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Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disorder affecting 6-20% of women of childbearing age worldwide. Immune cell imbalance and dysregulation of inflammatory factors can lead to systematic low-grade chronic inflammation (SLCI), which plays a pivotal role in the pathogenesis of PCOS. A significant higher infiltration of immune cells such as macrophages and lymphocytes and pro-inflammatory factors IL-6 and TNF-α has been detected in PCOS organ systems, impacting not only the female reproductive system but also other organs such as the cardiovascular, intestine, liver, thyroid, brain and other organs. Obesity, insulin resistance (IR), steroid hormones imbalance and intestinal microecological imbalance, deficiencies in vitamin D and selenium, as well as hyperhomocysteinemia (HHcy) can induce systematic imbalance between pro-inflammatory and anti-inflammatory cells and molecules. The pro-inflammatory cells and cytokines also interact with obesity, steroid hormones imbalance and IR, leading to increased metabolic imbalance and reproductive-endocrine dysfunction in PCOS patients. This review aims to summarize the dysregulation of immune response in PCOS organ system and the intrinsic mechanisms affecting SLCI in PCOS to provide new insights for the systemic inflammatory treatment of PCOS in the future.

BackgroundThe treatment of vitiligo is complex, and providing guidance based on lifestyle habits is a good option that has not been summarized or analyzed.ObjectiveTo elucidate the relationship between vitiligo and lifestyle factors.MethodsFour databases (PubMed, Embase, Cochrane, and China National Knowledge Internet) were searched for articles published between 1980 and December 2022. Keywords such as smoking, drinking, exercise, diet, and sleep were used.ResultsBased on the search strategy, 875 relevant studies were retrieved, and 73 were included in this study, of which 41 studies with 8,542 patients with vitiligo were included in the meta-analysis. Vitamin C [mean difference (MD), −0.342; 95% confidence interval (CI), −1.090–0.407; p >0.05), folic acid (MD, −1.463; 95% CI, −7.133–4.208; p >0.05), and selenium (MD, 0.350; 95% CI, −0.687–1.387; p >0.05) levels did not differ between the groups. Vitamin E (MD, −1.408; 95% CI, −2.611–−0.206; p

IntroductionNadofaragene firadenovec (Ad-IFNα/Syn3) is now approved for BCG-unresponsive bladder cancer (BLCA). IFNα is a pleiotropic cytokine that causes direct tumor cell killing via TRAIL-mediated apoptosis, angiogenesis inhibition, and activation of the innate and adaptive immune system. We established an immunocompetent murine BLCA model to study the effects of murine adenoviral IFNα (muAd-Ifnα) gene therapy on cancer cells and the tumor microenvironment using a novel murine equivalent of Nadofaragene firadenovec (muAd-Ifnα).MethodsTumors were induced by instilling MB49 cells into the bladders of mice; luciferase imaging confirmed tumor development. Mice were treated with adenovirus control (Ad-Ctrl; empty vector), or muAd-Ifnα (3x1011 VP/mL), and survival analysis was performed. For single-cell sequencing (scRNAseq) analysis (72h), bladders were harvested and treated with collagenase/hyaluronidase and TrypLE for cell dissociation. Single cells were suspended in PBS/1% FBS buffer; viability was assessed with Vicell cell counter. scRNAseq analysis was performed using 10X genomics 3’ sequencing. Raw RNAseq data were pre-processed using Cell Ranger single-cell software. Seurat (R package) was used to normalize and cluster the scRNA data. Pooled differential gene expression analysis in specific cell clusters was performed with DESeq2.ResultsWe identified 16 cell clusters based on marker expression which were grouped into epithelial (tumor), uroplakin-enriched, endothelial, T-cells, neutrophils, and macrophage clusters. Top differentially expressed genes between muAd-Ifnα and Ad-Ctrl were identified. Within the specific cell clusters, IPA analysis revealed significant differences between muAd-Ifnα and control. IFNα signaling and hypercytokinemia/chemokinemia were upregulated in all clusters. Cell death pathways were upregulated in tumor and endothelial clusters. T-cells demonstrated upregulation of the immunogenic cell death signaling pathway and a decrease in the Th2 pathway genes. Macrophages showed upregulation of PD1/PD-L1 pathways along with downregulation of macrophage activation pathways (alternate and classical). Multiplex immunofluorescence confirmed increased infiltration with macrophages in muAd-Ifnα treated tumors compared to controls. PD1/PD-L1 expression was reduced at 72h.DiscussionThis single-cell analysis builds upon our understanding of the impact of Ad-IFNα on tumor cells and other compartments of the microenvironment. These data will help identify mechanisms to improve patient selection and therapeutic efficacy of Nadofaragene firadenovec.

BackgroundInflammatory scores are known to reflect the systemic inflammatory burden. Despite this, the association between the inflammatory score and the risk of all-cause and cardiovascular mortality in patients with metabolic syndrome (MetS) remains poorly understood. To address this gap in the literature, this study investigated this potential association between these two factors.MethodsA total of 3401 patients with MetS from the National Health and Nutrition Examination Survey (1999–2010) were enrolled. Survival status and cause of death were obtained by linking data from the National Death Index (NDI). The inflammatory score was calculated based on the sum of the Z-scores for white blood cell (WBC) count and C-reactive protein (CRP) at baseline. The patients were divided into inflammatory score quartiles. Cox proportional hazards regression was used to determine the association between inflammatory score and mortality. Restricted cubic splines (RCS) were used to explore the dose-response relationship between inflammatory score and mortality. Stratified analyses and interaction tests were conducted according to sex, age, body mass index (BMI), alcohol consumption, smoking status, hypertension, diabetes, and stroke status.ResultsAfter a mean follow-up of 145.9 months, 1039 all-cause deaths and 295 cardiovascular deaths were recorded. The results of multivariate Cox regression analysis showed that compared to the lowest quartile (Q1), patients in the highest quartile (Q4) had a 1.74-fold increased risk of all-cause mortality (Model 3: HR = 1.74, 95%CI 1.30–2.32, P < 0.001) and a 1.87-fold increased risk of cardiovascular mortality (Model 3: HR = 1.87, 95%CI 1.12–3.13, P = 0.020). There was a ‘J’-shaped nonlinear relationship between the inflammatory score and all-cause mortality (P for nonlinearity = 0.001), and a marginally significant ‘J’-shaped relationship with cardiovascular mortality (P for nonlinearity = 0.057). The threshold points of the inflammatory score for adverse outcomes were - 0.643 and - 0.621, respectively.ConclusionThe inflammatory score is independently associated with increased all-cause and cardiovascular mortality in patients with MetS, and risk stratification of these patients using inflammatory scores may provide specific therapeutic strategies to improve their prognosis.

IntroductionIn light of the public health burden of the COVID-19 pandemic, boosting the safety and immunogenicity of COVID-19 vaccines is of great concern. Numerous Traditional Chinese medicine (TCM) preparations have shown to beneficially modulate immunity. Based on pilot experiments in mice that showed that supplementation with Huoxiang Suling Shuanghua Decoction (HSSD) significantly enhances serum anti-RBD IgG titers after inoculation with recombinant SARS-CoV-2 S-RBD protein, we conducted this randomized, double-blind, placebo-controlled clinical trial aimed to evaluate the potential immunogenicity boosting effect of oral HSSD after a third homologous immunization with Sinovac’s CoronaVac SARS-CoV-2 (CVS) inactivated vaccine.MethodsA total of 70 participants were randomly assigned (1:1 ratio) to receive a third dose of CVS vaccination and either oral placebo or oral HSSD for 7 days. Safety aspects were assessed by recording local and systemic adverse events, and by blood and urine biochemistry and liver and kidney function tests. Main outcomes evaluated included serum anti-RBD IgG titer, T lymphocyte subsets, serum IgG and IgM levels, complement components (C3 and C4), and serum cytokines (IL-6 and IFN-γ). In addition, metabolomics technology was used to analyze differential metabolite expression after supplementation with HSSD.ResultsFollowing a third CVS vaccination, significantly increased serum anti-RBD IgG titer, reduced serum IL-6 levels, increased serum IgG, IgM, and C3 and C4 levels, and improved cellular immunity, evidenced by reduce balance deviations in the distribution of lymphocyte subsets, was observed in the HSSD group compared with the placebo group. No serious adverse events were recorded in either group. Serum metabolomics results suggested that the mechanisms by which HSSD boosted the immunogenicity of the CVS vaccine are related to differential regulation of purine metabolism, vitamin B6 metabolism, folate biosynthesis, arginine and proline metabolism, and steroid hormone biosynthesis.ConclusionOral HSSD boosts the immunogenicity of the CVS vaccine in young and adult individuals. This trial provides clinical reference for evaluation of TCM immunomodulators to improve the immune response to COVID-19 vaccines.

