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BACKGROUND & AIMS: The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC.METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans.RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis.CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH.IMPACT AND IMPLICATIONS: Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis.

Objective: Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. Design Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. Results: neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1(+) dendritic cell activation and CD8(+) T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8(+) T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8(+) T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. Conclusion: CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC., Cancer Research UK (CRUK); Newcastle Experimental Cancer Medicine Centre; Accelerator Award; Fondazione AIRC; MRC program; AstraZeneca; Wellcome Trust; Newcatle University Faculty of Medical Sciences; WE Harker Foundation; Ministry of Economy and Competitiveness (MINECO) (MICINN); Fundació Universitària Agustí Pedro i Pons; Instituto de Salud Carlos III (ISCIII); European Union (EU); European Social Fund; German Research Foundation (DFG); Fulbright España; National Institutes of Health (NIH); Samuel Waxman Cancer Research Foundation; Spanish National Health Institute; Fundación Científica de la Asociación Española Contra el Cáncer; Generalitat de Catalunya; Sara Borrell Fellowship

We aimed to explore whether large airway remodeling and small airway structural changes exist in subjects with small airway asthma phenotype and to evaluate the relationships between quantitative high-resolution computed tomography (qHRCT) parameters and lung function.We enrolled 15 subjects with small airway asthma phenotype and 18 healthy controls. The two groups were matched by age, sex and body square area (BSA) with propensity score matching (PSM). Pulmonary function and qHRCT parameters [wall thickness (WT), wall area (WA), lumen area (LA), wall area percentage (WA%) of the 4th-6th generations in the right upper lobe apical segmental bronchus (RB1), adjusted by BSA, WT/BSA, WA/BSA, and LA/BSA, relative volume change -860 HU to -950 HU (RVCThe small airway asthma phenotype had significantly higher WA%, RVCCombining physiological tests with imaging approaches can lead to better evaluation of small airway disfunction (SAD) in asthmatic patients. Additionally, despite nonexistent airflow obstruction in patients with small airway asthma phenotype, large airway remodeling and small airway structural changes may appear simultaneously in the early stage of disease.

Objective To address the feasibility and predictive value of multimodal image-based 3D reconstruction in assessing features of neurovascular relationship particularly regarding the detection of offending vessels, degree of compression exerted on the nerve root, in patients who underwent microvascular decompression for primary trigeminal neuralgia. Methods This study includes 58 patients who underwent microvascular decompression for primary trigeminal neuralgia. All patients underwent preoperative 3.0-T magnetic resonance imaging (MRI) scan of 3D-TOF MRA and 3D-FIESTA sequences in combination. Multimodal MRIs were then registered with open-source software 3D Slicer, followed by 3D image reconstruction to get 3D models for detection of possible neurovascular relationship in the cerebellopontine angle (CPA). Evaluations were performed by 2 doctors and compared with the intraoperative findings and surgery video. Results For detection of offending vessels, multimodal image-based 3D reconstruction sensitivity was 93.1% (54/58). Compared with the intraoperative findings, the k coefficients for evaluating the offending vessel and the degree of compression were >0.70 (P Conclusions Multimodal image-based 3D reconstruction proved to be reliable and practical in detecting offending vessel and in predicting the degree of nerve compression. The 3D anatomical model is consistent with the structural position found during surgery, which means that the method is valuable in the formulation of preoperative plans.

Purpose To evaluate the value of impulse oscillometry (IOS) and quantitative HRCT parameters for differentiating asthma-COPD overlap (ACO) in COPD patients. Patients and Methods We enrolled 44 controls and 66 COPD patients, divided into the pure COPD group (n=40) and the ACO group (n=26). Spearman correlation analysis was utilized to assess the relationship between the quantitative HRCT and IOS parameters. A binary logistic regression analysis was performed to analyze the associations between the different variables and the risk of ACO. Receiver operating characteristic (ROC) curves were employed to identify the optimal cutoff and assess the diagnostic value of relative volume change -856 HU to -950 HU (RVC-856 to -950), decrease in the resistance from 5 Hz to 20 Hz (R5-R20) and their combination in predicting ACO. Bootstrapping validation was used to evaluate the internal validation. The concordance index (C-index) and calibration plot were calculated to assess the discrimination and calibration of the prediction model. Results Binary logistic regression analysis indicated that RVC-856 to -950 and the IOS parameters (R5-R20, R5, X5) were independently correlated with a higher risk of developing ACO after adjusting for age, sex, body mass index (BMI), history of smoking, exacerbation and atopy or allergic rhinitis. A correlation analysis showed a good correlation between the pulmonary function parameters and RVC-856 to -950, with a weaker correlation with the % area of low attenuation (LAA%) in ACO patients. Combining RVC-856 to -950 and R5-R20 to predict ACO, the AUC was 0.909, and the optimal cutoff value was >-0.62 for RVC-856 to -950 and >0.09 for R5-R20. Good calibration and favorable discrimination were displayed with a higher C-index. Conclusion More serious small airway impairment exists in ACO patients. The combination of RVC-856 to -950 and R5-R20 could be applied to differentiate ACO from COPD patients.

