Scandinavian Journal of Immunology最新文献

We aimed to investigate the effects of Salvianolic acid A (SA), an active ingredient of Salvia miltiorrhiza Bunge, on the proliferation, metastasis and CD40-AKT-NF-κB signalling pathway in endometrial carcinoma (EC). Human EC cell lines (Ishikawa and HEC-1A) were treated with varying concentrations of SA, CD40 soluble ligand (sCD40L) or a combination of both. Cell viability, proliferation, invasion and migration were assessed using MTT, colony formation and transwell assays. Flow cytometry was used to analyse apoptosis and cell cycle progression. qRT-PCR evaluated the mRNA level of CD40. The protein expression of CD40, p-AKT, p-mTOR, p-p65, and p52 was evaluated via Western blot and immunofluorescence. A subcutaneous tumour model was used to examine the impact of SA on tumour growth, followed by immunohistochemical analysis of Ki-67, CD40, p-AKT and p-mTOR. SA treatment reduced EC cell viability, proliferation, invasion and migration, while also triggering apoptosis and inducing cell cycle arrest in the G0/G1 phase in a dose-dependent way. These effects correlated with marked downregulation of CD40, p-AKT, p-mTOR, p-p65 and p52 expression. Conversely, activation of CD40 signalling with sCD40L promoted EC cell malignancy and overturned the anti-tumour effects of SA on EC cells. Additionally, SA treatment suppressed tumour growth in xenograft mouse models, along with reduced levels of Ki67, CD40, p-AKT, p-mTOR, p-p65 and p52 in mouse tumour tissues, which were counteracted by sCD40L co-treatment. SA effectively suppresses endometrial carcinoma progression by targeting the CD40-AKT-NF-κB pathway.

Autoimmune polyendocrine syndrome Type-1 (APS-1) is a rare, but severe organ-specific autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. Lack of AIRE causes autoreactive T cells to escape negative selection and alters the T regulatory cell subset. However, little is known about how the immune cell subsets vary across the lifespan in APS-1. Here we analysed the peripheral distribution of 13 immune cell subsets along the lifespan using epigenetic quantification. We found the largest discrepancy in immune cells to appear early in APS-1 patients' lives, coinciding with the time point they obtained most of their clinical symptoms. We further revealed longitudinal changes in cell compositions both within the adaptive and the innate arms of the immune system. We found that cell frequencies of B cells, T-cell subgroups, nonclassical monocytes, and Natural Killer cells to be reduced in young APS-1 patients. We also found B-cell frequencies to decrease with ageing in both patients and healthy controls. Our results suggest that Tregs, follicular helper T, and natural killer cells have opposing trends of cell frequencies during life, indicating the importance of considering the age profiles of cohorts which could otherwise lead to conflicting conclusions.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterised by aberrant activation and differentiation of autoreactive T and B cells, as well as the overproduction of autoantibodies. CD6, a cell-surface glycoprotein, regulates lymphocyte activation, differentiation and survival, and is implicated in the pathogenesis of various autoimmune disorders. In SLE, the CD6/activated leukocyte cell adhesion molecule (ALCAM) pathway promotes renal T-cell immune responses. However, the distribution, expression, and function of CD6 in lupus B cells remain poorly understood. In this work, we employed flow cytometry and multi-colour immunohistochemical staining to analyse the expression and distribution of CD6 on peripheral B cells. Correlation analysis was performed to assess the associations of CD6 and clinical indicators of disease severity. We found that SLE patients exhibited significantly reduced CD6 expression on peripheral CD19⁺ B, CD19⁺CD27^- B, CD19⁺CD27⁺ B, naïve B, CD19⁺CD27^-IgD^- double-negative B (DNB) and CD19⁺CD27⁺IgD⁺ B cells. Moreover, CD6 expression was negatively correlated with serum levels of alanine transaminase (ALT), lactate dehydrogenase (LDH) and the degree of white blood cell (WBC) depletion. Notably, SLE patients positive for antinuclear antibody (ANA) or anti-SSA antibody displayed lower CD6 expression on circulating B cells. Additionally, CD6 expression in B cells was predominantly localised in the extrafollicular (EF) region of human tonsils, suggesting a potential regulatory role of CD6 in EF B-cell responses. In conclusion, dysregulated CD6 expression on peripheral B cells might be related to liver/kidney injury and ANA/anti-SSA antibody production in SLE patients.