ObjectiveThe aim of this study was to investigate the clinical traits and consequences of systemic lupus erythematosus (SLE) complicated by active cytomegalovirus (CMV) infection.MethodsThis retrospective review involved the examination of medical records for patients diagnosed with SLE who had an active CMV infection at the time of their discharge from Peking Union Medical College Hospital between June 2016 and December 2022. The consistency between plasma CMV deoxyribonucleic acid (DNA) viral load and pp65 antigenemia was analyzed using the chi-square test. Related factors for CMV disease in SLE complicated by active CMV infection patients were analyzed by univariate analysis and multivariable stepwise logistic regression. Cox hazards regression analysis was used to determine predictors for all-cause mortality and CMV recurrence within 3 months.ResultsA total of 206 patients were enrolled in this study. Of the 123 patients who were detected with both plasma CMV DNA viral load and pp65 antigenemia within an interval not exceeding 72 h, the consistency between plasma CMV DNA viral load and pp65 antigenemia was not good (Kappa = −0.304, p < 0.001). Plasma CMV DNA viral load ≥ 1,600 copies/mL [odds ratio (OR) 4.411, 95% CI 1.871–10.402, p = 0.001], current glucocorticoids dose (equivalent to prednisolone) ≥60 mg/d (OR 2.155, 95% CI 1.071–4.334, p = 0.031), and elevated alanine transaminase (OR 3.409, 95% CI 1.563–7.435, p = 0.002) were significant clinical clues indicating CMV disease in SLE. Multivariable Cox hazards regression analysis showed that CMV organ involvement [hazard ratio (HR) 47.222, 95% CI 5.621–396.689, p < 0.001], SLE multi-system involvement (HR 1.794, 95% CI 1.029–3.128, p = 0.039), and elevated hypersensitive C-reactive protein (hsCRP) (HR 5.767, 95% CI 1.190–27.943, p = 0.030) were independent risk factors for 3-month all-cause mortality. CMV organ involvement (HR 3.404, 95% CI 1.074–10.793, p = 0.037) was an independent risk factor for CMV recurrence within 3 months.ConclusionIn SLE patients, plasma CMV DNA viral load seemed to have a higher value in the diagnosis of CMV disease; patients with CMV organ involvement, SLE multi-system involvement, and elevated hsCRP might have a higher risk of 3-month all-cause mortality; and patients with CMV organ involvement might have a higher risk of CMV recurrence within 3 months.

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases with complex pathogenesis involving epidermal barrier dysfunction, skin microbiome abnormalities and type-2-skewed immune dysregulation. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays critical roles in various biological processes. However, the role of STAT3 in epidermal keratinocytes in AD remains unclear. In this study, we generated an epidermal keratinocyte-specific Stat3-deficient mouse strain (termed Stat3 cKO mice). After topical 2,4-dinitrochlorobenzene (DNCB) treatment, Stat3 cKO mice developed worsened AD-like skin inflammation with increased Ki67+ cells, decreased filaggrin and loricrin expression, and downregulated S100A9 and LL37. The dominant microbial population in Stat3 cKO mice changed from Ralstonia to Staphylococcus. DNCB-treated Stat3 cKO mice displayed more infiltrating type-2 inflammatory cells, including mast cells, eosinophils, and CD4+T cells, accompanied by increased skin IL-4 and serum IgE levels. Moreover, thymic stromal lymphopoietin (TSLP), mainly produced by keratinocytes, was highly expressed in the ear skin of Stat3 cKO mice and chemoattracted more TSLPR+ cells. TSLP blockade significantly alleviated DNCB-induced AD-like skin inflammation in Stat3 cKO mice. Thus, epidermal keratinocyte-specific STAT3 deficiency can aggravate AD-like skin inflammation in mice, possibly through TSLP dysregulation.

ObjectivesThe treatment of locally advanced oral or oropharyngeal squamous cell carcinoma (LAOOPSCC) is surgery and radiotherapy or chemoradiotherapy but with unsatisfactory survival rate. Neoadjuvant programmed death-1 (PD-1) therapy are being used in several clinical trials. Therefore, in this retrospective study we aimed to determine the feasibility of neoadjuvant tislelizumab plus chemotherapy followed by surgery for LAOOPSCC.Materials and methodsThe clinical data of 33 patients with LAOOPSCC who received neoadjuvant PD-1 inhibitors and chemotherapy between April 2021 and October 2022 were retrospectively analyzed. Patients with stage III-IV LAOOPSCC received tislelizumab, albumin-bound paclitaxel, and cisplatin every 3 weeks (Q3W) for two cycles, followed by surgery and adjuvant radiotherapy or concurrent chemoradiotherapy. A median follow-up period was 20 months.ResultsThe objective response rate (ORR) was 66.7%, with the major pathological response (MPR) rate at 54.5%, and the pathological complete response (pCR) rate was 33.3%. Sixteen patients underwent limited surgeries, and 15 patients were remitted from undergoing mandibulectomy and 9 patients were remitted from undergoing near total glossectomy or total glossectomy. A significant difference in the overall survival (OS) and disease-free survival (DFS) was observed in patients who achieved major pathological response (MPR) than who did not. The most common adverse events in neoadjuvant therapy were alopecia, decreased appetite or anorexia, leukopenia, and fatigue.ConclusionNeoadjuvant PD-1 inhibitors combined with chemotherapy are feasible and safe, with a high pathological response and possible organ preservation in oral or oropharyngeal squamous cell carcinoma. However, further studies with a larger cohort of patients and longer follow-up period is required to strengthen our findings and evaluate the survival benefits of the treatment.

IntroductionPeople living with HIV (PLWH) are at a higher risk of severe disease with SARS-CoV-2 virus infection. COVID-19 vaccines are effective in most PLWH. However, suboptimal immune responses to the standard two-shot regimen are a concern, especially for those with moderate to severe immunodeficiency. An additional dose is recommended as part of the extended primary series in Taiwan. Herein, we study the efficacy of this additional shot in PLWH with mild immunodeficiency compared to that in healthy non-HIV people.MethodsIn total, 72 PLWH that were asymptomatic or with mild immunodeficiency (CD4 counts ≥200/mm3) and suppressed virology, and 362 healthcare workers of our hospital were enrolled. None of the participants had a history of SARS-CoV-2 infection. They received mRNA-1273 and ChAdOx1 vaccines. Anti-SARS-CoV-2 neutralizing and anti-Spike IgG antibodies, and SARS-CoV-2-specific T cell responses were evaluated.ResultsThe standard two-shot regimen elicited lower responses in PLWH than the healthcare workers without HIV infection, although the difference was statistically insignificant. They had comparable levels of neutralizing and anti-Spike antibodies and comparable effector CD4+ and CD8+ T cell responses. The third shot boosted the SARS-CoV-2 immunity significantly more with better antibody responses and higher IFN-γ and IL-2 responses of the CD4+ and CD8+ T cells in PLWH compared to those without HIV. Upon in vitro stimulation with extracted Wuhan strain SARS-CoV-2 proteins, CD8+ T cells from PLWH after 3 shots had more durable effector responses than the non-HIV controls with extended time of stimulation.ConclusionThis subtle difference between PLWH and non-HIV people implied immune exhaustion with two shots in non-HIV people. Slightly compromised immunity in PLWH indeed preserved the functional capacity for further response to the third shot or natural infection.

BackgroundImmunoglobulin A nephropathy (IgAN) is one of the leading causes of end-stage kidney disease (ESKD). Many studies have shown the significance of pathological manifestations in predicting the outcome of patients with IgAN, especially T-score of Oxford classification. Evaluating prognosis may be hampered in patients without renal biopsy.MethodsA baseline dataset of 690 patients with IgAN and an independent follow-up dataset of 1,168 patients were used as training and testing sets to develop the pathology T-score prediction (Tpre) model based on the stacking algorithm, respectively. The 5-year ESKD prediction models using clinical variables (base model), clinical variables and real pathological T-score (base model plus Tbio), and clinical variables and Tpre (base model plus Tpre) were developed separately in 1,168 patients with regular follow-up to evaluate whether Tpre could assist in predicting ESKD. In addition, an external validation set consisting of 355 patients was used to evaluate the performance of the 5-year ESKD prediction model using Tpre.ResultsThe features selected by AUCRF for the Tpre model included age, systolic arterial pressure, diastolic arterial pressure, proteinuria, eGFR, serum IgA, and uric acid. The AUC of the Tpre was 0.82 (95% CI: 0.80–0.85) in an independent testing set. For the 5-year ESKD prediction model, the AUC of the base model was 0.86 (95% CI: 0.75–0.97). When the Tbio was added to the base model, there was an increase in AUC [from 0.86 (95% CI: 0.75–0.97) to 0.92 (95% CI: 0.85–0.98); P = 0.03]. There was no difference in AUC between the base model plus Tpre and the base model plus Tbio [0.90 (95% CI: 0.82–0.99) vs. 0.92 (95% CI: 0.85–0.98), P = 0.52]. The AUC of the 5-year ESKD prediction model using Tpre was 0.93 (95% CI: 0.87–0.99) in the external validation set.ConclusionA pathology T-score prediction (Tpre) model using routine clinical characteristics was constructed, which could predict the pathological severity and assist clinicians to predict the prognosis of IgAN patients lacking kidney pathology scores.

