s neck. The results of using CAR-T-cell therapy to achieve an incidental cure for psoriasis highlight the potential for exploring cell-based therapies for complex autoinflammatory skin diseases.

Liquid-liquid phase separation (LLPS) is integral to various biological processes, facilitating signal transduction by creating a condensed, membrane-less environment that plays crucial roles in diverse physiological and pathological processes. Recent evidence has underscored the significance of LLPS in human health and disease. However, its implications in respiratory diseases remain poorly understood. This review explores current insights into the mechanisms and biological roles of LLPS, focusing particularly on its relevance to respiratory diseases, aiming to deepen our understanding and propose a new paradigm for studying phase separation in this context.

Inflammatory diseases compromise a clinically common and diverse group of conditions, causing detrimental effects on body functions. Gasdermins (GSDM) are pore-forming proteins, playing pivotal roles in modulating inflammation. Belonging to the GSDM family, gasdermin D (GSDMD) actively mediates the pathogenesis of inflammatory diseases by mechanistically regulating different forms of cell death, particularly pyroptosis, and cytokine release, in an inflammasome-dependent manner. Aberrant activation of GSDMD in different types of cells, such as immune cells, cardiovascular cells, pancreatic cells and hepatocytes, critically contributes to the persistent inflammation in different tissues and organs. The contributory role of GSDMD has been implicated in diabetes mellitus, liver diseases, cardiovascular diseases, neurodegenerative diseases, and inflammatory bowel disease (IBD). Clinically, alterations in GSDMD levels are potentially indicative to the occurrence and severity of diseases. GSDMD inhibition might represent an attractive therapeutic direction to counteract the progression of inflammatory diseases, whereas a number of GSDMD inhibitors have been shown to restrain GSDMD-mediated pyroptosis through different mechanisms. This review discusses the current understanding and future perspectives on the role of GSDMD in the development of inflammatory diseases, as well as the clinical insights of GSDMD alterations, and therapeutic potential of GSDMD inhibitors against inflammatory diseases. Further investigation on the comprehensive role of GSDM shall deepen our understanding towards inflammation, opening up more diagnostic and therapeutic opportunities against inflammatory diseases.

ObjectivesThe present study aimed to assess influenza vaccine hesitancy and vaccine literacy levels among youth and adults in China, as well as the association between them.MethodsAn online cross-sectional survey was conducted in Mainland China. Participants’ total vaccine literacy and three sub-dimension vaccine literacy (knowledge literacy, competence literacy, and decision-making literacy) were assessed by a validated vaccine literacy scale. Having received influenza vaccination in the past three years or intending to accept it in next influenza season indicates less influenza vaccine hesitancy.ResultsAmong 997 participants, a sub-optimal vaccine literacy was observed, with a mean score of 66.83 ± 10.27. Regression models 1–4 revealed that participants with middle (aOR: 1.431, P=0.039, 95% CI: 1.018~2.010) or high (aOR: 1.651, P=0.006, 95% CI: 1.157~2.354) total vaccine literacy, as well as those with high competence literacy (aOR: 1.533, P=0.017, 95% CI: 1.079~2.180), or high decision-making literacy (aOR: 1.822, P=0.001, 95% CI: 1.261~2.632) were more likely to have been vaccinated against influenza at least once in past three years. However, those with a high knowledge literacy were associated with a lower influenza vaccine rate (aOR: 0.676, P=0.046, 95% CI: 0.460~0.994). Regression models 5–8 revealed that participants with middle (aOR: 1.661, P=0.008, 95% CI: 1.142~2.414) or high total vaccine literacy (aOR: 2.645, P=0.000, 95% CI: 1.774~3.942), as well as those with middle (aOR: 1.703, P=0.005, 95% CI: 1.177~2.464) or high competence literacy (aOR: 2.346, P=0.000, 95% CI: 1.159~3.461), or high decision-making literacy (aOR: 2.294, P=0.000, 95% CI: 1.531~3.436) were more likely to express the willingness to receive the influenza vaccine in the next influenza season.ConclusionThe participants’ influenza vaccine hesitancy was negatively associated with their total vaccine literacy levels and two of the three sub-dimensions: competence literacy and decision-making literacy. Knowledge literacy suggested a positive or no relationship with influenza vaccine hesitancy.

Linear IgA bullous dermatosis (LABD) is an acquired autoimmune subepidermal blistering disorder. Diagnosis always relies on skin pathology and direct immunofluorescence (DIF), with typical linear deposits of IgA along the basement membrane zone (BMZ). The typical clinical manifestation is tense bullae arranged like the “string of pearls” companied with severe pruritus. Dapsone is often considered first-line therapy for LABD, and it is necessary to test the HLA-B*1301 gene to prevent the occurrence of dapsone-induced hypersensitivity syndrome (DHS). Here we report a case of LABD resistant to corticosteroid and sulfasalazine, while waiting for HLA-B*1301 gene test results, dupilumab was used to control severe pruritus.

ObjectiveTo clarify the impact of intravenous infusion of gamma globulin (IVIg) on antinuclear antibodies (ANAs) in children.MethodsA retrospective analysis was performed on the data of children with nonspecific autoantibody-related diseases whose antinuclear antibody (ANA) and autoantibody profiles were detected in our hospital from January to March 2022. A total of 108 patients with a clear history of IVIg infusion within 28 days composed the IVIg group, and 1201 patients without a history of IVIg infusion composed the non-IVIg group.ResultsAll patients in the IVIg group had either positive ANAs or positive autoantibodies. Anti-SSA, anti-Ro52 and anti-AMA Mi2 were the top three autoantibodies in the IVIg group. The proportions of patients who were positive for either of these three autoantibodies in the IVIg group were significantly greater than those in the non-IVIg group (all P

Atherosclerosis (AS) is recognized as a chronic inflammatory condition characterized by the accumulation of lipids and inflammatory cells within the damaged walls of arterial vessels. It is a significant independent risk factor for ischemic cardiovascular disease, ischemic stroke, and peripheral arterial disease. Despite the availability of current treatments such as statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and lifestyle modifications for prevention, AS remains a leading cause of morbidity and economic burden worldwide. Thus, there is a pressing need for the development of new supplementary and alternative therapies or medications. Huangqin (Scutellaria baicalensis Georgi. [SBG]), a traditional Chinese medicine, exerts a significant immunomodulatory effect in AS prevention and treatment, with baicalin being identified as one of the primary active ingredients of traditional Chinese medicine. Baicalin offers a broad spectrum of pharmacological activities, including the regulation of immune balance, antioxidant and anti-inflammatory effects, and improvement of lipid metabolism dysregulation. Consequently, it exerts beneficial effects in both AS onset and progression. This review provides an overview of the immunomodulatory properties and mechanisms by which baicalin aids in AS prevention and treatment, highlighting its potential as a clinical translational therapy.

ObjectivesThis study aimed to examine the effectiveness of the best response rate (BRR) as a surrogate for overall survival (OS), using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), in patients with unresectable hepatocellular carcinoma (HCC) undergoing hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) combined with molecular targeting and immunotherapy.MethodsThis study enrolled 111 consecutive patients who had complete imaging data. The median age of patients was 58 years (IQR 50.5-65.0). Among the patients, those with Barcelona Clinic Liver Cancer (BCLC) stage A, BCLC stage B, and BCLC stage C comprised 6.4%, 19.1%, and 73.6%, respectively. The optimal threshold of BRR can be determined using restricted cubic splines (RCS) and the rank sum statistics of maximum selection. Survival curves of patients in the high rating and low rating groups were plotted. We then used the change-in-estimate (CIE) method to filter out confounders and the inverse probability of treatment weighting (IPTW) to balance confounders between the two groups to assess the robustness of the results.ResultsThe median frequency of the combination treatment regimens administered in the overall population was 3 times (IQR 2.0-3.0). The optimal BRR truncation value calculated was −0.2. Based on this value, 77 patients were categorized as the low rating group and 34 as the high rating group. The differences in the OS between the high and low rating groups were statistically significant (7 months [95%CI 6.0-14.0] vs. 30 months [95%CI 30.0-]; p< 0.001). Using the absolute 10% cut-off value, the CIE method was used to screen out the following confounding factors affecting prognosis: successful conversion surgery, baseline tumor size, BCLC stage, serum total bilirubin level, number of interventional treatments, alpha-fetoprotein level, presence of inferior vena cava tumor thrombus, and partial thrombin activation time. The survival curve was then plotted again using IPTW for confounding factors, and it was found that the low rating group continued to have better OS than the high rating group. Finally, the relationship between BRR and baseline factors was analyzed, and inferior vena cava tumor thrombus and baseline tumor size correlated significantly with BRR.ConclusionsBRR can be used as a surrogate endpoint for OS in unresectable HCC patients undergoing FOLFOX-HAIC in combination with molecular targeting and immunotherapy. Thus, by calculating the BRR, the prognosis of HCC patients after combination therapy can be predicted. Inferior vena cava tumor thrombus and baseline tumor size were closely associated with the BRR.

