Scandinavian Journal of Immunology最新文献

Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options, and impairment of natural killer (NK) cell cytotoxicity within the tumour microenvironment remains a major challenge. The present study investigated the role of the NogoA/Nogo receptor 1 (NgR1) axis in modulating NK cell-mediated cytotoxicity against TNBC cells. NK-92 and MDA-MB-231 cells were co-cultured at optimised effector-to-target ratios, followed by treatment with the NgR1 antagonist NEP1-40. Cell viability was assessed by WST-1 assay, apoptosis was evaluated using AO/DAPI staining, gene expression was analysed by RT-PCR, and downstream pathways together with immune infiltration were examined in silico. Blockade of NogoA/NgR1 signalling increased NK-92-mediated cytotoxicity (p < 0.0001). NEP1-40 reduced tumour cell viability from approximately 81% to 50% and significantly increased apoptotic cell death (p < 0.0001). Expression analysis revealed repression of oncogenic and migration-associated genes, including CDK4, MYC, NF-κB1, VEGFA, FGF1, N-cadherin and CD155, consistent with enhanced NK cell-mediated cytotoxicity and reduced tumour immune evasion. Functional annotation identified the PI3K/AKT pathway alongside cell cycle-related processes as candidate downstream mechanisms, while correlation analysis showed that most NogoA-regulated genes were significantly negatively associated with NK cell infiltration (p < 0.05), highlighting their role in immune escape. These findings suggest that NogoA regulates both tumour behaviour and immune remodelling in TNBC by enhancing NK cell-mediated cytotoxicity, promoting apoptosis and suppressing immune evasion pathways. Targeting the NgR1/NogoA axis may therefore represent a promising approach to strengthen NK cell-based immunotherapy, offering a novel therapeutic avenue in TNBC.

Immune dysregulation is involved in Parkinson's disease (PD), but the roles of C-X-C motif chemokine receptor 3 (CXCR3)/chemokine receptor 6 (CXCR6) on T cells and their correlation with peripheral inflammation remain unclear. This study investigated their expression on peripheral blood T cells and correlation with inflammation in PD. A total of 36 PD patients and 26 healthy controls were enrolled; their clinical information and laboratory test results (including the systemic immunoinflammatory index [SII], neutrophil-to-lymphocyte ratio [NLR], monocyte-to-lymphocyte ratio [MLR], platelet-to-lymphocyte ratio [PLR], monocyte-to-high-density lipoprotein ratio [MHR], and erythrocyte distribution width over platelets ratio [RPR]) were recorded. Meanwhile, a multicolour flow cytometry protocol using six cell surface antibodies (CD3, CD4, CD8, CD45RO, CXCR3, and CXCR6) was applied. The results showed that CD8⁺ T cells were significantly reduced in the PD group compared with healthy controls (p < 0.001), and CXCR3 expression was significantly increased on peripheral blood CD4⁺ effector T cells and CD8⁺ T cells of PD patients (p < 0.001). Additionally, CXCR6 expression was significantly elevated on cytotoxic T lymphocytes (CTLs) (p < 0.0001) but showed no significant difference on CD4⁺ T cells between PD patients and controls (p > 0.05). Compared with healthy controls, PD patients had significantly increased peripheral blood C-reactive protein (CRP) levels (p < 0.001) but remarkably decreased monocytes, lymphocytes, and MHR (p < 0.01). Collectively, the upregulated expression of CXCR3 and CXCR6 predominantly on CD8⁺ T lymphocytes may contribute to PD pathogenesis, though no significant correlation between the expression of these receptors and peripheral inflammation was observed.