IntroductionArtemisinin (ART) is very common as a diet additive due to its immunoregulatory activities. Nonetheless, the immunoregulatory mechanism of ART in marine fish remains unknown. This study comprehensively examined the effects and explored the potential mechanism of ART ameliorating intestinal immune disease (IID) in fat greenlings (Hexagrammos otakii).Methods and resultsThe targets of ART were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Here, eight putative targets of ART were collected and identified with the Uniprot database, and 1419 IID-associated target proteins were filtered through the Drugbank, Genecards, OMIM, and PHARMGKB Databases. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways point out that ART may have immunoprotective effects by regulating cellular responses to stress, hypoxia, inflammation, and vascular endothelial growth factor stimulus through the hypoxia-inducible factor 1 (HIF-1) signaling pathway. The findings of molecular docking indicated that ART contains one active ingredient and three cross-targets, which showed a kind combination with hypoxia-inducible factor 1-alpha (HIF1-a), transcription factor p65 (RELA), and vascular endothelial growth factor A (VEGF-A), respectively. Furthermore, an ART feeding model was established to assess the ART’s immunoprotect effect on the intestine of H.otakii in vivo. The D48 group showed smaller intestinal structural changes after being challenged by Edwardsiella tarda. The supplementation of ART to the diet improved total superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and reduced the malondialdehyde (MDA) in intestine of H. otakii. The expression of transcription factor p65, HIF1-α, VEGF-A, cyclin D1, matrix metalloprotease 9 (MMP9), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) was decreased after dietary ART in the intestinal of H. otakii.DiscussionThe present results demonstrated that dietary ART improved antioxidants and immunity, optimized the intestinal structure, and increased resistance to E. tarda through the SOD2/nuclear-factor-kappa- B (NFkB)/HIF1-a/VEGF-A pathway in the intestinal tract of H.otakii. This study integrated pharmacological analysis and experimental validation and revealed the mechanism of ART on IID, which provides insight into the improvement of IID in H. otakii.

Influenza A virus infection (IAV) often leads to acute lung injury that impairs breathing and can lead to death, with disproportionate mortality in children and the elderly. Surfactant Protein A (SP-A) is a calcium-dependent opsonin that binds a variety of pathogens to help control pulmonary infections by alveolar macrophages. Alveolar macrophages play critical roles in host resistance and susceptibility to IAV infection. The effect of SP-A on IAV infection and antiviral response of macrophages, however, is not understood. Here, we report that SP-A attenuates IAV infection in a dose-dependent manner at the level of endosomal trafficking, resulting in infection delay in a model macrophage cell line. The ability of SP-A to suppress infection was independent of its glycosylation status. Binding of SP-A to hemagglutinin did not rely on the glycosylation status or sugar binding properties of either protein. Incubation of either macrophages or IAV with SP-A slowed endocytic uptake rate of IAV. SP-A interfered with binding to cell membrane and endosomal exit of the viral genome as indicated by experiments using isolated cell membranes, an antibody recognizing a pH-sensitive conformational epitope on hemagglutinin, and microscopy. Lack of SP-A in mice enhanced IFNβ expression, viral clearance and reduced mortality from IAV infection. These findings support the idea that IAV is an opportunistic pathogen that co-opts SP-A to evade host defense by alveolar macrophages. Our study highlights novel aspects of host-pathogen interactions that may lead to better understanding of the local mechanisms that shape activation of antiviral and inflammatory responses to viral infection in the lung.

IntroductionFemale breast cancer is the most common malignancy worldwide, with a high disease burden. The degradome is the most abundant class of cellular enzymes that play an essential role in regulating cellular activity. Dysregulation of the degradome may disrupt cellular homeostasis and trigger carcinogenesis. Thus we attempted to understand the prognostic role of degradome in breast cancer by means of establishing a prognostic signature based on degradome-related genes (DRGs) and assessed its clinical utility in multiple dimensions.MethodsA total of 625 DRGs were obtained for analysis. Transcriptome data and clinical information of patients with breast cancer from TCGA-BRCA, METABRIC and GSE96058 were collected. NetworkAnalyst and cBioPortal were also utilized for analysis. LASSO regression analysis was employed to construct the degradome signature. Investigations of the degradome signature concerning clinical association, functional characterization, mutation landscape, immune infiltration, immune checkpoint expression and drug priority were orchestrated. Cell phenotype assays including colony formation, CCK8, transwell and wound healing were conducted in MCF-7 and MDA-MB-435S breast cancer cell lines, respectively.ResultsA 10-gene signature was developed and verified as an independent prognostic predictor combined with other clinicopathological parameters in breast cancer. The prognostic nomogram based on risk score (calculated based on the degradome signature) showed favourable capability in survival prediction and advantage in clinical benefit. High risk scores were associated with a higher degree of clinicopathological events (T4 stage and HER2-positive) and mutation frequency. Regulation of toll-like receptors and several cell cycle promoting activities were upregulated in the high-risk group. PIK3CA and TP53 mutations were dominant in the low- and high-risk groups, respectively. A significantly positive correlation was observed between the risk score and tumor mutation burden. The infiltration levels of immune cells and the expressions of immune checkpoints were significantly influenced by the risk score. Additionally, the degradome signature adequately predicted the survival of patients undergoing endocrinotherapy or radiotherapy. Patients in the low-risk group may achieve complete response after the first round of chemotherapy with cyclophosphamide and docetaxel, whereas patients in the high-risk group may benefit from 5-flfluorouracil. Several regulators of the PI3K/AKT/mTOR signaling pathway and the CDK family/PARP family were identified as potential molecular targets in the low- and high-risk groups, respectively. In vitro experiments further revealed that the knockdown of ABHD12 and USP41 significantly inhibit the proliferation, invasion and migration of breast cancer cells.ConclusionMultidimensional evaluation verified the clinical utility of the degradome signature in predicting prognosis, risk stratification and guiding treatment for patients with breast cancer.

Radiotherapy is the major treatment of non-small cell lung cancer (NSCLC). The radioresistance and toxicity are the main obstacles that leading to therapeutic failure and poor prognosis. Oncogenic mutation, cancer stem cells (CSCs), tumor hypoxia, DNA damage repair, epithelial-mesenchymal transition (EMT), and tumor microenvironment (TME) may dominate the occurrence of radioresistance at different stages of radiotherapy. Chemotherapy drugs, targeted drugs, and immune checkpoint inhibitors are combined with radiotherapy to treat NSCLC to improve the efficacy. This article reviews the potential mechanism of radioresistance in NSCLC, and discusses the current drug research to overcome radioresistance and the advantages of Traditional Chinese medicine (TCM) in improving the efficacy and reducing the toxicity of radiotherapy.

Spontaneous remission (SR) of local recurrence after adjuvant immunotherapy has rarely been reported, and the underlying mechanism is poorly understood. Herein, we reported a patient with stage cT2aN2M0 squamous cell lung carcinoma who received neoadjuvant and adjuvant treatment with nivolumab plus chemotherapy. The patient experienced a late relapse in the subcarinal lymph node seven months after the last dosage of treatment but achieved SR in the next three months without additional antitumor therapy. The complete response lasted for eleven months and counting. Notably, high copies of pathogenic microorganisms were detected in the patient’s bronchoalveolar lavage fluid along with the recurrence but disappeared after SR. The patient also experienced a lymph node puncture-induced fever but had no other symptoms. A longitudinal analysis of infiltrated immune cells in the recurrent lymph node was performed by multiplex immunofluorescence and whole transcriptome sequencing, which revealed that CD8+ T cells were recruited during the initial relapse, specifically in the stromal area, then migrated into the tumor tissue, and continued to increase after elimination of tumor cells. Meanwhile, the initial recruitment of CD8+ T cells was coupled with a higher proportion of B cells, and the abundant neutrophil population was synchronous with the infiltration of CD8+ T cells into tumor cells. This is the first report on an Non-small cell lung cancer (NSCLC) patient with a late relapse after adjuvant immune checkpoint inhibitor (ICI) therapy who achieved SR. Our case highlights the complexity and plasticity of antitumor immunity and is expected to help find efficient strategies against the resistance of ICI treatment.

