Clinical and experimental immunology最新文献

Dysregulation of interleukin (IL) 16 has been implicated in SLE, yet its cellular source and role in disease pathogenesis remain unclear. We analysed circulating IL16+ immune cells from 40 SLE patients, including 32 with active disease (SLEDAI-2K ≥ 4) using spectral flow cytometry. Plasma (pIL16) and urine IL16 (uIL16) levels were measured, and correlations with clinical variables were assessed. IL16 effects on T cell migration were studied in vitro. Active SLE patients showed broadly reduced proportions of cells expressing IL16, including CD4+T, CD8+T, B, and NK cells. This reduction was prominent in several cell subsets including Th1-like cells and plasmablasts. Further sub-analyses of lupus nephritis (LN) versus non-LN, demonstrated significantly reduced IL16 expression e.g., in Th1-like and double negative B cell subsets in LN. In parallel, SLE patients displayed increased pIL16 levels, and LN patients showed increased uIL16 which associated positively with disease activity SLEDAI-2K index and negatively with complement C4 levels and IL16+CD4+T-cell counts. In vitro, IL16 induced CXCR4 and CCR5 mediated migration of Th1-cells and attracted CD8+T cells via CXCR4, which was partially inhibited by IL16 blockade. We demonstrate reduced intracellular IL16 expression in SLE lymphocytes, with low IL16+CD4+T cell proportions in LN correlating with increased uIL16. Extracellular IL16 may drive Th1 and CD8+T cell infiltration, contributing to organ inflammation. IL16 blockade reduced T cell migration, highlighting its potential as therapeutic target.

Type I Interferon (IFN) induced gene expression analysis ("IFN signature") is employed to categorize pathological conditions that exhibit Type I IFN dysregulation and to direct customized therapeutic strategies. For instance, it is used to differentiate patients with IFN-related inflammation from those with conditions primarily mediated by other cytokines, such as juvenile idiopathic arthritis and periodic fevers. Nevertheless, there is currently no standardized method available for clinical practice, and comparing values at different time points or between centers poses a challenge. In this work, we described a standardized method based on the development and validation of a synthetic control to solve the problem of test comparison. Inter-assay and inter-laboratory variability were assessed by multiple repeated analyses within the same laboratory, and between two different laboratories involved in the study. The method has been validated by evaluating the IFN signature of 39 patients with inflammatory disorders known to be related or not to Type I IFN (i.e. monogenic interferonopathies, systemic lupus erythematosus, juvenile dermatomyositis, periodic fevers, and juvenile idiopathic arthritis). The proposed method proved to be highly reproducible among centers and able to discriminate among IFN-related or non-IFN-related inflammation. The use of a synthetic control minimized the inter-assay and inter-laboratory variability, and thus facilitate data sharing among centers to improve knowledge of IFN-related inflammation and patient's care.

Background: Acquired angioedema due to C1-inhibitor deficiency (AAE-C1-INH) is very rare compared to its prototype, hereditary angioedema. An updated characterization of the AAE-C1-INH cohort in the UK is required to inform management.

Objectives: To describe the disease burden of AAE-C1-INH, long-term prophylaxis (LTP) and the clinical, immunochemical, and treatment profiles of AAE-associated diseases in the UK.

Method: Retrospective data on 117 AAE-C1-INH patients were collected using a national survey proforma across 25/34 Adult Clinical Immunology and Allergy centres in the UK. Other European cohorts were compared.

Results: The median age at AAE-C1-INH diagnosis was 65 years with 3.4% of patients diagnosed below 40 years. The median delay in diagnosis was 1 year. Antifibrinolytics and attenuated androgens showed comparable efficacy to LTP, at 88.9% and 89.5%, respectively. A haematological disorder was identified in 83.8% of AAE-C1-INH patients compared to 3.4% of autoimmune diseases. The predominant haematological disorders were splenic marginal zone lymphoma 34% followed by MGUS 16%. The severity of angioedema did not depend on the associated disease. Anti-C1INH-autoantibodies testing was limited to 23.1%. Rituximab monotherapy was effective in treating 9/9 splenic marginal zone lymphoma and 1/2 MGUS-associated AAE-C1-INH. Rituximab efficacy was independent of anti-C1INH-autoantibodies detection with response in 3/3 seronegative and 4/4 seropositive patients.