IntroductionDiabetic nephropathy (DN), distinguished by detrimental changes in the renal glomeruli, is regarded as the leading cause of death from end-stage renal disease among diabetics. Cellular senescence plays a paramount role, profoundly affecting the onset and progression of chronic kidney disease (CKD) and acute kidney injuries. This study was designed to delve deeply into the pathological mechanisms between glomerulus-associated DN and cellular senescence.MethodsGlomerulus-associated DN datasets and cellular senescence-related genes were acquired from the Gene Expression Omnibus (GEO) and CellAge database respectively. By integrating bioinformatics and machine learning methodologies including the LASSO regression analysis and Random Forest, we screened out four signature genes. The receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic performance of the selected genes. Rigorous experimental validations were subsequently conducted in the mouse model to corroborate the identification of three signature genes, namely LOX, FOXD1 and GJA1. Molecular docking with chlorogenic acids (CGA) was further established not only to validate LOX, FOXD1 and GJA1 as diagnostic markers but also reveal their potential therapeutic effects.Results and discussionIn conclusion, our findings pinpointed three diagnostic markers of glomerulus-associated DN on the basis of cellular senescence. These markers could not only predict an increased risk of DN progression but also present promising therapeutic targets, potentially ushering in innovative treatments for DN in the elderly population.

Anti-CD19 chimeric antigen receptor (CAR)-T cells not only target CD19-positive malignant lymphoma cells but also normal B cells. The utility of CAR-T cell therapy has been reported in rheumatoid arthritis and systemic lupus erythematosus; however, its use in Sjögren’s disease (SjD) remains unknown. In this study, we describe the case of a 76-year-old woman with active SjD for 10 years who was diagnosed with diffuse large B-cell lymphoma. After receiving anti-CD19 CAR-T cell therapy, she achieved complete remission (CR) on day 28. Since the onset of her 10-year history with SjD, she was negative for antinuclear antibodies and anti-Ro-52 for the first time on day 90 after CAR-T cell therapy. Six months after CAR-T cell therapy, the CR status was maintained, serum cytokine levels returned to their normal levels, and dry mouth symptoms improved. The EULAR Sjögren’s Syndrome Disease Activity Index score decreased from 5 to 2, indicating a partial remission of SjD activity compared with that before CAR-T cell treatment. In the early stage of treatment, she presented with grade 2 cytokine release syndrome and grade 1 neurotoxicity, which were completely controlled after an active intervention. This case highlights the potential application of CAR-T cells in treating autoimmune diseases, such as SjD.

IntroductionTumor-infiltrating myeloid cells (TIMs) are key regulators in tumor progression, but the similarity and distinction of their fundamental properties in pancreatic ductal adenocarcinoma (PDAC) remain elusive.MethodIn this study, we conducted scRNA-seq data analysis of cells from 12 primary tumor (PT) tissues, 4 metastatic (Met) tumor tissues, 3 adjacent normal pancreas tissues (Para), and PBMC samples across 16 PDAC patients, and revealed a heterogeneous TIMs environment in PDAC.ResultSystematic comparisons between tumor and non-tumor samples of myeloid lineages identified 10 necroptosis-associated genes upregulated in PDAC tumors compared to 5 upregulated in paratumor or healthy peripheral blood. A novel RTM (resident tissue macrophages), GLUL-SQSTM1- RTM, was found to act as a positive regulator of immunity. Additionally, HSP90AA1+HSP90AB1+ mast cells exhibited pro-immune characteristics, and JAK3+TLR4+ CD16 monocytes were found to be anti-immune. The findings were validated through clinical outcomes and cytokines analyses. Lastly, intercellular network reconstruction supported the associations between the identified novel clusters, cancer cells, and immune cell populations.ConclusionOur analysis comprehensively characterized major myeloid cell lineages and identified three subsets of myeloid-derived cells associated with necroptosis. These findings not only provide a valuable resource for understanding the multi-dimensional characterization of the tumor microenvironment in PDAC but also offer valuable mechanistic insights that can guide the design of effective immuno-oncology treatment strategies.

BackgroundOvarian cancer (OC) is a highly heterogeneous and malignant gynecological cancer, thereby leading to poor clinical outcomes. The study aims to identify and characterize clinically relevant subtypes in OC and develop a diagnostic model that can precisely stratify OC patients, providing more diagnostic clues for OC patients to access focused therapeutic and preventative strategies.MethodsGene expression datasets of OC were retrieved from TCGA and GEO databases. To evaluate immune cell infiltration, the ESTIMATE algorithm was applied. A univariate Cox analysis and the two-sided log-rank test were used to screen OC risk factors. We adopted the ConsensusClusterPlus algorithm to determine OC subtypes. Enrichment analysis based on KEGG and GO was performed to determine enriched pathways of signature genes for each subtype. The machine learning algorithm, support vector machine (SVM) was used to select the feature gene and develop a diagnostic model. A ROC curve was depicted to evaluate the model performance.ResultsA total of 1,273 survival-related genes (SRGs) were firstly determined and used to clarify OC samples into different subtypes based on their different molecular pattern. SRGs were successfully stratified in OC patients into three robust subtypes, designated S-I (Immunoreactive and DNA Damage repair), S-II (Mixed), and S-III (Proliferative and Invasive). S-I had more favorable OS and DFS, whereas S-III had the worst prognosis and was enriched with OC patients at advanced stages. Meanwhile, comprehensive functional analysis highlighted differences in biological pathways: genes associated with immune function and DNA damage repair including CXCL9, CXCL10, CXCL11, APEX, APEX2, and RBX1 were enriched in S-I; S-II combined multiple gene signatures including genes associated with metabolism and transcription; and the gene signature of S-III was extensively involved in pathways reflecting malignancies, including many core kinases and transcription factors involved in cancer such as CDK6, ERBB2, JAK1, DAPK1, FOXO1, and RXRA. The SVM model showed superior diagnostic performance with AUC values of 0.922 and 0.901, respectively. Furthermore, a new dataset of the independent cohort could be automatically analyzed by this innovative pipeline and yield similar results.ConclusionThis study exploited an innovative approach to construct previously unexplored robust subtypes significantly related to different clinical and molecular features for OC and a diagnostic model using SVM to aid in clinical diagnosis and treatment. This investigation also illustrated the importance of targeting innate immune suppression together with DNA damage in OC, offering novel insights for further experimental exploration and clinical trial.

The intestinal mucosa is constantly exposed to commensal microbes, opportunistic pathogens, toxins, luminal components and other environmental stimuli. The intestinal mucosa consists of multiple differentiated cellular and extracellular components that form a critical barrier, but is also equipped for efficient absorption of nutrients. Combination of genetic susceptibility and environmental factors are known as critical components involved in the pathogenesis of intestinal diseases. The innate immune system plays a critical role in the recognition and elimination of potential threats by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This host defense is facilitated by pattern recognition receptors (PRRs), in which the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has gained attention due to its role in sensing host and foreign double-stranded DNA (dsDNA) as well as cyclic dinucleotides (CDNs) produced by bacteria. Upon binding with dsDNA, cGAS converts ATP and GTP to cyclic GMP-AMP (cGAMP), which binds to STING and activates TANK binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), inducing type I interferon (IFN) and nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokines, which have diverse effects on innate and adaptive immune cells and intestinal epithelial cells (IECs). However, opposite perspectives exist regarding the role of the cGAS-STING pathway in different intestinal diseases. Activation of cGAS-STING signaling is associated with worse clinical outcomes in inflammation-associated diseases, while it also plays a critical role in protection against tumorigenesis and certain infections. Therefore, understanding the context-dependent mechanisms of the cGAS-STING pathway in the physiopathology of the intestinal mucosa is crucial for developing therapeutic strategies targeting the cGAS-STING pathway. This review aims to provide insight into recent findings of the protective and detrimental roles of the cGAS-STING pathway in intestinal diseases.