BackgroundTo understand the awareness of COVID-19 vaccine, the willingness to vaccinate and the influencing factors of willingness to vaccinate in inflammatory bowel disease (IBD) patients.MethodsThe online questionnaire was distributed to conduct a survey to analyze and evaluate the willingness, awareness and trust in vaccines of IBD patients. Bivariate analyses and logistic regression models were used to analysis influencing factors.ResultsWe sent the questionnaire to the WeChat group for patient management and 304 patients responded, out of which 16 respondents had to be excluded and 288 respondents were included for the analysis. Among them, 209 patients vaccinated with COVID-19 vaccine. Among the non-vaccinated 79 patients, the main reasons for their concerns were afraid of vaccination aggravating IBD and fear of adverse effects. Our results showed that IBD patients with long disease duration were more willing to receive COVID-19 vaccination (P

ObjectiveThe prevalence of food allergy (FA) has been increasing in recent years and has become an important public health, food safety, and clinical nutrition problem. However, population-based studies on the prevalence of FA are very limited in China. This study aims to determine the prevalence and pattern of parent-reported FA among school children in Jiangxi Province, China.MethodsA multicenter cross-sectional study on FA was conducted on primary school children aged 6-11 years old using random cluster sampling with a questionnaire survey. Parent-reported FA was used and defined as individual-reported FA by parent or guardian through a questionnaire in this study.ResultAmong the total of 8,856 (96.36%) complete questionnaires received, 727 (8.2%) children had adverse reactions to food (ARF). The prevalence rates of parent-reported FA and doctor-diagnosed FA were 6.2% and 3.3%, respectively. Animal-derived foods were the main causative source of FA, and the three leading allergenic foods were shrimp, mango, and mollusks. Skin reactions were the most common clinical manifestations of FA, accounting for 63.7%, and 45.32% of the subjects with parent-reported FA experienced severe allergic reactions. There was a significant difference in parent-reported FA between different survey centers, and FA risk increased significantly in children with other allergic diseases (P

Deficit schizophrenia (DS) patient is a homogenous subtype of schizophrenia that includes primary and enduring negative symptoms. This study aimed to compare the differences in cognitive functioning and plasma levels of C-reactive protein (CRP) and inflammatory cytokines among DS patients, nondeficit schizophrenia (NDS) patients, and healthy controls (HCs). A total of 141 schizophrenia patients and 67 HCs were included in this study. The schizophrenia patients were divided into DS (N= 51) and NDS (N=90) groups based on the Proxy for the Deficit Syndrome Scale (PDS). The Positive and Negative Syndrome Scale (PANSS) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were used to evaluate the clinical symptoms and cognitive performances, respectively. The plasma level of CRP, IL-1β, Il-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNF-α, and IFN-γ were measured using enzyme-linked immunosorbent assays (ELISAs). Our results showed that DS patients had the worst cognitive performance, especially in the immediate memory, attention, and language dimensions, compared to the NDS and HC groups. Compared to the HCs group, DS patients had higher levels of CRP, IL-1β, IL-6, IL-8, IFN-γ, and total proinflammatory cytokines, and NDS patients had higher levels of IL-1β, IFN-γ, and proinflammatory cytokines. We also found that CRP levels were significantly increased in DS patients compared to NDS patients. Moreover, stepwise logistic regression analysis revealed that CRP is an independent risk factor for DS. Sex stratification analysis showed significant differences in almost all cytokines in female samples but not in male samples. The significant differences in cognitive performance and inflammatory components among groups suggest that deficit syndrome is an independent endophenotype of schizophrenia patients with unique immune-inflammatory features, but may have sex characteristics.

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.

The outcomes of 80 patients with hematologic malignancies who received haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) combined with unrelated cord blood (UCB) from March 2017 to June 2020 were analyzed in this retrospective study. Anti-thymocyte globulin(ATG) was administered at a dose of 7.5 mg/kg. The median time for neutrophil and platelet engraftment was 13(range: 8-22) days and 14(range: 8-103) days, respectively. The 30-day cumulative incidence of neutrophil engraftment was 100%, and the 100-day cumulative incidence of platelet engraftment was 95%. All patients achieved complete haploidentical peripheral blood stem cell engraftment, and no cord blood chimerism was observed. The cumulative incidence of grades II-IV and grades III-IV acute graft-versus-host disease (aGVHD) on 100-day was 26.3%(95%CI: 17.2%–36.3%) and 5.0%(95%CI: 1.6%–11.4%), respectively. The estimated cumulative incidence of chronic GVHD (cGVHD) and moderate-severe cGVHD at 3-year was 43.3%(95%CI: 31.6%–54.4%) and 16.0%(95%CI: 8.7%–25.2%), respectively. The estimated 3-year cumulative incidence of relapse and non-relapse mortality was 18.8%(95%CI: 10.0%–29.7%) and 17.8%(95%CI: 9.9%–27.5%), respectively. The estimated 3-year probabilities of overall survival, disease-free survival, GVHD/relapse-free survival were 77.6%(95%CI: 68.3%–88.1%), 63.4%(95%CI: 52.6%–76.5%), and 55.5%(95%CI: 44.8%–68.7%), respectively. These satisfying results suggested that haplo-PBSCT combined with UCB is an alternative transplantation protocol for hematologic malignancies.

Coronary atherosclerotic heart disease (CAD) is a chronic inflammatory cardiovascular disease with high morbidity and mortality. Growing data indicate that many immune cells are involved in the development of atherosclerosis. However, the immunological roles of γδ T cells in the initiation and progression of CAD are not fully understood. Here, we used flow cytometry to determine phenotypical changes of γδ T cells and their subpopulations in peripheral blood samples collected from 37 CAD patients. The Pearson correlation coefficient was used to analyze the relationship between the clinical parameter (serum LDL-C level) and the changes of immunophenotypes of γδ T cells. Our results demonstrated that the frequencies and absolute numbers of total γδ T cells and Vδ2+ T cells were significantly decreased in CAD patients when compared to healthy individuals. However, the proportion of Vδ1+ T cells was much lower in CAD patients than that of healthy individuals. Most importantly, a significant alteration of the Vδ1/Vδ2 ratio was found in CAD patients. In addition, a series of surface markers that are associated with costimulatory signals (CD28, CD40L, CD80, CD86), activation levels (CD69, CD25, HLA-DR), activating NK cell receptors (NKp30, NKp46, NKG2D) and inhibitory receptors (PD-1, CTLA-4, PD-1, Tim-3) were determined and then analyzed in the total γδ T cells, Vδ2+T cells and Vδ2-T cells of CAD patients and healthy individuals. The data demonstrated that immunological activities of total γδ T cells, Vδ2+T cells, and Vδ2-T cells of CAD patients were much lower than those in healthy individuals. Moreover, we found that there were positive correlations between the serum LDL-C levels and frequencies of CD3+γδ+ T cells, CD69+Vδ2+T cells, NKG2D+Vδ2+T cells, and NKp46+Vδ2+T cells. By contrast, there was an inverse correlation between the levels of serum LDL-C and the frequencies of CD69+Vδ2-T cells and NKp46+Vδ2-T cells. Accordingly, these findings could help us to better understand the roles of γδ T cells in the CAD, and shed light on the development of novel diagnostic techniques and therapeutic strategies by targeting γδ T cells for CAD patients.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare, heterogeneous, but treatable autoimmune-mediated peripheral neuropathy characterized by demyelination. CIDP can occur independently or simultaneously with a variety of diseases such as diabetes, monoclonal gammopathy of undetermined significance (MGUS), connective tissue disease, and HIV. It is important to identify CIDP and specific peripheral neuropathies caused by these diseases; this review aims to summarize the CIDP literatures related to diabetes, MGUS, SLE, and HIV, and to be helpful for the management of such patients.

Commensal bacteria and other microorganisms that reside in the human body are closely associated with the development and treatment of cancers. Recently, tumor microbiome (TM) has been identified in a variety of cancers such as pancreatic, lung, and breast cancers. TM has different compositions in different tumors and has different effects on tumors. TM plays an important role in the formation of the tumor microenvironment, regulation of local immunity, and modification of tumor cell biology, and directly affects the efficacy of drug treatment for tumors. TM is expected to be a biomarker for tumors, and engineered tumor-targeting bacteria and anti-cancer microbial agents (GEN-001) have an important role in the treatment of tumors. This paper reviews the relevant studies on TM in recent years and describes its distribution in different tumors, its correlation with clinical features, its effect on local immunity, and the research directions of TM in tumor treatment.