To determine leptin's effect on the thymus, we gathered data on leptin levels, ghrelin, cortisol and cytokine levels. The aim of the study was to map leptin's effect on the thymus when malnourished. Pubmed and Embase were searched for articles by the search terms 'malnutrition' and 'leptin'. The risk of bias was assessed by using JBI critical appraisal tools. Results were presented in tables and forest plots generated using STATA. A total of 16 articles were included. All articles included in the study are researching leptin, cortisol, or ghrelin, as well as cytokines. Forest plots were created for leptin, ghrelin, cortisol, Interleukin 10 (IL-10) and Interferon gamma (IFN-γ). Leptin had an overall effect size of 3.01 (95% CI 0.51; 5.51), ghrelin had an overall effect size of -1.71 (-2.97, -0.45), cortisol had an overall effect size of -1.16 (-1.49, -0.83), IL-10 had an overall effect size of -0.34 (95% CI -0.54; -0.14) and IFN-γ had an overall effect size of -0.02 (95% CI -0.25; 0.22), respectively. Our data revealed a decrease in leptin levels and an increase in cortisol, ghrelin and IL-10 when compared with control. This review displayed a relationship between leptin, cortisol, ghrelin and thymus atrophy. The change in T-helper cells contributes to the increased thymocyte depletion seen when severely malnourished. Leptin cannot explain all the changes observed, but may give insight into how it is a contributing factor in the changes the thymus undergoes.

Characterizing the immune response and pathogen tissue dissemination during progressive Treponema pallidum (T. pallidum) infection in the human is crucial for comprehending syphilis but it remains poorly understood, due to the unethical nature of inoculating volunteers with T. pallidum. An urgent new model is needed to study this issue. A human haematopoietic stem cell (Hu-HSC) mice model of syphilis was constructed through inoculation with T. pallidum. Blood and tissue samples were collected at serial time points (0, 3, 7, 14, 28 and 42 days post-infection) to analyse changes in the immune response and the presence of T. pallidum polA DNA and mRNA in the Hu-HSC mice. Treponema pallidum increased the percentage of helper T cell (Th) 1 and Th2 cells and induced the expression of Th1 and Th2 cytokines in the Hu-HSC mice, with a pattern of increasing and then decreasing response. However, there were no significant changes in the percentage of Th17 and Treg cells. Treponema pallidum polA DNA was detected in various organs such as the liver and spleen, indicating the dissemination of T. pallidum in the tissues. Furthermore, these organs were found to maintain the activity of T. pallidum through the detection of T. pallidum polA mRNA. These results suggested that Treponema pallidum induced the Th1 and Th2 immune response and disseminated in tissues in Hu-HSC mice. This study can provide a basis for future in vivo research on syphilis using the Hu-HSC mouse model and offer new references for explaining the pathogenesis of human syphilis.

Aplastic Anaemia (AA) is a rare, life-threatening condition characterised by bone marrow failure and pancytopenia. The primary treatment options include haematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST), each with distinct advantages and limitations. While HSCT offers a potential cure, its use is limited by factors such as donor availability, graft-versus-host disease, and its unsuitability for older patients. In contrast, IST is less invasive and more widely accessible, with a success rate of 60%-90%, but it carries a high risk of relapse and progression to myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and clonal evolution. Predictive markers are crucial for personalising treatment, monitoring efficacy and assessing relapse risk. However, only a few markers are currently implemented in clinical decision-making. This review focuses on the clinical, immunological and genetic markers, including cytokine levels, telomere length and paroxysmal nocturnal haemoglobinuria (PNH) clone size, which have been identified as potential predictors of IST response in AA. Most studies have been retrospective in nature, with variability in techniques and therapies, leading to inconsistency and limited reproducibility. Future large-scale prospective studies, conducted with standardised protocols, are essential to validate these markers. The development of a robust scoring system that integrates clinical and molecular data holds promise for improving personalised treatment approaches, ultimately enhancing AA management and patient outcomes.