The phenotypic spectrum of myelin oligodendrocyte glycoprotein (MOG)- IgG–associated disorders (MOGAD) has broadened in the past few years, and atypical phenotypes are increasingly recognized. Isolated seizures and MRI-negative brainstem and cerebellar symptoms or encephalitis have rarely been reported as a feature of MOGAD and represent a diagnostic challenge. Meanwhile, the coexistence of MOG IgG and other CNS autoimmune antibodies is infrequent. We report a patient presented with isolated epileptic onset, relapsed with MRI-negative brainstem symptoms and MRI-negative encephalitis. He was positive for MOG IgG throughout the disease course while concomitant NMDAR IgG was not detected positive until second relapse. He showed decreasing response to conventional first-line therapy. The last relapse was during a COVID-19 epidemic with limited inpatient resources. Fortunately, he was ultimately controlled on subcutaneous ofatumumab, a novel fully humanized anti-CD20 mAb. This is the first report about subcutaneous ofatumumab treatment in MOG and NMDAR IgG double positive encephalitis with 12-month follow-up, depicting its potential as a therapeutic option.

BackgroundAmeloblastoma is a locally invasive and aggressive epithelial odontogenic neoplasm. The BRAF-V600E gene mutation is a prevalent genetic alteration found in this tumor and is considered to have a crucial role in its pathogenesis. The objective of this study is to develop and validate a radiomics-based machine learning method for the identification of BRAF-V600E gene mutations in ameloblastoma patients.MethodsIn this retrospective study, data from 103 patients diagnosed with ameloblastoma who underwent BRAF-V600E mutation testing were collected. Of these patients, 72 were included in the training cohort, while 31 were included in the validation cohort. To address class imbalance, synthetic minority over-sampling technique (SMOTE) is applied in our study. Radiomics features were extracted from preprocessed CT images, and the most relevant features, including both radiomics and clinical data, were selected for analysis. Machine learning methods were utilized to construct models. The performance of these models in distinguishing between patients with and without BRAF-V600E gene mutations was evaluated using the receiver operating characteristic (ROC) curve.ResultsWhen the analysis was based on radiomics signature, Random Forest performed better than the others, with the area under the ROC curve (AUC) of 0.87 (95%CI, 0.68-1.00). The performance of XGBoost model is slightly lower than that of Random Forest, and its AUC is 0.83 (95% CI, 0.60-1.00). The nomogram evident that among younger women, the affected region primarily lies within the mandible, and patients with larger tumor diameters exhibit a heightened risk. Additionally, patients with higher radiomics signature scores are more susceptible to the BRAF-V600E gene mutations.ConclusionsOur study presents a comprehensive radiomics-based machine learning model using five different methods to accurately detect BRAF-V600E gene mutations in patients diagnosed with ameloblastoma. The Random Forest model’s high predictive performance, with AUC of 0.87, demonstrates its potential for facilitating a convenient and cost-effective way of identifying patients with the mutation without the need for invasive tumor sampling for molecular testing. This non-invasive approach has the potential to guide preoperative or postoperative drug treatment for affected individuals, thereby improving outcomes.

Mast cell leukemia is a rare and aggressive disease, predominantly with KIT D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia responded to the midostaurin treatment with a 50% overall response rate (ORR), but complete remission rate is approximately 0%. Therefore, the potential mechanisms of midostaurin resistance and the exact impacts of midostaurin on both gene expression profile and mast cell leukemia microenvironment in vivo are essential for design tailored combination therapy targeting both the tumor cells and the tumor microenvironment. Here we report a 59-year-old male mast cell leukemia patient with KIT F522C mutation treated with midostaurin. Single-cell sequencing of peripheral blood and whole exome sequencing (WES) of bone marrow were performed before and 10 months after midostaurin treatment. In accordance with the clinical response, compared to the pretreatment aberration, the decline of mast cells and increase of T-, NK, B-cells in peripheral blood, and the decrease of the KIT F522C mutation burden in bone marrow were observed. Meanwhile, the emergence of RUNX1 mutation, upregulations of genes expression (RPS27A, RPS6, UBA52, RACK1) on tumor cells, and increased frequencies of T and NK cells with TIGIT, CTLA4, and LAG3 expression were observed after midostaurin treatment, predicting the disease progression of this patient. As far as we know, this is the first case reporting the clinical, immunological, and molecular changes in mast cell leukemia patients before and after midostaurin treatment, illustrating the in vivo mechanisms of midostaurin resistance in mast cell leukemia, providing important clues to develop a sequential option to circumvent tumor progression after targeting oncogene addiction and prolong patients’ survival.

Interferon regulatory factor (IRF) 7 was originally identified as master transcriptional factor that produced IFN-I and regulated innate immune response, subsequent studies have revealed that IRF7 performs a multifaceted and versatile functions in multiple biological processes. In this review, we provide a comprehensive overview on the current knowledge of the role of IRF7 in immunity and autoimmunity. We focus on the latest regulatory mechanisms of IRF7 in IFN-I, including signaling pathways, transcription, translation, and post-translational levels, the dimerization and nuclear translocation, and the role of IRF7 in IFN-III and COVID-19. In addition to antiviral immunity, we also discuss the role and mechanism of IRF7 in autoimmunity, and the further research will expand our understanding of IRF7.

BackgroundAutoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a recently discovered inflammatory central nervous system (CNS) disease, whose clinical characteristics and prognostic factors for short-term outcomes have not been defined yet. We aimed to assess the symptoms, laboratory tests, imaging findings, treatment, and short-term prognosis of GFAP-A.MethodsA double-center retrospective cohort study was performed between May 2018 and July 2022. The clinical characteristics and prognostic factors for short-term outcomes were determined.ResultsWe enrolled 33 patients with a median age of 28 years (range: 2–68 years), 15 of whom were children (

BackgroundAbnormal lipid metabolism is common in patients with primary biliary cholangitis (PBC). PBC and Sjögren’s syndrome (SS) frequently coexist in clinical practice; however, the lipid characteristics of both diseases are unknown. Therefore, we aimed to analyze the plasma lipid profiles of both diseases.MethodsPlasma samples from 60 PBC patients, 30 SS patients, and 30 healthy controls (HC) were collected, and untargeted lipidomics was performed using ultrahigh-performance liquid chromatography high-resolution mass spectrometry. Potential lipid biomarkers were screened through an orthogonal projection to latent structure discriminant analysis and further evaluated using receiver operating characteristic (ROC) analysis.ResultsA total of 115 lipids were differentially upregulated in PBC patients compared with HC. Seventeen lipids were positively associated with the disease activity of PBC, and ROC analysis showed that all of these lipids could differentiate between ursodeoxycholic acid (UDCA) responders and UDCA non-responders. The top six lipids based on the area under the curve (AUC) values were glycerophosphocholine (PC) (16:0/16:0), PC (18:1/18:1), PC (42:2), PC (16:0/18:1), PC (17:1/14:0), and PC (15:0/18:1). In comparison with SS, 44 lipids were found to be differentially upregulated in PBC. Additionally, eight lipids were found to have a good diagnostic performance of PBC because of the AUC values of more than 0.9 when identified from SS and HC groups, which were lysophosphatidylcholines (LysoPC) (16:1), PC (16:0/16:0), PC (16:0/16:1), PC (16:1/20:4), PC (18:0/20:3), PC (18:1/20:2), PC (20:0/22:5), and PC (20:1/22:5).ConclusionOur study revealed differentially expressed lipid signatures in PBC compared with HC and SS. PC is the main lipid species associated with disease activity and the UDCA response in patients with PBC.

Host immune activation is critical for enterovirus 71 (EV71) clearance and immunopathogenesis. However, the mechanism of innate immune activation, especially of cell membrane-bound toll-like receptors (TLRs), against EV71 remains unknown. We previously demonstrated that TLR2 and its heterodimer inhibit EV71 replication. In this study, we systematically investigated the effects of TLR1/2/4/6 monomers and TLR2 heterodimer (TLR2/TLR1, TLR2/TLR6, and TLR2/TLR4) on EV71 replication and innate immune activation. We found that the overexpression of human- or mouse-derived TLR1/2/4/6 monomers and TLR2 heterodimer significantly inhibited EV71 replication and induced the production of interleukin (IL)-8 via activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways. Furthermore,human–mouse chimeric TLR2 heterodimer inhibited EV71 replication and activated innate immunity. Dominant-negative TIR-less (DN)-TLR1/2/4/6 did not exert any inhibitory effects, whereas DN-TLR2 heterodimer inhibited EV71 replication. Prokaryotic expression of purified recombinant EV71 capsid proteins (VP1, VP2, VP3, and VP4) or overexpression of EV71 capsid proteins induced the production of IL-6 and IL-8 via activation of the PI3K/AKT and MAPK pathways. Notably, two types of EV71 capsid proteins served as pathogen-associated molecular patterns for TLR monomers (TLR2 and TLR4) and TLR2 heterodimer (TLR2/TLR1, TLR2/TLR6, and TLR2/TLR4) and activated innate immunity. Collectively, our results revealed that membrane TLRs inhibited EV71 replication via activation of the antiviral innate response, providing insights into the EV71 innate immune activation mechanism.