Conclusion: The diagnosis of AAE-C1-INH should not be overlooked below the age of 40 years. The choice of oral LTP should be informed by the propensity to side effects. B cell depletion could be considered in treating monoclonal B cell disorder-associated-AAE-C1-INH in the absence of haematological indications. Further studies are required to address the clinical utility of anti-C1INH-autoantibodies.

Severe trauma can lead to numerous serious complications, threating the well-being and vitality of the afflicted. The quantity and functionality of polymorphonuclear neutrophils (PMNs) undergo rapid transformations in response to severe trauma, playing a pivotal role in the trauma response. The absence of CCAAT/enhancer-binding protein ε (C/EBPε) profoundly impairs the functionality of PMNs, a function of paramount importance in trauma. In this study, by generating mice with C/EBPε knocked out or overexpressed, we substantiate that C/EBPε ensures the restoration of PMN function, enhancing the expression of antimicrobial proteins and thereby promoting trauma recovery. Furthermore, diminished expression of C/EBPε is observed in trauma patients, with levels displaying a negative correlation with ISS and APACHE II scores, suggesting its potential as a prognostic indicator for clinical treatment. Mechanistically, we uncover the upregulation of SIRT1 and the inhibition of P300 participating in the suppression of C/EBPε acetylation, consequently reducing the resilience of mice to trauma. Therapeutic interventions, whether through the sole administration of PMN, nicotinamide (NAM) treatment, or their combination, all result in an increased survival rate in traumatic mice. In conclusion, our study elucidates the role of C/EBPε in enhancing the resilience to trauma and identifies C/EBPε acetylation as a critical regulatory mechanism, offering potential therapeutic approaches involving PMN transfusion and NAM treatment.

Leniolisib, an oral, targeted phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, was well-tolerated and efficacious versus placebo in treating individuals with activated PI3Kδ syndrome (APDS), an ultra-rare inborn error of immunity (IEI), in a 12-week randomised controlled trial. However, longer-term comparative data versus standard of care are lacking. This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum immunoglobulin M (IgM) levels versus current standard of care, using data from the leniolisib single-arm open-label extension study 2201E1 (NCT02859727) and the European Society for Immunodeficiencies (ESID) registry. The endpoints were chosen following feasibility assessment considering comparability and availability of data from both sources. Baseline characteristics between groups were balanced through inverse probability of treatment weighting. The leniolisib-treated group included 37 participants, with 62 and 49 participants in the control group for the respiratory tract infections and serum IgM analyses, respectively. Significant reductions in the annual rate of respiratory tract infections (rate ratio: 0.34; 95% confidence interval [CI]: 0.19, 0.59) and serum IgM levels (treatment effect: -1.09 g/L; 95% CI: -1.78, -0.39, P = 0.002) were observed in leniolisib-treated individuals versus standard of care. The results were consistent across all sensitivity analyses, regardless of censoring, baseline infection rate definition, missing data handling, or covariate selection. These novel data provide an extended comparison of leniolisib treatment versus standard of care, highlighting the potential for leniolisib to deliver long-term benefits by restoring immune system function and reducing infection rate, potentially reducing complications and treatment burden.

Myasthenia gravis (MG) is an autoimmune disease commonly associated with immune disorders in thymoma. The role of thymus myoid cells (TMCs) in the pathogenesis of autoimmune diseases has attracted much attention. Therefore, the present study was designed to reveal the impact of TMCs on the pathophysiology of tumor-associated MG (TAMG). This study included clinical patients and healthy volunteers and validated the potential role of TMCs in TAMG progression using a TMCs-deficient mouse model. Correlative findings showed that TMCs deletion affected thymic architecture in MG patients, as evidenced by the expression of key myogenic factors as well as AChR and RyRs receptors in the thymus. Further experimental validation showed that TMCs deletion increased the levels of Th1 and Th17 cells, decreased the levels of Th2 and Treg cells, and altered the secretion of corresponding cytokines, including IL-2, IL-4, IL-17, IL-22, and TGF-β concentrations. Co-culture of CD4+ T cells with Thy0517 cells or CD4+ T cells with a myoblastoid cell line using the Transwell system demonstrated that deletion of TMC inhibited the differentiation of CD4+ T cells to Treg cells. In this study, we hypothesized that TMCs are involved in TAMG progression by regulating CD4+ T cell differentiation.

