Scandinavian Journal of Immunology最新文献

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.

Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies globally, characterized by significant heterogeneity, late-stage diagnosis, and resistance to treatment. In recent years, the advent of immune-checkpoint blockades (ICBs) and targeted immune cell therapies has marked a substantial advancement in HCC treatment. However, the clinical efficacy of these existing therapies is still limited, highlighting the urgent need for new breakthroughs. Natural killer (NK) cells, a subset of the innate lymphoid cell family, have shown unique advantages in the anti-tumour response. With increasing evidence suggesting the crucial role of dysfunctional NK cells in the pathogenesis and progression of HCC, considerable efforts have been directed toward exploring NK cells as a potential therapeutic target for HCC. In this review, we will provide an overview of the role of NK cells in normal liver immunity and in HCC, followed by a detailed discussion of various NK cell-based immunotherapies and their potential applications in HCC treatment.

Evaluating immune status is a challenging and time-consuming process that involves analysing various biomarkers through numerous assays. The sensitive label-free technique of multispectral imaging of cell autofluorescence involves directly assessing the molecular composition of cells to gather biological information. Cells were cultured in RPMI 1640 modified media supplemented with penicillin-streptomycin and 10% foetal bovine serum at 37°C, with 5% CO₂ and 95% humidity. Activation and differentiation was confirmed using immunofluorophores against relevant markers. Multispectral microscopy utilized defined spectral regions, which spanned the excitation (345-476 nm) and emission (414-675 nm) wavelength ranges. In total, 56 distinct spectral channels were applied. These channels cover the spectrum of several fluorophores notably NAD(P)H and flavins, whose concentrations depend on cellular metabolism. We identified distinct spectral signatures for characterizing cells from the Jurkat, Ramos, THP-1, and HL-60 immune cell lines. These signatures correspond to four major immune cell types: T cells (Lymphocytes), B cells (Lymphocytes), monocytes and neutrophils. Moreover, our investigation explored the potential identification of both activated and resting forms of these cells, including the discrimination of M0, M1 and M2 polarized macrophages. Classification accuracy ranged from 92% to 100% based on receiver operator characteristic area under the curve (ROC AUC) assessment. These results indicate that the multispectral evaluation of cell autofluorescence is applicable for characterization of immune status. This includes the assessment of cell types and their activation status, all achievable through a single non-invasive assay.

Oocyte donation (OD) pregnancies show a higher fetal-maternal incompatibility and a higher risk of developing pre-eclampsia (PE) than autologous pregnancies. As maternal monocytes play a role in the tolerization of the allogeneic fetus, the aim of this study was to analyse monocyte phenotypes in healthy and PE OD pregnancies. We collected maternal peripheral blood at different gestational time points in healthy (n = 10) and PE (n = 5) OD pregnancies. Fetal-maternal human leukocyte antigen (HLA) mismatches were calculated. We used a 35-colour antibody panel for Aurora spectral flow cytometry to analyse the composition and surface marker expression of monocyte subsets. Expression of CD38 on intermediate monocytes significantly increased throughout gestation in healthy OD pregnancies. Compared with the healthy group, the PE group exhibited even higher CD38 expression on monocyte subsets, with statistical significance. Immune inhibiting receptors CD85j (LILRB1) and CD85d (LILRB2), as well as monocyte recruitment regulating molecules CCR2 and CD91, also showed significantly enhanced expression on monocyte subsets during PE. When comparing healthy and PE OD only in pregnancies with high HLA mismatches, the different CD38 and CD85j expression in monocyte subsets was still significant. In conclusion, in healthy OD pregnancies, the upregulated CD38 expression might reflect a proinflammatory condition specifically at the third trimester. In PE OD pregnancies, expression of both inflammatory and immune regulatory markers is increased in maternal peripheral monocyte subsets. The elevated expression of CCR2 and CD91 on these subsets might reflect monocyte chemotaxis and the effect from systemic vascular dysfunction at the late stage of PE.

The effects of vitamin D and vitamin A in immune cells are mediated through the vitamin D receptor (VDR) and retinoic acid receptor (RAR), respectively. These receptors share the retinoid X receptor (RXR) co-factor for transcriptional regulation. We investigated the effects of active vitamin D₃ (1,25(OH)₂D₃) and 9-cis retinoic acid (9cRA) on T helper (T_H)1 and T_H2 cytokines and transcription factors in primary human blood-derived CD4⁺ T cells. We aimed to address the discrepancies in this field, particularly regarding the effects of 9cRA and the vitamins in combination. 1,25(OH)₂D₃ upregulated IL-13 and suppressed IFNγ, while 9cRA had the opposite effects. This was largely independent of a T_H1/T_H2 phenotype shift. Combined vitamin supplementation produced intermediate cytokine levels, not only through transcriptional regulation by VDR-RXR and RAR-RXR but also through 1,25(OH)₂D₃ counteracting the effects of 9cRA on solely 9cRA-responsive genes. Similar results were observed in hereditary vitamin D-resistant rickets (HVDRR) patient T cells, where VDR cannot bind to DNA, indicating that RXR binding to either receptor can limit the other's activity. Additionally, we observed downregulated RAR upon 9cRA supplementation and its re-localization out of the nucleus upon 1,25(OH)₂D₃ supplementation, suggesting a mechanism of indirect regulation by VDR. VDR protein levels were also upregulated upon 9cRA supplementation, suggesting a novel negative feedback mechanism of 9cRA transcriptional activity, whereby 9cRA promotes its own competitor. This study sets the stage for future research into the combined immunomodulatory mechanisms of 1,25(OH)₂D₃ and 9cRA, involving both direct transcriptional regulation and indirect regulation via RXR competitive binding.

This study retrospectively analyzed the outcomes of 61 pediatric patients with inborn errors of immunity (IEI) who underwent hematopoietic stem cell transplantation (HSCT) between 2011 and 2023. Patients were categorized into primary immunodeficiency disorders (PIDD), primary immune dysregulation disorders (PIRD), and congenital defects of phagocyte number or function (CDP). Median ages at diagnosis and HSCT were 9 and 30 months, respectively. With a median follow-up of 51 months, the overall survival (OS) was 70%, with a 100-day post-transplant OS of 80%. Transplant-related mortality (TRM) was 29%, with rates of 42%, 22.5%, and 27% for PIRD, PIDD, and CDP, respectively. This study highlights the importance of early diagnosis and HSCT in improving survival for IEI patients, while also emphasizing the need for continuous improvements in transplant protocols to minimize TRM and enhance quality of life.