Background and objectivesThe activated complement profile in IgA nephropathy (IgAN) is still unclear. Our study investigated the profile of urinary complements in IgAN patients and its correlations with clinical and pathological characteristics.MethodsUrinary protein abundance was detected by liquid chromatography-tandem mass spectrometry (LC–MS/MS) in 50 IgAN, 50 membranous nephropathy (MN), and 68 healthy controls (HC). Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to identify differentially expressed proteins in IgAN patients. The differentially expressed complement proteins were screened in IgAN patients, and their correlations with laboratory or pathological parameters were analyzed. Thereafter, 7 complement components were validated by enzyme-linked immunosorbent assay (ELISA) in the urine samples of 45 IgAN patients.ResultsThere were 786 differentially expressed proteins between IgAN and HC. KEGG analysis showed that differentially expressed urinary proteins in IgAN were enriched with complement. Of these, 67% of urinary complement protein abundance was associated with the estimated glomerular filtration rate. The urinary complement-related protein collectin12 (colec12), complement H factor (CFH), complement H factor-related protein 2 (CFHR2), and complement B factor (CFB) were positively correlated with serum creatinine; colec12, CFHR2, CFB, and C8g were positively correlated with glomerulosclerosis; CFH, CFHR2, C8g, and C9 were positively correlated with tubular atrophy/interstitial fibrosis.ConclusionAbnormally increased components of complement pathways significantly correlate with reduced renal function, proteinuria, and renal histological damage in IgAN. It could provide a potential biomarker panel for monitoring IgAN and provide clues for therapeutic choice targeting complement system of IgAN patients.

IntroductionThe condition of refractory lupus nephritis (LN) negatively affects the prognosis and life expectancy of the patients, posing a challenge to manage in clinical. This interventional study evaluated the efficacy as well as safety of leflunomide in patients with refractory LN.MethodsTwenty patients with refractory LN were enrolled in this study. A daily dose of 20–40 mg of leflunomide was given to the patients orally. Meanwhile, immunosuppressives were withdrawn, and corticosteroids were gradually tapered. There was an average follow-up period of 3, 6, and 12 months for most patients while some were observed for as long as 24 months. We recorded biochemical parameters and side effects. We calculated the response rate using intention-to-treat analysis.ResultsEighteen patients (90%) completed the study. At 3 months, 80% (16/20) of the patients achieved more than a 25% decrease in 24-hour urine protein quantity. At 6 months, three patients (15%) achieved a partial response, and five patients (25%) achieved a complete response. However, by 12 months and 24 months, the complete response rate dropped to 15% and 20%, respectively. The objective responses were 30% (6/20), 40% (8/20), 40% (8/20), and 30% (6/20) at 3, 6, 12, and 24 months, respectively. Two patients withdrew from the study due to developing cytopenia and leucopenia.ConclusionIn patients diagnosed with refractory LN, our study shows that leflunomide could be a promising treatment option owing to its response rate and safety profile.

IntroductionDysregulated macrophage polarization (excessive M1-like or limited M2-like macrophages) in the early decidua contributes to allogeneic fetal rejection and thus early spontaneous abortion. However, the modulators of M1/M2 balance at the early maternal-fetal interface remain mostly unknown.MethodsFirst-trimester decidual tissues were collected from normal pregnant women undergoing elective pregnancy terminations and patients with spontaneous abortion. We measured the expression of placental growth factor (PlGF) and Fms-like-tyrosine-kinase receptor 1 (FLT-1), and characterized the profiles of macrophages in decidua. Notably, we investigated the effect of recombinant human PlGF (rhPlGF) on decidual macrophages (dMφs) from normal pregnancy and revealed the underlying mechanisms both in vitro and in vivo.ResultsThe downregulated expression of PlGF/ FLT-1 may result in spontaneous abortion by inducing the M1-like deviation of macrophages in human early decidua. Moreover, the CBA/J×DBA/2 abortion-prone mice displayed a lower FLT-1 expression in uterine macrophages than did CBA/J×BALB/c control pregnant mice. In in vitro models, rhPlGF treatment was found to drive the M2-like polarization of dMφs via the STAT3/CEBPB signaling pathway. These findings were further supported by a higher embryo resorption rate and uterine macrophage dysfunction in Pgf knockout mice, in addition to the reduced STAT3 transcription and C/EBPβ expression in uterine macrophages.DiscussionPlGF plays a key role in early pregnancy maintenance by skewing dMφs toward an M2-like phenotype via the FLT-1-STAT3-C/EBPβ signaling pathway. Excitingly, our results highlight a rationale that PlGF is a promising target to prevent early spontaneous abortion.

The human placenta is a unique temporary organ with a mysterious immune tolerance. The formation of trophoblast organoids has advanced the study of placental development. HLA-G is uniquely expressed in the extravillous trophoblast (EVT) and has been linked to placental disorders. With older experimental methodologies, the role of HLA-G in trophoblast function beyond immunomodulation is still contested, as is its role during trophoblast differentiation. Organoid models incorporating CRISPR/Cas9 technology were used to examine the role of HLA-G in trophoblast function and differentiation. JEG-3 trophoblast organoids (JEG-3-ORGs) were established that highly expressed trophoblast representative markers and had the capacity to differentiate into EVT. CRISPR/Cas9 based on HLA-G knockout (KO) significantly altered the trophoblast immunomodulatory effect on the cytotoxicity of natural killer cells, as well as the trophoblast regulatory effect on HUVEC angiogenesis, but had no effect on the proliferation and invasion of JEG-3 cells and the formation of TB-ORGs. RNA-sequencing analysis further demonstrated that JEG-3 KO cells followed similar biological pathways as their wild-type counterparts during the formation of TB-ORGs. In addition, neither HLA-G KO nor the exogenous addition of HLA-G protein during EVT differentiation from JEG-3-ORGs altered the temporal expression of the known EVT marker genes. Based on the JEG-3 KO (disruption of exons 2 and 3) cell line and the TB-ORGs model, it was determined that HLA-G has a negligible effect on trophoblast invasion and differentiation. Despite this, JEG-3-ORG remains a valuable model for studying trophoblast differentiation.

BackgroundPeople living with HIV (PLWH) are more vulnerable to SARS-CoV-2. However, evidence on the immunogenicity of coronavirus disease 2019 (COVID-19) vaccines in this population is insufficient. The objective of this study is to assess the immunogenicity and safety of the two-dose schedule of Sinovac CoronaVac for 6 months postvaccination in PLWH.MethodsWe conducted a multicenter prospective cohort study among PLWH and HIV-negative adults in China. Participants who received two doses of CoronaVac prior to the recruitment were allocated into two groups and followed up for 6 months. The neutralizing antibodies (nAbs), immunoglobulin G against the receptor-binding domain of the spike protein (S-IgG), and gamma-interferon (IFN-γ) were measured to assess the associations among CoronaVac immunogenicity and related factors. Adverse reactions were collected to evaluate the safety profile of vaccination.ResultsA total of 203 PLWH and 100 HIV-negative individuals were enrolled. A small portion of participants reported mild or moderate adverse reactions without serious adverse events. Median nAbs level in PLWH (31.96 IU/mL, IQR: 12.34-76.40) was lower than that in the control group (46.52 IU/mL, IQR: 29.08-77.30) at the 2-4 weeks postvaccination (P=0.002), and the same trend was presented for median S-IgG titer (37.09 vs. 60.02 IU/ml) (both P

The isolation of Stropharia rugosoannulata polysaccharide (SRP) by three-phase extraction was optimized, and its structure and biological activities were identified. The optimal extraction conditions were: mass fraction of ammonium sulfate, 20%; volume ratio of sample solution to t-butanol, 1:1.5; extraction temperature, 35°C. Under these conditions, the yield of SRP was 6.85% ± 0.13%. SRP was found to be composed of glucose (35.79%), galactose (26.80%), glucuronic acid (9.92%), fructose (8.65%), xylose (7.92%), fucose (4.19%), arabinose (3.46%) and rhamnose (3.26%), with the molecular weight of 27.52 kDa. The results of DPPH, hydroxyl, ABTS+ radical scavenging and reducing power tests showed that SRP had good antioxidant capacities. SRP had no cytotoxic effect on RAW264.7 macrophages at the concentrations of 25-200 μg/mL, and could significantly promote phagocytosis activity and cell migration according to CCK-8 assay, phagocytosis assay and cell scratch experiment. SRP can significantly stimulate the transcript expression levels of TNF-α, IL-1β and IL-6, as determined by RT-PCR and Western blot assays. SRP activated the TLR4/NF-κB signaling pathway, and autophagy also occurred. These results suggest that SRP is a safe antioxidant and immunomodulator, and that it can be used in the development of functional foods and/or pharmaceuticals.