We previously explored a panel of adjuvants formulated with pre-fusion RSV-F protein and found that AS02 may be a promising candidate adjuvant for developing RSV-F subunit vaccines with improved immunogenicity and desired immune response type. In this study, we performed a head-to-head comparison of the effect of intramuscular injection to that of subcutaneous injection on the immune response and protective efficacy of recombinant RSV-F subunit vaccine with or without adjuvants (Alhydrogel, squalene-based emulsion adjuvants MF59, AS03, and AS02) in BALB/c mice. After inoculations, antigen-specific antibodies, neutralizing antibodies, antibody subtypes, cytokines, and the persistence of immune response were evaluated. Moreover, challenge tests were also performed to illustrate the possible effect of inoculation routes and adjuvant on virus clearance and histochemistry changes in the lungs of mice. The results indicated that intramuscular inoculation is a more effective and antigen dose-sparing route to enhance the immune response, although subcutaneous inoculation induced faster and stronger IgG antibodies after the initial immunization. Furthermore, adjuvant, but not immunization route, is a more critical factor to affect the humoral/cellular immune response and the immune bias. In addition, adjuvant inoculated via the intramuscular route is safer than that via the subcutaneous route, especially for AS02. This study highlights the importance of the adjuvant and immunization routes in the design and clinical transformation of adjuvanted vaccines. Further investigation is needed to illustrate the mechanism underlying the above difference in both efficiency and safety.

BackgroundPrevious studies have established several animal models for experimental autoimmune uveitis (EAU) in rodents without the fovea centralis in the human retina. This study aimed to develop and explore the application of a novel EAU model in tree shrews with a cone-dominated retina resembling the human fovea.MethodsTree shrews were clinically and pathologically evaluated for the development and characteristics of EAU immunized with six inter-photoreceptor retinoid-binding proteins (IRBPs). IRBP-specific T-cell proliferation and serum cytokine of tree shrews were evaluated to determine the immune responses. Differentially expressed genes (DEGs) were identified in the eyes of tree shrews with EAU by RNA-sequencing. The disruptive effects of the DEG RGS4 inhibitor CCG 203769 and dihydroartemisinin on the EAU were investigated to evaluate the potential application of tree shrew EAU.ResultsIRBP1197–1211 and R14 successfully induced chronic EAU with subretinal deposits and retinal damage in the tree shrews. The immunological characteristics presented the predominant infiltration of microglia/macrophages, dendritic cells, and CD4-T-cells into the uvea and retina and pathogenic T helper (Th) 1 and Th17 responses. The subretinal deposits positively expressed amyloid β-protein (Aβ), CD8, and P2Y purinoceptor 12 (P2RY12). The crucial DEGs in R14-induced EAU, such as P2RY2 and adenylate cyclase 4 (ADCY4), were enriched for several pathways, including inflammatory mediator regulation of transient receptor potential (TRP) channels. The upregulated RGS4 in IRBP-induced EAU was associated with mitogen-activated protein kinase (MAPK) activity. RGS4 inhibition and dihydroartemisinin could significantly alleviate the retinal pathological injuries of IRBP1197-1211-induced EAU by decreasing the expression of CD4 T-cells.ConclusionOur study provides a novel chronic EAU in tree shrews elicited by bovine R14 and tree shrew IRBP1197-1211 characterized by retinal degeneration, retinal damage with subretinal Aβ deposits and microglia/macrophage infiltration, and T-cell response, probably by altering important pathways and genes related to bacterial invasion, inflammatory pain, microglial phagocytosis, and lipid and glucose metabolism. The findings advance the knowledge of the pathogenesis and therapeutics of the fovea-involved visual disturbance in human uveitis.

Programmed cell death (PCD) plays an important role in the onset and progression of various cancers. The molecular events surrounding the occurrence of abnormally expressed long noncoding RNAs (lncRNAs) leading to colon cancer (CC) have become a focus. We comprehensively evaluated the roles of PCD-related lncRNAs in the clinical management of CC and their immune responses. Therefore, we screened 41 prognostic PCD-related lncRNAs in The Cancer Genome Atlas database using co-expression analysis and assigned patients to groups according to the results of cluster analysis. The immune response and functions of cluster 2 were substantially suppressed, which might explain the poor prognosis in this group. A prognostic model comprising eight PCD-related lncRNAs was developed, and its effectiveness was verified using an external database. High-and low-risk groups had different epigenetic modifications and changes in immune cell infiltration. Patients in the high-risk group were resistant to immunotherapy and various chemotherapeutic drugs. Studies in vitro and in vivo further confirmed a carcinogenic role of the lncRNA U62317.4. Our findings of the prognostic value of PCD-related lncRNAs revealed their important roles in immune response disorders, thus providing valuable insights into the clinical management and molecular mechanisms of CC.

BackgroundThe tumor microenvironment (TME) is crucial for tumor recurrence, prognosis, and therapeutic responses. We comprehensively investigated the TME characterization associated with relapse and survival outcomes of gastric cancer (GC) to predict chemotherapy and immunotherapy response.MethodsA total of 2,456 GC patients with complete gene-expression data and clinical annotations from twelve cohorts were included. The TME characteristics were evaluated using three proposed computational algorithms. We then developed a TME-classifier, a TME-cluster, and a TME-based risk score for the assessment of tumor recurrence and prognosis in patients with GC to predict chemotherapy and immunotherapy response.ResultsPatients with tumor recurrence presented with inactive immunogenicity, namely, high infiltration of tumor-associated stromal cells, low infiltration of tumor-associated immunoactivated lymphocytes, high stromal score, and low immune score. The TME-classifier of 4 subtypes with distinct clinicopathology, genomic, and molecular characteristics was significantly associated with tumor recurrence (P = 0.002), disease-free survival (DFS, P

BackgroundInherited susceptibility and environmental carcinogens are crucial players in lung cancer etiology. The lung microbiome is getting rising attention in carcinogenesis. The present work sought to investigate the microbiome in lung cancer patients affected by familial lung cancer (FLC) and indoor air pollution (IAP); and further, to compare host gene expression patterns with their microbiome for potential links.MethodsTissue sample pairs (cancer and adjacent nonmalignant tissue) were used for 16S rRNA (microbiome) and RNA-seq (host gene expression). Subgroup microbiome diversities and their matched gene expression patterns were analyzed. Significantly enriched taxa were screened out, based on different clinicopathologic characteristics.ResultsOur FLC microbiome seemed to be smaller, low-diversity, and inactive to change; we noted microbiome differences in gender, age, blood type, anatomy site, histology type, TNM stage as well as IAP and smoking conditions. We also found smoking and IAP dramatically decreased specific-OTU biodiversity, especially in normal lung tissue. Intriguingly, enriched microbes were in three categories: opportunistic pathogens, probiotics, and pollutant-detoxication microbes; this third category involved Sphingomonas, Sphingopyxis, etc. which help degrade pollutants, but may also cause epithelial damage and chronic inflammation. RNA-seq highlighted IL17, Ras, MAPK, and Notch pathways, which are associated with carcinogenesis and compromised immune system.ConclusionsThe lung microbiome can play vital roles in carcinogenesis. FLC and IAP subjects were affected by fragile lung epithelium, vulnerable host-microbes equilibrium, and dysregulated immune surveillance and response. Our findings provided useful information to study the triple interplay among environmental carcinogens, population genetic background, and diversified lung microbiome.

The AID/APOBEC family which converts cytidine to uridine on RNA or DNA experienced dynamic expansion in primates in order to resist exogenous viruses and endogenous retrotransposons. Recently, expansion of AID/APOBEC-like homologs has also been observed in the extant jawless vertebrate lamprey. To reveal what causes such expansion and leads to the functional diversification of lamprey cytosine deaminases (CDAs), we reassessed the CDA genes in Lethenteron japonicum (Lj). We first confirmed the expansion of LjCDA1L1 (CDA1-like 1) genes and found the expression correlation of LjCDA2 and LjCDA1L2 with LjVLRs (variable lymphocyte receptors). Among up to 14 LjCDA1L1 proteins, LjCDA1L1_4a has an extremely high deamination activity on ssDNA and buDNA and, unexpectedly, on dsDNA. LjCDA1L1s can also restrict the infection of HSV-1 particles. Thus, the arms race between the host and pathogens along with the recruitment by VLR assembly may participate together to form a driving force in the expansion and diversification of the lamprey AID/APOBEC family.