Ischemic stroke and acute lung injury are prevalent life-threatening conditions marked by intricate molecular mechanisms and elevated mortality rates. Despite evident pathophysiological distinctions, a notable similarity exists in the gene responses to tissue injury observed in both pathologies. This similarity extends to both protein-encoding RNAs and non-coding RNAs. Extracellular vesicles (EVs) are nano-scale vesicles derived through cell secretion, possessing unique advantages such as high biocompatibility, low immunogenicity, intrinsic cell targeting, and facile chemical and genetic manipulation. Importantly, miRNAs, the most prevalent non-coding RNAs, are selectively concentrated within EVs. Macrophages/microglia serve as immune defense and homeostatic cells, deriving from progenitor cells in the bone marrow. They can be classified into two contrasting types: classical proinflammatory M1 phenotype or alternative anti-inflammatory M2 phenotype. However, there exists a continuum of various intermediate phenotypes between M1 and M2, and macrophages/microglia can transition from one phenotype to another. This review will investigate recent discoveries concerning the impact of EVs derived from macrophages/microglia under various states on the progression of ischemic stroke and acute lung injury. The focus will be on the involvement of miRNAs within these vesicles. The concluding remarks of this review will underscore the clinical possibilities linked to EV-miRNAs, accentuating their potential as both biomarkers and therapeutic targets.

Vaccines are crucial for protecting health globally; however, their widespread use relies on rigorous clinical development programmes. This includes Phase 3 randomized controlled trials (RCTs) to confirm their safety, immunogenicity, and efficacy. Traditionally, such trials used fixed designs with predetermined assumptions, lacking the flexibility to change during the trial or stop early due to overwhelming evidence of either efficacy or futility. Modern vaccine trials benefit from innovative approaches like adaptive designs, allowing for planned trial adaptations based on accumulating data. Here, we provide an overview of the evolution of Phase 3 vaccine trial design and statistical analysis methods from traditional to more innovative contemporary methods. This includes adaptive trial designs, which offer ethical advantages and enable early termination if indicated; Bayesian methods, which combine prior knowledge and observed trial data to increase efficiency and enhance result interpretation; modern statistical analysis methods, which enable more accurate and precise inferences; the estimand framework, which ensures the primary question of interest is addressed in a trial; novel approaches using machine learning methods to assess heterogeneity of treatment effects; and statistical advances in safety analysis to evaluate reactogenicity and clinical adverse events. We conclude with insights into the future direction of vaccine trials, aiming to inform clinicians and researchers about conventional and novel RCT design and analysis approaches to facilitate the conduct of efficient, timely trials.

Amlexanox (ALX) is a small-molecule drug for the treatment of inflammatory, autoimmune, metabolic, and tumor diseases. At present, there are no studies on whether ALX has a therapeutic effect on inflammatory bowel disease (IBD). In this study, we used a mouse model of dextran sulfate sodium-induced colitis to investigate the effect of ALX-targeted inhibition of TBK1 on colitis. We found that the severity of colitis in mice was correlated with TBK1 expression. Notably, although ALX inhibited the activation of the TBK1-NF-κB/TBK1-IRF3 pro-inflammatory signaling pathway, it exacerbated colitis and reduced survival in mice. The results of drug safety experiments ruled out a relationship between this exacerbating effect and drug toxicity. In addition, ELISA results showed that ALX promoted the secretion of IL-1β and IFN-α, and inhibited the production of cytokines IL-6, TNF-α, IL-10, TGF-β, and secretory IgA. Flow cytometry results further showed that ALX promoted T-cell proliferation, activation, and differentiation, and thus played a pro-inflammatory role; also, ALX inhibited the generation of dendritic cells and the polarization of macrophages to M1 type, thus exerting anti-inflammatory effect. These data suggest that the regulation of ALX on the function of different immune cells is different, so the effect on the inflammatory response is bidirectional. In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation of the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.