BackgroundWhile the tumor microenvironment (TME) affects immune checkpoint blockade (ICB) efficacy, ICB also reshapes the characteristics of TME. Thus far, studies have focused on the TME evolution during neoadjuvant or adjuvant ICB therapy in gastric cancer (GC). However, the interaction between TME characteristics and neoadjuvant immunotherapy plus chemotherapy remains to be elucidated.MethodsWe performed single-cell RNA sequencing on ten GC specimens pre- and post-neoadjuvant camrelizumab plus mFOLFOX6 to determine the impact of the TME on the efficacy of the combination therapy and the remodeling of TME by the therapy.ResultsA high baseline interferon gamma (IFN-γ) signature in CD8+ T cells predicts better responses to the combination therapy. We also observed that the IFN-γ signature significantly decreased in multiple cell types, and the exhausted signature of CD8+ T cells was significantly suppressed during the neoadjuvant therapy.ConclusionsOur data reveal interactions between the TME and neoadjuvant immunotherapy plus chemotherapy in GC. Importantly, it also highlights the signature of CD8+ T cells in predicting response to the combination therapy in GC.

ObjectiveNumerous researches have reported the role of air pollution in the development of autoimmune diseases. However, few have evaluated the relationship between inhalable particulate matter (PM) exposure and Sjögren’s syndrome (SS). This study aimed to analyze the association between exposure to two particulate pollutants (PM2.5, PM10) and SS-related hospitalizations.MethodsDaily data were obtained on PM2.5 and PM10, meteorological factors, and hospital hospitalizations for SS between 2016 and 2021. The daily data on PM2.5 and PM10, meteorological factors, and the number of SS hospitalizations were collected between 2016 and 2021. A distributed lag non-linear model and a generalized linear model were established to explore the association between PM2.5 and PM10 exposure and hospitalizations for SS. Stratified analyses were performed to explore possible gender-, age-, and season-related differences in PM2.5 and PM10 effects.ResultsExposure to PM2.5 was related to the evaluated risk of hospitalizations for SS (RR=1.015, 95% CI: 1.001-1.029, lag 3 day), similarly, PM10 exposure had a statistically significant positive association with SS hospitalizations (RR =1.013, 95% CI: 1.001-1.026, lag 3 day). Stratified analyses found that exposure to PM2.5 and PM10 exhibited higher impact on SS-related hospitalizations in female patients and exposure to PM2.5 was also associated with the higher risk of SS-related hospitalizations in patients aged ≥ 65 years. In addition, exposure to PM2.5, PM10 in colder season were more likely to increase SS-related hospitalizations.ConclusionOur findings suggested that exposure to PM2.5 and PM10 were significantly linked to an elevated risk of hospitalizations for SS.

BackgroundAnoikis is a form of programmed cell death or programmed cell death(PCD) for short. Studies suggest that anoikis involves in the decisive steps of tumor progression and cancer cell metastasis and spread, but what part it plays in bladder cancer remains unclear. We sought to screen for anoikis-correlated long non-coding RNA (lncRNA) so that we can build a risk model to understand its ability to predict bladder cancer prognosis and the immune landscape.MethodsWe screened seven anoikis-related lncRNAs (arlncRNAs) from The Cancer Genome Atlas (TCGA) and designed a risk model. It was validated through ROC curves and clinicopathological correlation analysis, and demonstrated to be an independent factor of prognosis prediction by uni- and multi-COX regression. In the meantime, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, immune infiltration, and half-maximal inhibitory concentration prediction (IC50) were implemented with the model. Moreover, we divided bladder cancer patients into three subtypes by consensus clustering analysis to further study the differences in prognosis, immune infiltration level, immune checkpoints, and drug susceptibility.ResultWe designed a risk model of seven arlncRNAs, and proved its accuracy using ROC curves. COX regression indicated that the model might be an independent prediction factor of bladder cancer prognosis. KEGG enrichment analysis showed it was enriched in tumors and immune-related pathways among the people at high risk. Immune correlation analysis and drug susceptibility results indicated that it had higher immune infiltration and might have a better immunotherapy efficacy for high-risk groups. Of the three subtypes classified by consensus clustering analysis, cluster 3 revealed a positive prognosis, and cluster 2 showed the highest level of immune infiltration and was sensitive to most chemistries. This is helpful for us to discover more precise immunotherapy for bladder cancer patients.ConclusionIn a nutshell, we found seven arlncRNAs and built a risk model that can identify different bladder cancer subtypes and predict the prognosis of bladder cancer patients. Immune-related and drug sensitivity researches demonstrate it can provide individual therapeutic schedule with greater precision for bladder cancer patients.

ObjectiveIncreasing evidence suggested that gaseous pollutants were associated with the development of autoimmune diseases, while there were few studies on the association between gaseous pollutants and Sjögren’s syndrome (SS). This study sought to assess the relationship between exposure to several gaseous pollutants and the hospitalizations for SS.MethodsThe data regarding SS hospitalizations, gaseous pollutants, and meteorological factors in Hefei from 2016 to 2021 were collected. A distributed lag non-linear model combined with a generalized linear model were adopted to analyze the association between gaseous pollutants and SS hospitalizations, and stratified analyses were also conducted.ResultsWe detected significant associations between gaseous pollutants (NO2, SO2, O3, CO) and SS hospitalizations. Exposure to NO2 was linked with the elevated risk of hospitalizations for SS (RR=1.026, lag1 day). A positive correlation between CO exposure and hospitalizations for SS was found (RR=1.144, lag2 day). In contrast, exposure to SO2, O3 was respectively related to the decreased risk of hospitalizations for SS (SO2: RR=0.897, lag14 day; O3: RR=0.992, lag9 day). Stratified analyses found that female patients were more vulnerable to these gaseous pollutants. SS patients ≥ 65 years were more susceptible to NO2, CO exposure, and younger patients were more vulnerable to O3 exposure. In addition, exposure to O3, CO in cold season were more likely to affect hospitalizations for SS.ConclusionOur results demonstrated a significant association between exposure to NO2, CO and elevated risk of hospitalizations for SS, and SO2, O3 exposure might be linked to reduced risk of SS hospitalizations.

Epithelial ovarian cancer (EOC) ranks as the second most common cause of gynecologic cancer death. The conventional treatment for patients with EOC is postoperative therapy along with platinum chemotherapy. However, a more efficient treatment regimen is of great need for these patients diagnosed with advanced disease (FIGO stages III–IV), whose survival is approximately 29%. Immunotherapy seems to be an encouraging therapeutic strategy for EOC. Given the crucial role in the complicated interactions between tumor cells and other cells, the tumor microenvironment (TME) influences the response to immunotherapy. In this review, we discuss feasible strategies for EOC immunotherapy by exploiting the reciprocity of cancer cells and the constituents of the TME.