Cardiofaciocutaneous syndrome (CFCS) is a RASopathy involving craniofacial, cardiac, cutaneous, and neurologic features. MAP2K1 mutations, particularly in the kinase domain, are linked to CFCS type 3. Immune dysfunction has not previously been reported with the p.Tyr130His variant. To describe the case of combined immunodeficiency (CID) associated with the MAP2K1 p.Tyr130His variant. A 4-month-old female with CFCS presented with recurrent infections, growth failure, and ectodermal findings. Immunologic workup revealed hypogammaglobulinemia, low T cell subsets, and absent vaccine responses. Genetic analysis identified the MAP2K1 p.Tyr130His variant. She was started on intravenous immunoglobulin and prophylaxis, with clinical improvement. We describe a case of CID associated with the MAP2K1 p.Tyr130His variant adding to the growing evidence of immune dysregulation in CFCS.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children and adolescents usually follows a mild or asymptomatic course. In this brief report, we investigated the cellular and humoral responses to SARS-CoV-2 in six healthy Spanish female adolescents, aged 14 to 16, using blood samples collected early in 2021, well before COVID-19 vaccinations. Using IFNγ-ELISPOT assays, we detected T cell recall responses in four of these adolescents to a peptide pool encompassing the SARS-CoV-2 Spike protein. The same subjects also exhibited IgM antibodies against the Nucleocapsid and Spike proteins as determined by ELISA in sera samples. However, no IgG antibodies were detected against Spike protein and none of the sera samples were capable of blocking viral entry in a spike-dependent infection assay using SARS-CoV-2 pseudoviruses. The detected immune responses are consistent with the presence of pre-existing cross-reactive immunity to SARS-CoV-2 in children/adolescents, which could have contributed to protect this segment of the population.

Post-COVID-19 syndrome (PCS; also known as post-acute sequelae of COVID-19, PASC and Long COVID) manifests with various clinical symptoms of unclear aetiology that persist or develop months after acute infection with SARS-CoV-2. Potential triggers for PCS include reactivation of latent viruses and autoimmune reactions. In our retrospective cross-sectional and explorative study we compared 48 PCS patients with 48 individuals that recovered fully from COVID-19 (convalescents, CC). We focused on characterising humoral immunity by recording IgG antibody reactivity patterns against Epstein-Barr virus (EBV) EBNA1 antigen using peptide microarray and ELISA methodology as well as determining the presence of autoantibodies. The overall binding landscape of IgG antibodies for the EBV EBNA1 protein was similar for the patients with sequelae versus the convalescents. However, the PCS patients displayed stronger reactivity for epitopes contained within the glycine-alanine repeat region of EBNA1, in particular residues 90-325, and within the central part, amino acids 393-420. Intriguingly, in the latter case, the EBNA1 peptide (residues 405-419) that discriminated the PCS and CC cohorts was localised in a different segment C-terminal from the sequence proposed to be mechanistically associated with multiple sclerosis. The screening for autoantibodies against nuclear/cytoplasmic antigens in HEp-2 cells and against CRYAB, cardiolipin, beta-2-glycoprotein I, IFN-alpha2, IFN-omega, and IL-15 antigens did neither reveal higher prevalence nor increased reactivity in the PCS patients compared to the convalescents. In conclusion, elevated antibody levels against linear peptides derived from residues 90-325 and 405-419 of EBV EBNA1 were the most distinctive characteristics in our cohort of post-COVID-19 syndrome patients.

Leukotriene B₄ (LTB₄), a potent chemotactic and immune-modulating eicosanoid, signals via two receptors (BLT₁ and BLT₂), leading to rapid but transient migratory, adhesive and secretory responses in phagocytes. Previously, we reported that BLT₁ is the predominating BLT in human umbilical vein endothelial cells (HUVEC). However, little is known about how ligation of these receptors affects adhesive and secretory endothelial responses over time. Here, we demonstrate that in HUVEC, LTB₄ dose-dependently and stereospecifically causes a biphasic tethering of neutrophils, where the second phase is robust, similar to that induced by lipopolysaccharide, and persists for 3-8 h. LTB₄ also causes up-regulation of E-selectin, ICAM-1 and VCAM-1 and release of MCP-1 and nitric oxide (but not of IL-8 or HMGB1). These responses appeared to be mediated via BLT₁ and BLT₂ as judged by BLT₁ shRNA gene silencing and/or treatment with BLT₁ and BLT₂ specific antagonists prior to LTB₄ activation of HUVEC. Moreover, LTB₄ responses used primarily the MAP kinase/Erk pathway. Our findings suggest a new role for LTB₄ not only in early but also in late vascular inflammatory responses.