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-β, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-β. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-β, and is distracted from itself., Our understanding on the humoral immunity induced by SARS-CoV-2 is still lacking. Here the authors analyze B cell responses at the single cell level to find that, in severe COVID-19 patients, plasmablasts shift from IFN to TGFβ instruction to produce IgA antibodies that are not specific to dominant SARS-CoV-2 antigens.

Psoriasis is an immune-mediated systemic disease. Neutrophils are enriched in psoriasis lesions and can form neutrophil extracellular traps (NETs) to activate keratinocytes. Receptor-interacting protein kinase RIPK1 and RIPK3 are involved in necroptosis and NET formation.To elucidate whether RIPK1 regulates circulating neutrophils to form NETs and inflammation in psoriasis.Blood samples of psoriasis patients (RIPK1 and RIPK3 expression in protein levels were decreased in monocytes and neutrophils from peripheral blood of psoriasis patients. In isolated psoriasis neutrophils, RIPK1 and Caspase8 mRNA were downregulated while RIPK3 and MLKL mRNA were elevated, leading to the necroptosis pathway. In addition, RIPK1-inhitor-necrostatin-1 (Nec-1) enhanced NETosis in psoriasis neutrophilsOur data demonstrated that downregulated RIPK1 expression in psoriasis neutrophils may enhance NET generation. RIPK1 may be identified as a novel therapeutic target in psoriasis.

Background Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematous (SLE) and accounts for significant mortality and morbidity. Previous research has demonstrated that macrophage migration inhibitory factor (MIF) is involved in the pathogenesis of lupus nephritis, but the detailed mechanism is not elucidated. The aim of this study was to explore the pathogenesis of MIF in lupus nephritis with the pristane-induced mouse model of SLE. Methods Mif-/- mice and Wild type mice in the C57BL/6 (B6) background were used to induce Lupus model by pristane. 24 hour urine and sera were collected in the sixth month and mice were sacrificed to harvest tissues. Serum ANA, anti-dsDNA antibodies, C3, urinary creatinine and albumin were detected by ELISA. Related inflammatory cytokines were detected by Bio-Plex Pro™ assays and ELISA. CYR61 mRNA expression was detected by RT-qPCR and CYR61 protein expression were detected by Western blot. Immunofluorescence was used to detect the expression of MIF, ICs and C3 deposition and related cytokines expression in the kidneys. Immunohistochemical staining was used to detect macrophage infiltration and periodic acid-Schiff (PAS) staining were used for kidney histology. The Mann-Whitney test and Student’s t test were used to compare multiple group differences. The correlation were analyzed by Spearman correlation. Results Mif -/- mice with pristane-induced SLE have less inflammatory cytokines expression in sera. The Mif-/- mice have reduced renal injury, less macrophage infiltration, CYR61 and inflammatory cytokines expression in the kidneys. MIF induced the expression of CYR61, which can induce the expression of IL-1β, IL-6 and MCP-1 in bone marrow-derived macrophages (BMDM) in a cell-based assay. Conclusions The results suggest that MIF plays an important role in kidney injury by inducing macrophages infiltration and inflammatory cytokines expression in situ. Our finding support the pathogenic contribution of high expression MIF alleles in SLE and suggest that MIF antagonism might offer an effective therapeutic option in lupus nephritis.

Objective To investigate risk factors for aneurysm rupture in intracranial aneurysm clipping (IAC). Methods Patients admitted for IAC from April 2010 to December 2017 in the Fujita Health University Hospital or the First Affiliated Hospital of Xiamen University were retrospectively reviewed. Clinical parameters were recorded and analyzed using univariate and multivariate analysis. The Hunt-Hess grade was used to assess the preoperative clinical status of patients. Modified Rankin Scale was applied to evaluate the prognosis of patients 6 months after surgery. Results Univariate analysis showed that the preoperative clinical status ( p = 0.015) and the preoperative aneurysm rupture ( p = 0.005) were significantly associated with intraoperative aneurysm rupture (IAR) during clipping. Multivariate logistic regression analysis showed that the preoperative aneurysm rupture was an independent risk factor of IAR ( p < 0.001, OR = 10.518). There was no significant difference in the prognosis between patients with and without IAR ( p > 0.05). No significant differences existed on aspects of incidences and time points of rupture in the operations conducted by experienced surgeons compared with that conducted by less-experienced surgeons ( p > 0.05). Conclusion Preoperative aneurysm rupture is the independent risk factor for aneurysm rupture during IAC. Intraoperative rupture, if treated properly in time, has no influence on the prognosis of patients receiving IAC. Less-experienced surgeons can also reduce the incidence rate of IAR by strictly controlling surgical indications.