BackgroundImmune suppression contributes to nosocomial infections (NIs) and poor prognosis in sepsis. Recent studies revealed that CD71+ erythroid cells had unappreciated immunosuppressive functions. This study aimed to investigate the values of CD71+ erythroid cells (CECs) in predicting NIs and prognosis among adult septic patients. The potential factors associated with the expansion of CECs were also explored.MethodsIn total, 112 septic patients and 32 critically ill controls were enrolled. The frequencies of CD71+ cells, CD71+CD235a+ cells, and CD45+ CECs were measured by flow cytometry. The associations between CECs and NIs and 30-day mortality were assessed by ROC curve analysis and Cox and competing-risk regression models. Factors associated with the frequency of CECs were identified by linear regression analysis.ResultsThe percentage of CD71+ cells, CECs, and CD45+ CECs were higher in septic patients than critically ill controls. In septic patients, the percentages of CD71+ cells, CECs, and CD45+ CECs were associated with NI development, while CD71+ cells and CECs were independently associated with 30-day mortality. Linear regression analysis showed that the levels of interleukin (IL)-6 and interferon (IFN)-γ were positively associated with the frequencies of CD71+ cells, CECs, and CD45+ CECs, while IL-10 was negatively associated with them. Additionally, the levels of red blood cells (RBCs) were negatively associated with the percentage of CD45+ CECs.ConclusionsCECs were expanded in sepsis and can serve as independent predictors of the development of NI and 30-day mortality. Low levels of RBCs and high levels of IL-6 and IFN-γ may contribute to the expansion of CECs in sepsis.Trial RegistrationChiCTR, ChiCTR1900024887. Registered 2 August 2019, http://www.chictr.org.cn/showproj.aspx?proj=38645

P2Y1 receptor is a G-protein-coupled receptor that plays a critical role in the immune response of inflammatory bowel diseases. However, its regulatory effects on CD4+ T cell response have not been fully elucidated. The study aimed to characterize the role of P2Y1R in Th17 cell differentiation and colonic inflammation. Our results demonstrated that P2Y1R was significantly increased in the splenocytes of colitic mice, which was positively associated with the expression of RORγt and IL-17A. P2Y1R deficiency significantly ameliorated DSS-induced colitis and its Th17 responses. In parallel, P2Y1R deficiency greatly impaired the differentiation of Th17 cell, down-regulated the mRNA expression of IL-17A and RORγt, and protein expression of RORγt in vitro. More importantly, it was found that P2Y1R deficiency markedly increased AMPK phosphorylation of Th17 polarized CD4+ T cells, and antagonist of AMPK significantly reversed the inhibitory effect of P2Y1R deficiency on Th17 cell generation in vivo and in vitro. Overall, these findings demonstrated that P2Y1R deficiency could suppress Th17 cell differentiation in an AMPK-dependent manner to ameliorate colitis, and P2Y1R can act as an important regulator of Th17 cell differentiation to control colonic inflammation.

BackgroundThe benefits of intravenous immunoglobulin administration are controversial for critically ill COVID-19 patients.MethodsWe analyzed retrospectively the effects of immunoglobulin administration for critically ill COVID-19 patients. The primary outcome was 28-day mortality. Inverse probability of treatment weighting (IPTW) with propensity score was used to account for baseline confounders. Cluster analysis was used to perform phenotype analysis.ResultsBetween January 1 and February 29, 2020, 754 patients with complete data from 19 hospitals were enrolled. Death at 28 days occurred for 408 (54.1%) patients. There were 392 (52.0%) patients who received intravenous immunoglobulin, at 11 (interquartile range (IQR) 8, 16) days after illness onset; 30% of these patients received intravenous immunoglobulin prior to intensive care unit (ICU) admission. By unadjusted analysis, no difference was observed for 28-day mortality between the immunoglobulin and non-immunoglobulin groups. Similar results were found by propensity score matching (n = 506) and by IPTW analysis (n = 731). Also, IPTW analysis did not reveal any significant difference between hyperinflammation and hypoinflammation phenotypes.ConclusionNo significant association was observed for use of intravenous immunoglobulin and decreased mortality of severe COVID-19 patients. Phenotype analysis did not show any survival benefit for patients who received immunoglobulin therapy.

Microglia are the resident immune cells of the central nervous system that exert diverse roles in the pathogenesis of ischemic stroke. During the past decades, microglial polarization and chemotactic properties have been well-studied, whereas less attention has been paid to phagocytic phenotypes of microglia in stroke. Generally, whether phagocytosis mediated by microglia plays a beneficial or detrimental role in stroke remains controversial, which calls for further investigations. Most researchers are in favor of the former proposal currently since efficient clearance of tissue debris promotes tissue reconstruction and neuronal network reorganization in part. Other scholars propose that excessively activated microglia engulf live or stressed neuronal cells, which results in neurological deficits and brain atrophy. Upon ischemia challenge, the microglia infiltrate injured brain tissue and engulf live/dead neurons, myelin debris, apoptotic cell debris, endothelial cells, and leukocytes. Cell phagocytosis is provoked by the exposure of “eat-me” signals or the loss of “don’t eat-me” signals. We supposed that microglial phagocytosis could be initiated by the specific “eat-me” signal and its corresponding receptor on the specific cell type under pathological circumstances. In this review, we will summarize phagocytic characterizations of microglia after stroke and the potential receptors responsible for this programmed biological progress. Understanding these questions precisely may help to develop appropriate phagocytic regulatory molecules, which are promoting self-limiting inflammation without damaging functional cells.

Salmonella Infantis has emerged as a major clinical pathogen causing gastroenteritis worldwide in recent years. As an intracellular pathogen, Salmonella has evolved to manipulate and benefit from the cell death signaling pathway. In this study, we discovered that S. Infantis inhibited apoptosis of infected Caco-2 cells by phosphorylating Akt. Notably, Akt phosphorylation was observed in a discontinuous manner: immediately 0.5 h after the invasion, then before peak cytosolic replication. Single-cell analysis revealed that the second phase was only induced by cytosolic hyper-replicating bacteria at 3–4 hpi. Next, Akt-mediated apoptosis inhibition was found to be initiated by Salmonella SopB. Furthermore, Akt phosphorylation increased mitochondrial localization of Bcl-2 to prevent Bax oligomerization on the mitochondrial membrane, maintaining the mitochondrial network homeostasis to resist apoptosis. In addition, S. Infantis induced pyroptosis, as evidenced by increased caspase-1 (p10) and GSDMS-N levels. In contrast, cells infected with the ΔSopB strain displayed faster but less severe pyroptosis and had less bacterial load. The results indicated that S. Infantis SopB–mediated Akt phosphorylation delayed pyroptosis, but aggravated its severity. The wild-type strain also caused more severe diarrhea and intestinal inflammatory damage than the ΔSopB strain in mice. These findings revealed that S. Infantis delayed the cells’ death by intermittent activation of Akt, allowing sufficient time for replication, thereby causing more severe inflammation.

Immunoglobin G4-related disease (IgG4-RD) is one of the newly discovered autoimmune diseases characterized by elevated serum IgG4 concentrations and multi-organ fibrosis. Despite considerable research and recent advances in the identification of underlying immunological processes, the etiology of this disease is still not clear. Adaptive immune cells, including different types of T and B cells, and cytokines secreted by these cells play a vital role in the pathogenesis of IgG4-RD. Antigen-presenting cells are stimulated by pathogens and, thus, contribute to the activation of naïve T cells and differentiation of different T cell subtypes, including helper T cells (Th1 and Th2), regulatory T cells, and T follicular helper cells. B cells are activated and transformed to plasma cells by T cell-secreted cytokines. Moreover, macrophages, and some important factors (TGF-β, etc.) promote target organ fibrosis. Understanding the role of these cells and cytokines implicated in the pathogenesis of IgG4-RD will aid in developing strategies for future disease treatment and drug development. Here, we review the most recent insights on IgG4-RD, focusing on immune dysregulation involved in the pathogenesis of this autoimmune condition.

With the expansion of our knowledge on inborn errors of immunity (IEI), it gradually becomes clear that immune dysregulation plays an important part. In some cases, autoimmunity, hyperinflammation and lymphoproliferation are far more serious than infections. Thus, immune dysregulation has become significant in disease monitoring and treatment. In recent years, the wide application of whole-exome sequencing/whole-genome sequencing has tremendously promoted the discovery and further studies of new IEI. The number of discovered IEI is growing rapidly, followed by numerous studies of their pathogenesis and therapy. In this review, we focus on novel discovered primary immune dysregulation diseases, including deficiency of SLC7A7, CD122, DEF6, FERMT1, TGFB1, RIPK1, CD137, TET2 and SOCS1. We discuss their genetic mutation, symptoms and current therapeutic methods, and point out the gaps in this field.

Cigarette smoke damages a wide range of immunological functions, including innate and adaptive immune responses. Emerging literature demonstrates that inflammasome constitutes an essential component in innate immune response. In this review, we focus on the cumulative mechanisms of inflammasome in cigarette smoke-related diseases and physiopathological disorders, and summarize potential therapeutic opportunities targeting inflammasome. This review suggests that inflammasomes (NLRP3, NLRP6, NLRP12 and AIM2) are involved in the pathogenesis of several cigarette smoke-related diseases (including COPD, ALI, atherosclerosis, kidney injury, bladder dysfunction, and oral leukoplakia) and physiopathological disorders (macrophage dysfunction, endothelial barrier dysfunction, podocyte injury, and ubiquitin-mediated proteasomal processing). MyD88/NF-κB, HMGB1, production of ROS, endoplasmic reticulum stress and mitochondrial dysfunction, and Ca2+ influx are potentially involved in cigarette smoke induced-inflammasome activation. Strategies targeting ROS/NLRP3 inflammasome axis are most widely investigated and show potential therapeutic effects.