Peripheral immune tolerance is a cardinal feature of the adaptive immune system, which makes self-nonself discrimination and unresponsiveness toward self-antigens. Disruption in the regulation of these processes leads to damage to self-tissues and serious consequences, including autoimmune diseases. In the T cell compartment, the family of regulatory T cells (Treg cells) is the main component for the induction and maintenance of immune tolerance and preventing autoimmune diseases. Forkhead box P3 (FOXP3) is the key transcription factor for the function and Treg cell programming. Importantly, FOXP3 by itself is insufficient to completely specify the Treg cell program, suggesting that additional accessory transcription factors are involved both upstream and downstream, as well as alongside FOXP3, in directing Treg cell specification and its expression is controlled through various regulatory factors and epigenetic modifications. In the current review, we examine new insight into the regulatory mechanisms of Treg cell functions and programming with an emphasis on FOXP3, which opens new avenues for future therapeutic strategies of autoimmune disorders.

The diagnosis, management and potential eradication of cancer depend on tumour type, stage, extent and anatomical location. While surgery, chemotherapy and radiotherapy remain central, advances in molecular oncology have shifted treatment toward personalised approaches. Identification of tumour-specific molecular abnormalities and biomarkers has enabled targeted therapies that eliminate malignant cells while limiting damage to normal tissues. Cancer immunotherapy has emerged as a promising, non-invasive strategy that activates the immune system to recognise and attack tumour-specific antigens. Preventive vaccines based on weakened or inactivated viruses have achieved notable success in reducing virus-associated cancers. Therapeutic vaccines targeting tumour-associated antigens (TAAs) and patient-specific neoantigens aim to elicit strong cytotoxic and helper T-cell responses against established tumours. Advances in genomic sequencing, bioinformatics-driven neoantigen prediction and single-cell profiling now enable accurate identification of tumour-specific targets. This review highlights progress in cancer vaccine research, focusing on strategies targeting TAAs, neoantigens and delivery platforms such as dendritic cell-based systems, nucleic acid vaccines (DNA and mRNA), synthetic long peptides and viral or bacterial vectors. Clinical evidence shows that neoantigen vaccines induce potent tumour-specific T-cell responses with minimal autoimmunity and gain enhanced efficacy when combined with immune checkpoint inhibitors or adoptive T-cell transfer (ACT) using tumour-infiltrating lymphocytes (TILs). By reinvigorating anti-tumour T cells within the tumour microenvironment, these combination approaches support durable tumour regression and improved outcomes. Despite unresolved challenges, advances in AI-guided target discovery, nanotechnology-based delivery systems and scalable manufacturing offer promising solutions for achieving precise and durable cancer treatment.

We recently reported that a homozygous deletion in the complement factor H-related (CFHR) locus predisposed kidney transplant patients to rejection. As donors carried intact genes, the susceptibility may have resulted from an alloimmune reaction to FHR proteins. However, we found no evidence for an anti-FH response. It is therefore possible that CFHR deletions as such affect the rejection risk. Here, we used MLPA and WGS to fine-map and sequence the CFHR region in rs7542235-GG patients, a SNP tagging for ΔCFHR3-1 deletion. Our results confirmed that all patients with this SNP harboured deletions of various sizes encompassing CFHR1. Furthermore, patients with homozygous ΔCFHR3-1 were homozygous for rs6677604-A, a SNP tagging for deletions of CFHR3-1 locus, confirming that allele A tags for deletion of both CFHR3 and CFHR1. Proteomics analyses in a larger population demonstrated that rs7542235-G and rs6677604-A associate with expression levels of several proteins involved in regulating alloimmune response. We observed that while increasing the rejection risk, the ΔCFHR3-1 did not associate with baseline disease or specific clinical characteristics. To conclude, the various deletion types found in patients shared the deletion of the CFHR1 gene confirming its association with variant rs7542235. Also, both deletion-tagging alleles are associated with altered expression of FHR proteins.