BackgroundThere is a close relationship between radiotherapy and autophagy in tumors, but the prognostic role of radiotherapy-related autophagy genes (RRAGs) in lung adenocarcinoma (LUAD) remains unclear.MethodsData used in the current study were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Weighted gene co-expression network analysis (WGCNA) was executed to recognize module genes associated with radiotherapy. The differentially expressed genes (DEGs) between different radiotherapy response groups were filtered via edgeR package. The differentially expressed radiotherapy-related autophagy genes (DERRAGs) were obtained by overlapping the module genes, DEGs, and autophagy genes (ATGs). Then, prognostic autophagy genes were selected by Cox analyses, and a risk model and nomogram were subsequently built. Gene Set Enrichment Analysis (GSEA) and single-sample Gene Set Enrichment Analysis (ssGSEA) were performed to investigate potential mechanisms through which prognostic autophagy signatures regulate LUAD. Radiotherapy-resistant cell lines (A549IR and PC9IR) were established after exposure to hypo-fractionated irradiation. Ultimately, mRNA expression was validated by quantitative real-time PCR (qRT-PCR), and relative protein levels were measured in different cell lines by western blot.ResultsA total of 11 DERRAGs were identified in LUAD. After Cox analyses, SHC1, NAPSA, and AURKA were filtered as prognostic signatures in LUAD. Then, the risk score model was constructed using the prognostic signatures, which had a good performance in predicting the prognosis, as evidenced by receiver operating characteristics curves. Furthermore, Cox regression analyses demonstrated that risk score was deemed as an independent prognostic factor in LUAD. Moreover, GSEA and ssGSEA results revealed that prognostic RRAGs may regulate LUAD by modulating the immune microenvironment and affecting cell proliferation. The colony formation assay showed that the radiosensitivity of radiation-resistant cell lines was lower than that of primary cells. The western blot assay found that the levels of autophagy were elevated in the radiotherapy-resistant cell lines. Moreover, the expression of DERRAGs (SHC1, AURKA) was higher in the radiotherapy-resistant cells than in primary cells.ConclusionOur study explored the role of RRAGs in the prognosis of LUAD and identified three biomarkers. The findings enhanced the understanding of the relationship between radiotherapy, autophagy, and prognosis in LUAD and provided potential therapeutic targets for LUAD patients.

Breast cancer is a cancer of high complexity and heterogeneity, with differences in prognosis and survival among patients of different subtypes. Copy number variations (CNVs) within enhancers are crucial drivers of tumorigenesis by influencing expression of their targets. In this study, we performed an integrative approach to identify CNA-driven enhancers and their effect on expression of target genes in four breast cancer subtypes by integrating expression data, copy number data and H3K27ac data. We identified 672, 555, 531, 361 CNA-driven enhancer-gene pairs and 280, 189, 113 and 98 CNA-driven enhancer-lncRNA pairs in the Basal-like, Her2, LumA and LumB subtypes, respectively. We then reconstructed a CNV-driven enhancer-lncRNA-mRNA regulatory network in each subtype. Functional analysis showed CNA-driven enhancers play an important role in the progression of breast cancer subtypes by influencing P53 signaling pathway, PPAR signaling pathway, systemic lupus erythematosus and MAPK signaling pathway in the Basal-like, Her2, LumA and LumB subtypes, respectively. We characterized the potentially prognostic value of target genes of CNV-driven enhancer and lncRNA-mRNA pairs in the subtype-specific network. We identified MUM1 and AC016876.1 as prognostic biomarkers in LumA and Basal-like subtypes, respectively. Higher expression of MUM1 with an amplified enhancer exhibited poorer prognosis in LumA patients. Lower expression of AC016876.1 with a deleted enhancer exhibited poorer survival outcomes of Basal-like patients. We also identified enhancer-related lncRNA-mRNA pairs as prognostic biomarkers, including AC012313.2-MUM1 in the LumA, AC026471.4-PLK5 in the LumB, AC027307.2-OAZ1 in the Basal-like and AC022431.1-HCN2 in the Her2 subtypes. Finally, our results highlighted target genes of CNA-driven enhancers and enhancer-related lncRNA-mRNA pairs could act as prognostic markers and potential therapeutic targets in breast cancer subtypes.

Up to now, there has been insufficient clinical data to support the safety and effects of vaccination on pregnancy post COVID-19 vaccination. The γδ-T cells are considered an important component in the immune system to fight against viral infection and exhibit critical roles throughout the pregnancy period. However, the immunological roles of γδ-T cells in pregnant women with the COVID-19 vaccination remain unclear. Therefore, the objective of this study is to investigate the alteration of frequency and expression pattern of activation receptors and inhibitory receptors in γδ-T cell and its subsets in peripheral blood samples collected from non-pregnant vaccinated women, vaccinated pregnant women, and unvaccinated pregnant women. Our findings indicated that the frequency of CD3+γδ-T+ cells is lower in vaccinated pregnant women than in unvaccinated pregnant women. But no significant difference was found in the frequency of CD3+γδ-T+ cells between non-pregnant vaccinated women and vaccinated pregnant women. In addition, there were no significant differences in the frequencies of CD3+γδ-T+Vδ1+T cells, CD3+γδ-T+Vδ2+T cells, CD3+γδ-T+Vδ1-Vδ2-T cells, and Vδ1+T cell/Vδ2+T cell ratio between the pregnant women with or without COVID-19 vaccination. Similar results were found after comparing non-pregnant and pregnant women who received the COVID-19 vaccine. However, there was a significant difference in the fraction of Vδ1-Vδ2-T cells in CD3+γδ-T+ cells between non-pregnant vaccinated women and vaccinated pregnant women. The frequency of NKG2D+ cells in Vδ2+T cells was not significantly different in the vaccinated pregnant women when compared to that in unvaccinated pregnant women or non-pregnant vaccinated women. But the percentage of NKG2D+ cells in Vδ1+T cells was the lowest in pregnant women after COVID-19 vaccination. Furthermore, down-regulation of NKP46 and NKP30 were found in Vδ2+T and Vδ1+T cells in the vaccinated pregnant women, respectively. After the vaccination, up-regulation of PD-1 expression in Vδ1+T cells and Vδ2+T cells indicated γδ-T cells could respond to COVID-19 vaccination and display an exhausted phenotype following activation. In conclusion, COVID-19 vaccination influences subtypes of γδ-T cells during pregnancy, but the side effects might be limited. The phenotypical changes of Vδ1+T cells and Vδ2+T cells will be a promising predictor for evaluating the clinical outcome of the COVID-19 vaccine.

BackgroundChronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Although the treatment landscape for CLL is rapidly evolving, there are still some patients who develop drug resistance or disease refractory. Ferroptosis is a type of lipid peroxidation–induced cell death and has been suggested to have prognostic value in several cancers. Our research aims to build a prognostic model to improve risk stratification in CLL patients and facilitate more accurate assessment for clinical management.MethodsThe differentially expressed ferroptosis-related genes (FRGs) in CLL were filtered through univariate Cox regression analysis based on public databases. Least absolute shrinkage and selection operator (LASSO) Cox algorithms were performed to construct a prognostic risk model. CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) were performed to estimate the immune infiltration score and immune-related pathways. A total of 36 CLL patients in our center were enrolled in this study as a validation cohort. Moreover, a nomogram model was established to predict the prognosis.ResultsA total of 15 differentially expressed FRGs with prognostic significance were screened out. After minimizing the potential risk of overfitting, we constructed a novel ferroptosis-related prognostic score (FPS) model with nine FRGs (AKR1C3, BECN1, CAV1, CDKN2A, CXCL2, JDP2, SIRT1, SLC1A5, and SP1) and stratified patients into low- and high-risk groups. Kaplan–Meier analysis showed that patients with high FPS had worse overall survival (OS) (P

N6-methyladenosine (m6A) RNA modification is a new epigenetic regulation mechanism on eukaryotic mRNA. Few autoimmune diseases focused on the role of m6A in their pathogenies, and m6A modulation in the pathological process of primary Sjögren’s syndrome (pSS) is still unknown. In this work, three microarray datasets of pSS patients were downloaded from the GEO database: datasets #1 and #2 from the whole peripheral blood (PB) samples, dataset #3 from the labial salivary gland tissue samples, as well as a PB cohort collected from our hospital. Six differentially expressed m6A regulators were identified by comparing the PB dataset #1 of pSS and healthy controls using the Wilcox test and logistic regression analysis. Among them, four (ALKBH5, RBMX, RBM15B, and YTHDF1) were confirmed as down-regulated in PB dataset #2 and in our PB cohort by RT-PCR, and four (ALKBH5, METTL3, RBM15B, and YTHDF1) were confirmed as down-regulated in the dataset #3 of the labial gland tissue. In addition, discrepantly expressed m6A regulators accompanied by diverse immunocytes, including dendritic cells (DCs), T cells, and CD56dim natural killer cells, and among the regulators, ALKBH5 and METTL3 were comprehensively linked with the infiltrated immune cells. Notably, the most enriched autophagy mechanism mediated by m6A was observed in pSS using functional annotation analysis. Ten hub genes were identified using a protein-protein interaction network, and their expression in PB dataset #2 and the expression of three genes (PIK3CA, STAT1, and MAPK3) in the labial gland tissue dataset #3 were confirmed. Our study provides evidence that m6A methylation is widely involved in the immune infiltration and autophagy of pSS, thus contributing to the pathogenesis of this disease and potentially representing a novel therapeutic target.