T-cell activation, a pivotal process in the adaptive immune response, is initiated when the T cell receptor (TCR) recognises and binds to antigenic peptide-major histocompatibility complex (pMHC) molecules on the cell membrane. Emerging evidence indicates that mechanical cues regulate T-cell activation by modulating TCR signalling and mechanotransduction pathways, although the precise underlying mechanisms remain elusive. This review highlights recent findings suggesting that the TCR functions as a mechanosensor, capable of sensing and transmitting mechanical forces through conformational changes. Key steps in T-cell mechanotransduction are discussed, including the roles of the cytoskeleton, mechanosensitive channels such as Piezo 1 and microvilli in facilitating activation. Additionally, we analyse the mechanical responses of chimeric antigen receptor T cells. Understanding the mechanobiological mechanisms underlying T-cell activation offers novel insights and potential strategies for advancing immunotherapies and treating immune-related disorders.

The original Two Signal Model of lymphocyte activation stated that antigen-dependent lymphocyte cooperation is required for lymphocyte activation, whereas a single or a few antigen-specific lymphocytes can be inactivated by antigen. A virtue of this model is its ability to account for peripheral tolerance. Both the activation and inactivation of lymphocytes were envisaged to require the lymphocytes' antigen-specific receptors to interact with antigen, leading to signal 1. We consider here the proposition that the sensitivity to antigen concentration for the generation of signal 1, to support both differentiation processes, is the same. This situation optimizes the reliability of peripheral tolerance and minimizes the effects of lymphocyte inactivation in decreasing the diversity of the lymphocytes. We consider the broader implications of this Principle of Parsimonious Sensitivity in regulating the activity of lymphocytes.

The ChAdOx1 nCoV-19 vaccine has been in large-scale use during the COVID-19 pandemic. Limited efficacy compared to mRNA vaccines and certain potential side effects raise the question of whether anti-adenoviral vector antibodies influence immune responses against the vaccine. Complement activation by ChAdOx1 and leukocyte phagocytosis of ChAdOx1 in vitro were studied. Plasma IgG levels against ChAdOx1 and human adenovirus 2 (hAdV2) hexon protein were determined (n = 20) and IgGs from high- and low-titre plasmas were isolated (n = 3). Complement activation was measured as cleavage of C3 by immunoblotting and generation of C3a and sC5b-9 by ELISA. pHrodo-labelled ChAdOx1 was opsonized with complement and IgG, and phagocytosis by isolated blood PMNs in vitro was studied by flow cytometry. The transcriptomic profile of PMN cells exposed to ChAdOx1 was analysed by RNA-seq. ChAdOx1 activated the classical complement pathway in an anti-adenovirus antibody-dependent manner. Generation of the terminal complement complex sC5b-9 in individual sera correlated with anti-hAdV2 hexon and anti-ChAdOx1 IgG levels. Phagocytosis of ChAdOx1 also correlated significantly with anti-hAdV2 hexon IgG, anti-ChAdOx1 IgG and serum sC5b-9 levels. High-titre anti-hAdv2 hexon IgG increased phagocytosis in the presence of normal serum. Anti-vector antibodies induced rapid complement activation and promoted phagocytosis of the ChAdOx1 vaccine by neutrophils. Moreover, transcriptomic analysis revealed upregulation of complement-related genes induced by the ChAdOx1 vaccine in vitro. Anti-adenovirus vector antibodies and complement activation may thus influence the efficacy of the ChAdOx1 vaccine against SARS-CoV-2 and be also involved in vaccine-related side effects.