BackgroundGastric cancer (GC) is a highly heterogeneous tumor with different responses to immunotherapy. Identifying immune subtypes and landscape of GC could improve immunotherapeutic strategies.MethodsBased on the abundance of tumor-infiltrating immune cells in GC patients from The Cancer Genome Atlas, we used unsupervised consensus clustering algorithm to identify robust clusters of patients, and assessed their reproducibility in an independent cohort from Gene Expression Omnibus. We further confirmed the feasibility of our immune subtypes in five independent pan-cancer cohorts. Finally, functional enrichment analyses were provided, and a deep learning model studying the pathological images was constructed to identify the immune subtypes.ResultsWe identified and validated three reproducible immune subtypes presented with diverse components of tumor-infiltrating immune cells, molecular features, and clinical characteristics. An immune-inflamed subtype 3, with better prognosis and the highest immune score, had the highest abundance of CD8+ T cells, CD4+ T–activated cells, follicular helper T cells, M1 macrophages, and NK cells among three subtypes. By contrast, an immune-excluded subtype 1, with the worst prognosis and the highest stromal score, demonstrated the highest infiltration of CD4+ T resting cells, regulatory T cells, B cells, and dendritic cells, while an immune-desert subtype 2, with an intermediate prognosis and the lowest immune score, demonstrated the highest infiltration of M2 macrophages and mast cells, and the lowest infiltration of M1 macrophages. Besides, higher proportion of EVB and MSI of TCGA molecular subtyping, over expression of CTLA4, PD1, PDL1, and TP53, and low expression of JAK1 were observed in immune subtype 3, which consisted with the results from Gene Set Enrichment Analysis. These subtypes may suggest different immunotherapy strategies. Finally, deep learning can predict the immune subtypes well.ConclusionThis study offers a conceptual frame to better understand the tumor immune microenvironment of GC. Future work is required to estimate its reference value for the design of immune-related studies and immunotherapy selection.

Irinotecan (CPT-11)-induced gastrointestinal toxicity strongly limits its anticancer efficacy. Glycyrrhiza uralensis Fisch., especially flavonoids, has strong anti-inflammatory and immunomodulatory activities. Herein, we investigate the protective effect of the total flavonoids of G. uralensis (TFGU) on CPT-11–induced colitis mice from the perspective of gut microbiota and fecal metabolism. The body weight and colon length of mice were measured. Our results showed that oral administration of TFGU significantly attenuated the loss of body weight and the shortening of colon length induced by CPT-11. The elevated disease activity index and histological score of colon as well as the up-regulated mRNA and protein levels of TNF-α, IL-1β, and IL-6 in the colonic tissue of CPT-11–treated mice were significantly decreased by TFGU. Meanwhile, TFGU restored the perturbed gut microbial structure and function in CPT-11–treated mice to near normal level. TFGU also effectively reversed the CPT-11–induced fecal metabolic disorders in mice, mainly call backing the hypoxanthine and uric acid in purine metabolism. Spearman’s correlation analysis further revealed that Lactobacillus abundance negatively correlated with fecal uric acid concentration, suggesting the pivotal role of gut microbiota in CPT-11–induced colitis. Since uric acid is a ligand of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, TFGU was further validated to inhibit the activation of NLRP3 inflammasome by CPT-11. Our findings suggest TFGU can correct the overall gut microbial dysbiosis and fecal metabolic disorders in the CPT-11–induced colitis mice, underscoring the potential of using dietary G. uralensis as a chemotherapeutic adjuvant.

The mechanisms underlying sepsis-induced cardiomyopathy (SIC) remain poorly understood, and there are no specific therapeutics for SIC. We investigated the effects of maresin conjugates in tissue regeneration 1 (MCTR1) on SIC and explored its potential mechanisms. The experiments were conducted using an endotoxemia model induced by lipopolysaccharide (LPS). Mice were given MCTR1 intravenously 6 h after LPS stimulation. Echocardiography was performed to assess cardiac function 12 h after LPS administration. Treatment with MCTR1 significantly enhanced cardiac function and reduced LPS-induced increase of mRNA expression levels of inflammation cytokines. Transcriptomic analysis indicated that MCTR1 inhibited neutrophil chemotaxis via the IL-17 signaling pathway. We confirmed that MCTR1 reduced the expressions of neutrophil chemoattractants and neutrophil infiltration in the LPS-stimulated hearts. MCTR1 also resulted in a considerable reduction in IL-17A production mainly derived from γδ T cells. Moreover, our results provided the first evidence that neutralizing IL-17A or depletion of γδ T cells markedly decreased neutrophil recruitment and enhanced cardiac function in LPS-induced cardiac injury. These results suggest that MCTR1 alleviates neutrophil infiltration thereby improves cardiac function in LPS-induced cardiac injury via the IL-17 signaling pathway. Thus, MCTR1 represented a novel therapeutic strategy for patients with SIC.

Metformin is not only the first-line medication for the treatment of type 2 diabetes, but it is also effective as an anti-inflammatory, anti-oxidative and anti-tumor agent. However, the effect of metformin during viral hepatitis remains elusive. Using an adenovirus (Ad)-induced viral hepatitis mouse model, we found that metformin treatment significantly attenuated liver injury, with reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels and liver histological changes, presumably via decreased effector T cell responses. We then demonstrated that metformin reduced mTORC1 activity in T cells from infected mice, as evidenced by decreased phosphorylation of ribosome protein S6 (p-S6). The inhibitory effects on the mTORC1 signaling by metformin was dependent on the tuberous sclerosis complex 1 (TSC1). Mechanistically, metformin treatment modulated the phosphorylation of dynamin-related protein 1 (Drp-1) and mitochondrial fission 1 protein (FIS1), resulting in increased mass in effector T cells. Moreover, metformin treatment promoted mitochondrial superoxide production, which can inhibit excessive T cell activation in viral hepatitis. Together, our results revealed a protective role and therapeutic potential of metformin against liver injury in acute viral hepatitis via modulating effector T cell activation via regulating the mTORC1 pathway and mitochondrial functions.

Recent evidence indicates that p53 plays a protective role against various systemic autoimmune diseases by suppressing pro-inflammatory cytokine production and reducing the number of pathogenic T cells. However, whether abnormal p53 expression participates in the development of acute graft-versus-host disease (aGVHD) remains unclear. In this study, we demonstrated that p53 was downregulated in CD4+ T cells from patients with aGVHD compared with the non-aGVHD group. Furthermore, we confirmed that low expression of CCCTC-binding factor (CTCF) in CD4+ T cells from aGVHD cases is an important factor affecting histone H3K9/K14 hypoacetylation in the p53 promoter and p53 downregulation. Restoring CTCF expression in CD4+ T cells from aGVHD patients increased p53 amounts and corrected the imbalance of Th17 cells/Tregs. Taken together, these results provide novel insights into p53 downregulation in CD4+ T cells from aGVHD patients.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory illness, particularly in infants, the elderly, and immunocompromised adults. There is no licensed commercial vaccine against RSV. Importantly, formalin-inactivated RSV vaccines mediate enhanced respiratory disease. RSV fusion (F) protein with pre-fusion conformation is a promising candidate subunit vaccine. However, some problems remain to be solved, such as low immunogenicity and humoral immunity bias. Adjuvants can effectively enhance and adjust vaccine immune responses. In this study, we formulated pre-fusion RSV-F protein with the adjuvants, Alhydrogel, MF59, AS03, AS02, and glycol chitosan (GCS). We then conducted head-to-head comparisons of vaccine-induced immune responses in BALB/c mice. All adjuvanted vaccines enhanced antigen-specific and neutralizing antibody titers and viral clearance and gave an order of adjuvant activity: AS02 > AS03, MF59 > GCS, and Alhydrogel. Among them, AS02 elicited the highest antibody expression, which persisted until week 18. Moreover, AS02 significantly enhanced Th1 type immune response in immunized mice. Mice in the AS02 group also showed faster recovery from viral attacks in challenge tests. Further transcriptome analysis revealed that AS02 regulates immune balance by activating TLR-4 and promotes Th1-type immune responses. These results suggest that AS02 may be an excellent candidate adjuvant for RSV-F subunit vaccines. This study also provides valuable information regarding the effect of other adjuvants on immune responses of RSV-F subunit vaccines.