Cannabis (Cannabis sativa) is a widely used drug in the United States and the frequency of cannabis use is particularly high among people living with HIV (PLWH). One key component of cannabis, the non-psychotropic (−)-cannabidiol (CBD) exerts a wide variety of biological actions, including anticonvulsive, analgesic, and anti-inflammatory effects. However, the exact mechanism of action through which CBD affects the immune cell signaling remains poorly understood. Here we report that CBD modulates type I interferon responses in human macrophages. Transcriptomics analysis shows that CBD treatment significantly attenuates cGAS-STING-mediated activation of type I Interferon response genes (ISGs) in monocytic THP-1 cells. We further showed that CBD treatment effectively attenuates 2’3-cGAMP stimulation of ISGs in both THP-1 cells and primary human macrophages. Interestingly, CBD significantly upregulates expression of autophagy receptor p62/SQSTM1. p62 is critical for autophagy-mediated degradation of stimulated STING. We observed that CBD treated THP-1 cells have elevated autophagy activity. Upon 2’3’-cGAMP stimulation, CBD treated cells have rapid downregulation of phosphorylated-STING, leading to attenuated expression of ISGs. The CBD attenuation of ISGs is reduced in autophagy deficient THP-1 cells, suggesting that the effects of CBD on ISGs is partially mediated by autophagy induction. Lastly, CBD decreases ISGs expression upon HIV infection in THP-1 cells and human primary macrophages, leading to increased HIV RNA expression 24 hours after infection. However, long term culture with CBD in infected primary macrophages reduced HIV viral spread, suggesting potential dichotomous roles of CBD in HIV replication. Our study highlights the immune modulatory effects of CBD and the needs for additional studies on its effect on viral infection and inflammation.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by exocrine gland dysfunction and inflammation. Patients often have dry mouth and dry eye symptoms, which seriously affect their lives. Improving dry mouth and eye symptoms has become a common demand from patients. For this reason, researchers have conducted many studies on external secretory glands. In this paper, we summarize recent studies on the salivary glands of pSS patients from the perspective of the immune microenvironment. These studies showed that hypoxia, senescence, and chronic inflammation are the essential characteristics of the salivary gland immune microenvironment. In the SG of pSS, genes related to lymphocyte chemotaxis, antigen presentation, and lymphocyte activation are upregulated. Interferon (IFN)-related genes, DNA methylation, sRNA downregulation, and mitochondrial-related differentially expressed genes are also involved in forming the immune microenvironment of pSS, while multiple signaling pathways are involved in regulation. We further elucidated the regulation of the salivary gland immune microenvironment in pSS and relevant, targeted treatments.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world with great heterogeneity. Pyroptosis has recently been recognized as an inflammatory form of programmed cell death (PCD) and shares a close relationship with apoptosis. Although the role of apoptosis in CLL was comprehensively studied and successfully applied in clinical treatment, the relationship between pyroptosis genes and CLL remained largely unknown. In this study, eight differentially expressed pyroptosis-related genes (PRGs) were identified between CLL and normal B cells. In order to screen out the prognostic value of differentially expressed PRGs, univariate and multivariate Cox regression analyses were conducted and a risk model with three PRG signatures (GSDME, NLRP3, and PLCG1) was constructed. All CLL samples were stratified into high- and low-risk subgroups according to risk scores. The risk model showed high efficacy in predicting both overall survival (OS) and time to first treatment (TTFT). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) showed the dysregulation of immune and inflammatory response in the high-risk group. Single-sample GSEA (ssGSEA) of immune cell infiltration and the activity of immune-related pathways also displayed decreased antitumor immunity in the high-risk group. In conclusion, PRGs are of prognostic value in CLL and may play important roles in tumor immunity, and the underlying relationship between PRGs and CLL needs to be explored further.

Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells which are abnormally accumulated during the differentiation of myeloid cells. Immunosuppression is the main functional feature of MDSCs, which inhibit T cell activity in the tumor microenvironment (TME) and promote tumoral immune escape. The main principle for immunotherapy is to modulate, restore, and remodel the plasticity and potential of immune system to have an effective anti-tumor response. In the TME, MDSCs are major obstacles to cancer immunotherapy through reducing the anti-tumor efficacy and making tumor cells more resistant to immunotherapy. Therefore, targeting MDSCs treatment becomes the priority of relevant studies and provides new immunotherapeutic strategy for cancer treatment. In this review, we mainly discuss the functions and mechanisms of MDSCs as well as their functional changes in the TME. Further, we review therapeutic effects of immunotherapy against MDSCs and potential breakthroughs regarding immunotherapy targeting MDSCs and immune checkpoint blockade (ICB) immunotherapy.

Dendritic cells (DCs) are professional antigen-presenting cells that can recognize, capture, and process antigens. Fusing molecules targeting DCs with antigens can effectively improve the efficiency with which antigens are recognized and captured by DCs. This targeting strategy can be used for vaccine development to effectively improve the efficiency of antigen recognition and capture by DCs. The targeting sequence of porcine cytotoxic T-lymphocyte associated protein 4 (CTLA4), which binds porcine DCs, was identified in this study. Recombinant Lactobacillus reuteri (L. reuteri) expressing CTLA4-6aa (LYPPPY) and CTLA4-87aa fused to the porcine epidemic diarrhea virus (PEDV) protective antigen core neutralizing epitope (COE) were used to evaluate the ability of the two targeting motifs to bind the B7 molecule on DCs. Our results demonstrate that CTLA4-6aa could bind porcine DCs, and recombinant Lactobacillus expressing the CTLA4-6aa captured by porcine DCs was more efficient than those expressing CTLA4-87aa. In addition, the expression of DC markers, toll-like receptors, and cytokines was significantly higher in the 6aa-COE/L. reuteri-stimulated porcine DCs compared to DCs treated with 87aa-COE/L. reuteri (p

BackgroundPyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas.MethodsThe TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated.ResultsPatients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P

Dendritic cells (DCs) play a key role in the natural recognition of pathogens and subsequent activation of adaptive immune responses due to their potent antigen-presenting ability. Dendritic cell-targeting peptide (DCpep) is strongly targeted to DCs, which often express antigens, to enhance the efficacy of vaccines. Our previous study showed that recombinant Lactobacillus expressing human DCpep could significantly induce stronger immune responses than recombinant Lactobacillus without DCpep, but the mechanism remains unclear. In this study, the mechanism by which DCpep enhances the immune response against recombinant Lactobacillus was explored. Fluorescence-labeled human DCpep was synthesized to evaluate the binding ability of human DCpep to porcine monocyte-derived dendritic cells (Mo-DCs) and DCs of the small intestine. The effects of Mo-DC function induced by recombinant Lactobacillus expressing human DCpep fused with the porcine epidemic diarrhea virus (PEDV) core neutralizing epitope (COE) antigen were also investigated. The results showed that human DCpep bind to porcine DCs, but not to porcine small intestinal epithelial cells. Human DCpep can also improve the capture efficiency of recombinant Lactobacillus by Mo-DCs, promote the maturation of dendritic cells, secrete more cytokines, and enhance the ability of porcine DCs to activate T-cell proliferation. Taken together, these results promote advanced understanding of the mechanism by which DCpep enhances immune responses. We found that some DCpeps are conserved between humans and pigs, which provides a theoretical basis for the development of a DC-targeted vaccine.

Limited data are available about the underlying causes of hemophagocytic lymphohistiocytosis (HLH) in adults. We collected and analyzed the data of 555 cases of adult HLH. HLH in 242 patients were malignancies-related and lymphoid malignancies (42.0%, 233/555) were the most common causes. Aggressive natural killer-cell leukemia, diffuse large B-cell lymphoma, and extranodal natural killer/T-cell lymphoma, nasal type were the most common specified pathological subtypes. Epstein-Barr virus (EBV) (69.0%, 100/145) was the most common pathogen among the cases of infections-related HLH (26.1%, 145/555). Malignancies-related HLH showed male preponderance, more common splenomegaly, more severe anemia and thrombocytopenia, and significantly elevated soluble CD25. In patients with abnormal lymphoid cells in the bone marrow (BM) and increased EBV DNA copy number, 48.9% (45/92) of them were aggressive natural killer-cell leukemia. In patients with abnormal lymphoid cells in the BM and normal EBV DNA copy number, 66.2% (47/71) of them were B-cell non-Hodgkin lymphoma. In patients with elevated EBV DNA copy number but no abnormal lymphoid cells in the BM, 71.0% (98/138) of these cases were EBV infection. In conclusion, lymphoid malignancy is the most common underlying cause of adult HLH, followed by EBV infection. Based on the BM morphology and EBV load, we developed a diagnostic flow for rapid determination of the triggers for HLH.

Lung adenocarcinoma featured as mixed ground-glass opacity (mGGO) doubled its volume half of the time in comparison with that featured as pure ground-glass opacity (pGGO). The mechanisms underlying the heterogeneous appearance of mGGO remain elusive. In this study, we macro-dissected the solid (S) components and ground-glass (GG) components of mGGO and performed single-cell sequencing analyses of six paired components from three mGGO patients. A total of 19,391 single-cell profiles were taken into analysis, and the data of each patient were analyzed independently to obtain a common alteration. Cancer cells and macrophages were the dominant cell types in the S and GG components, respectively. Cancer cells in the S components, which showed relatively malignant phenotypes, were likely to originate from both the GG and S components and monitor the surrounding tumor microenvironment (TME) through an intricate cell interaction network. SPP1hi macrophages were enriched in the S components and showed increased activity of chemoattraction, while macrophages in the GG components displayed an active antimicrobial process with a higher stress-induced state. In addition, the CD47–SIRPA axis was demonstrated to be critical in the maintenance of the GG components. Taken together, our study unraveled the alterations of cell components and transcriptomic features between different components in mGGOs.

Intestinal epithelial barrier injury disrupts immune homeostasis and leads to many intestinal disorders. Lactobacillus reuteri (L. reuteri) strains can influence immune system development and intestinal function. However, the underlying mechanisms of L. reuteri LR1 that regulate inflammatory response and intestinal integrity are still unknown. The present study aimed to determine the effects of LR1 on the ETEC K88-induced intestinal epithelial injury on the inflammatory response, intestinal epithelial barrier function, and the MLCK signal pathway and its underlying mechanism. Here, we showed that the 1 × 109 cfu/ml LR1 treatment for 4 h dramatically decreased interleukin-8 (IL-8) and IL-6 expression. Then, the data indicated that the 1 × 108 cfu/ml ETEC K88 treatment for 4 h dramatically enhanced IL-8, IL-6, and tumor necrosis factor-α (TNF-α) expression. Furthermore, scanning electron microscope (SEM) data indicated that pretreatment with LR1 inhibited the ETEC K88 that adhered on IPEC-J2 and alleviated the scratch injury of IPEC J2 cells. Moreover, LR1 pretreatment significantly reversed the declined transepithelial electrical resistance (TER) and tight junction protein level, and enhanced the induction by ETEC K88 treatment. Additionally, LR1 pretreatment dramatically declined IL-8, IL-17A, IL-6, and TNF-α levels compared with the ETEC K88 group. Then, ETEC K88-treated IPEC-J2 cells had a higher level of myosin light-chain kinase (MLCK), higher MLC levels, and a lower Rho-associated kinase (ROCK) level than the control group, while LR1 pretreatment significantly declined the MLCK and MLC expression and enhanced ROCK level in the ETEC K88-challenged IPEC-J2 cells. Mechanistically, depletion of MLCK significantly declined MLC expression in IPEC-J2 challenged with ETEC K88 compared to the si NC+ETEC K88 group. On the other hand, the TER of the si MLCK+ETEC K88 group was higher and the FD4 flux in the si MLCK+ETEC K88 group was lower compared with the si NC+ETEC K88 group. In addition, depletion of MLCK significantly enhanced Claudin-1 level and declined IL-8 and TNF-α levels in IPEC-J2 pretreated with LR1 followed by challenging with ETEC K88. In conclusion, our work indicated that L. reuteri LR1 can decline inflammatory response and improve intestinal epithelial barrier function through suppressing the MLCK signal pathway in the ETEC K88-challenged IPEC-J2.

Gut microbiota is a microecosystem composed of various microorganisms. It plays an important role in human metabolism, and its metabolites affect different tissues and organs. Intestinal flora maintains the intestinal mucosal barrier and interacts with the immune system. The liver is closely linked to the intestine by the gut-liver axis. As the first organ that comes into contact with blood from the intestine, the liver will be deeply influenced by the gut microbiota and its metabolites, and the intestinal leakage and the imbalance of the flora are the trigger of the pathological reaction of the liver. In this paper, we discuss the role of gut microbiota and its metabolites in the pathogenesis and development of autoimmune liver diseases((including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), metabolic liver disease such as non-alcoholic fatty liver disease, cirrhosisits and its complications, and liver cancer from the perspective of immune mechanism. And the recent progress in the treatment of these diseases was reviewed from the perspective of gut microbiota.

Human leukocyte antigen G (HLA-G) is a potential checkpoint molecule that plays a key role in cervical carcinogenesis. The purpose of this study was to construct and validate a prognostic risk model to predict the overall survival (OS) of cervical cancer patients, providing a reference for individualized clinical treatment that may lead to better clinical outcomes. HLA-G-driven differentially expressed genes (DEGs) were obtained from two cervical carcinoma cell lines, namely, SiHa and HeLa, with stable overexpression of HLA-G by RNA sequencing (RNA-seq). The biological functions of these HLA-G-driven DEGs were analysed by GO enrichment and KEGG pathway using the “clusterProfiler” package. The protein-protein interactions (PPIs) were assessed using the STRING database. The prognostic relevance of each DEG was evaluated by univariate Cox regression using the TCGA-CESC dataset. After the TCGA-CESC cohort was randomly divided into training set and testing set, and a prognostic risk model was constructed by LASSO and stepwise multivariate Cox regression analysis in training set and validated in testing set or in different types of cervical cancer set. The predictive ability of the prognostic risk model or nomogram was evaluated by a series of bioinformatics methods. A total of 1108 candidate HLA-G-driven DEGs, including 391 upregulated and 717 downregulated genes, were obtained and were enriched mostly in the ErbB pathway, steroid biosynthesis, and MAPK pathway. Then, an HLA-G-driven DEG signature consisting of the eight most important prognostic genes CD46, LGALS9, PGM1, SPRY4, CACNB3, PLIN2, MSMO1, and DAGLB was identified as a key predictor of cervical cancer. Multivariate Cox regression analysis showed that this signature is an independent risk factor for the overall survival of CESC patients. Kaplan-Meier survival analysis showed that the 5-year overall survival rate is 23.0% and 84.6% for the high-risk and low-risk patients, respectively (P

ObjectivesThe aim of this study is to investigate the clinical significance of myeloperoxidase (MPO)–antineutrophil cytoplasmic antibody (ANCA) on eosinophilic granulomatosis with polyangiitis (EGPA) from a longitudinal Chinese cohort.MethodsA total of 120 patients with EGPA were consecutively enrolled and followed up. Two patients with PR3 ANCA was excluded and our analysis focused on the 118 patients with EGPA. On the basis of MPO-ANCA status, baseline clinical manifestations, treatment, and outcomes were analyzed. Logistic regression analysis was performed to analyze the independently associated factors for renal involvement.ResultsANCA positivity was observed in 24.2% of patients with EGPA. Patients with MPO-ANCA accounted for 20.8%. Patients with positive MPO-ANCA had higher levels of erythrocyte sedimentation rate (ESR), C-reactive protein, Birmingham Vasculitis Activity Score (BVAS), higher ratios of fever, myalgia, renal involvement, and biopsy-proven vasculitis. Heart manifestations and asthma were more common in patients with negative ANCA. Baseline MPO-ANCA titers positively correlated with ESR, eosinophil count, and BVAS and were higher in patients with methylprednisolone pulse. Among patients with renal involvement, patients with positive MPO-ANCA had higher proportions of female, fever, biopsy-proven vasculitis, and faster ESR; patients with negative ANCA developed more skin and cardiac involvement. MPO-ANCA positivity, male, and ear involvement were the independent factors associated with renal involvement. Intravenous cyclophosphamide and immunoglobulins were prescribed more frequently in patients with positive MPO-ANCA.ConclusionIn this cohort, patients with positive MPO-ANCA and negative ANCA displayed distinct clinical features, suggesting that MPO-ANCA might be a valuable biomarker for EGPA stratification. Baseline MPO-ANCA level correlated positively with disease activity of EGPA. MPO-ANCA was a significant independent factor associated with renal involvement.