T cell exhaustion is an obstacle to immunotherapy for solid tumors. An understanding of the mechanism by which T cells develop this phenotype in solid tumors is needed. Here, hypoxia, a feature of the tumor microenvironment, causes T cell exhaustion (TExh) by inducing a mitochondrial defect. Upon exposure to hypoxia, activated T cells with a TExh phenotype are characterized by mitochondrial fragmentation, decreased ATP production, and decreased mitochondrial oxidative phosphorylation activity. The TExh phenotype is correlated with the downregulation of the mitochondrial fusion protein mitofusin 1 (MFN1) and upregulation of miR-24. Overexpression of miR-24 alters the transcription of many metabolism-related genes including its target genes MYC and fibroblast growth factor 11 (FGF11). Downregulation of MYC and FGF11 induces TExh differentiation, reduced ATP production and a loss of the mitochondrial mass in T cell receptor (TCR)-stimulated T cells. In addition, we determined that MYC regulates the transcription of FGF11 and MFN1. In nasopharyngeal carcinoma (NPC) tissues, the T cells exhibit an increased frequency of exhaustion and loss of mitochondrial mass. In addition, inhibition of miR-24 signaling decreases NPC xenograft growth in nude mice. Our findings reveal a mechanism for T cell exhaustion in the tumor environment and provide potential strategies that target mitochondrial metabolism for cancer immunotherapy.

Psoriasis is a common chronic inflammatory systemic disease. Epidermal proteins are considered to be important in maintaining skin barrier function, innate immunity, and inflammation. To define more possible roles of the epidermis in the pathogenesis of psoriasis, quantified proteomic analysis was used to screen and analyze the differentially expressed epidermal proteins between 16 psoriasis patients and 15 healthy controls. Upregulated differential expression proteins (DEPs) include several significant functional protein clusters, including antimicrobial peptides (AMPs) and antiviral proteins (AVPs). The levels of 2–5-oligoadenylate synthase 2 (OAS2) in both epidermis and serum levels were significantly elevated in psoriasis and were also positively correlated with Psoriasis Area Severity Index (PASI) scores and Body Surface Area (BSA) scores. Moreover, OAS2 expression in psoriatic skin significantly decreased after IL-17R mono-antibody treatment. It has been clarified that inflamed keratinocytes were the main source of abnormally increased OAS2 in psoriasis skin by immunofluorescence and primary cell cultures. Keratinocyte-derived OAS2 can be induced by not only IFNβ, but also psoriasis associated cytokines like IL-17A and IL-6. This study revealed that AMPs and AVPs are two important functional protein clusters altering innate immune in psoriatic epidermis. OAS2 is a novel potential sensitive biomarker, which could predict the severity and activity of psoriasis, and could also be used as an indicator to evaluate or monitor the efficacy of clinical treatment.

Purpose: Previous studies have shown that parental abnormal physiological conditions such as inflammation, stress, and obesity can be transferred to offspring. The purpose of this study was to investigate the impact of parental uveitis on the development and susceptibility to experimental autoimmune uveitis (EAU) in offspring.Methods: Parental male and female B10RIII mice were immunized with interphotoreceptor retinoid binding protein (IRBP) 161–180 in complete Freund's adjuvant and were immediately allowed to mate. Gross examination of the offspring gestated with EAU was performed to determine the influence of parental uveitis on offspring development after birth. Gene expression profiles were analyzed in the affected eyes of offspring under EAU to identify differentially expressed genes (DEGs). Adult offspring were given 5, 25, and 50 μg IRBP161−180 to compare their susceptibility to EAU. Immunized mice were clinically and pathologically evaluated for the development of EAU. Ag-specific T-cell proliferation and IL-17 production from spleens and lymph nodes were evaluated on day 14 or 35 after immunization.Results: Hair loss, delay of eye opening, and swollen spleens in the offspring from parents with uveitis were observed from day 14 to 39 after birth. DEGs were involved in the immune system process, muscle system process, and cell development. The altered antigen processing and presentation, cell adhesion molecules, and phagosome in the eyes of the offspring from uveitis-affected parents were enriched. Offspring gestated with EAU showed a susceptibility to EAU and an earlier onset and higher severity of EAU compared to the control group mice. IRBP-specific lymphocyte proliferation and IL-17 production were observed in the EAU offspring with exposure to parental uveitis.Conclusions: The results suggest that mouse parents with uveitis can increase their offspring's susceptibility to EAU, probably through altering cell adhesion molecules and antigen processing and presentation related to the T-cell proliferation and Th17 response.

Sjögren's syndrome (SS) is a complex rheumatoid disease that mainly affects exocrine glands, resulting in xerostomia (dry mouth) and xerophthalmia (dry eye). SS is characterized by autoantibodies, infiltration into exocrine glands, and ectopic expression of MHC II molecules on glandular epithelial cells. In contrast to the well-characterized clinical and immunological features, the etiology and pathogenesis of SS remain largely unknown. Animal models are powerful research tools for elucidating the pathogenesis of human diseases. To date, many mouse models of SS, including induced models, in which disease is induced in mice, and genetic models, in which mice spontaneously develop SS-like disease, have been established. These mouse models have provided new insight into the pathogenesis of SS. In this review, we aim to provide a comprehensive overview of recent advances in the field of experimental SS.

The effects of the oral administration of Rehmannia glutinosa polysaccharide (RGP-1) on the immunoregulatory properties, antioxidant activity, and resistance against Aeromonas hydrophila in Cyprinus carpio L. were investigated. The purified RGP-1 (250, 500, and 1,000 μg/mL) was co-cultured with the head kidney cells of the common carp. The proliferation and phagocytosis activities of the head kidney cells, and the concentration of nitric oxide (NO) and cytokines in the culture medium were determined. Next, 300 common carps (47.66 ± 0.43 g) were randomly divided into five groups; the two control groups (negative and positive) were administered sterile PBS and the three treatment groups were administered different concentrations of RGP-1 (250, 500, and 1,000 μg/mL) for seven days. Subsequently, the positive and treatment groups were infected with A. hydrophila, and the negative group was administered sterile PBS for 24 h. The concentration of NO, cytokines, lysozyme (LZM), and alkaline phosphatase (AKP) in serum, the total antioxidant capacity (T-AOC), the levels of malonaldehyde (MDA) and glutathione (GSH), and the total activities of superoxide dismutase (T-SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the hepatopancreas of the common carp were tested. We observed that RGP-1 could significantly enhance the proliferation and phagocytosis activities (P < 0.05), besides inducing the production of NO, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-12) and anti-inflammatory cytokines (IL-10, TGF-β) (P < 0.05) in vitro. The in vivo experimental results revealed that RGP-1 significantly enhanced NO production, protein levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-12), LZM and AKP activities, and the antioxidant content (T-AOC, SOD, CAT, GSH, GSH-Px, and MDA) compared to that observed in the negative group prior to A. hydrophila infection (P < 0.05). NO, pro-inflammatory cytokines, LZM and AKP activities were significantly lower than that in the positive group after infection (P < 0.05). However, whether infected or not, the expression of anti-inflammatory cytokines (IL-10, TGF-β) increased significantly in the RGP-1-treated groups (P < 0.05). Therefore, the results suggested that RGP-1 could enhance the non-specific immunity, antioxidant activity and anti-A. hydrophila activity of the common carp, and could be used as a safe and effective feed additive in aquaculture.

Ruminants are critical as prey in transferring solar energy fixed by plants into carnivorous species, yet the genetic signature of the driving forces leading to the evolutionary success of the huge number of ruminant species remains largely unknown. Here we report a complete DNA map of the major histocompatibility complex (MHC) of the addax (Addax nasomaculatus) genome by sequencing a total of 47 overlapping BAC clones previously mapped to cover the MHC region. The addax MHC is composed of 3,224,151 nucleotides, harboring a total of 150 coding genes, 50 tRNA genes, and 14 non-coding RNA genes. The organization of addax MHC was found to be highly conserved to those of sheep and cattle, highlighted by a large piece of chromosome inversion that divided the MHC class II into IIa and IIb subregions. It is now highly possible that all of the ruminant species in the family of Bovidae carry the same chromosome inversion in the MHC region, inherited from a common ancestor of ruminants. Phylogenetic analysis indicated that DY, a ruminant-specific gene located at the boundary of the inversion and highly expressed in dendritic cells, was possibly evolved from DQ, with an estimated divergence time ~140 million years ago. Homology modeling showed that the overall predicted structure of addax DY was similar to that of HLA-DQ2. However, the pocket properties of P1, P4, P6, and P9, which were critical for antigen binding in the addax DY, showed certain distinctive features. Structural analysis suggested that the populations of peptide antigens presented by addax DY and HLA-DQ2 were quite diverse, which in theory could serve to promote microbial regulation in the rumen by ruminant species, contributing to enhanced grass utilization ability. In summary, the results of our study helped to enhance our understanding of the MHC evolution and provided additional supportive evidence to our previous hypothesis that an ancient chromosome inversion in the MHC region of the last common ancestor of ruminants may have contributed to the evolutionary success of current ruminants on our planet.