Clinical and experimental immunology最新文献

Post-transarterial chemoembolization (TACE) hypoxia plays a crucial role in hepatocellular carcinoma (HCC) progression. However, the effects of post-TACE hypoxia on HCC progression are not fully understood yet. This study aimed to elucidate the effects of post-TACE hypoxia-induced hypoxia-inducible factor-1α (HIF-1α)/WNT/β-catenin signaling on HCC progression. In this study, serum concentrations of soluble programed death ligand 1 (sPD-L1) and HIF-1α in HCC patients who underwent TACE were measured using enzyme-linked immunosorbent assay (ELISA). In vitro, WNT/β-catenin pathway activation was assessed by TOP/FOP luciferase activity, while HIF-1α-siRNA transfection was used to observe the interaction between HIF-1α and WNT/β-catenin. In vivo, mouse xenograft tumor models were used to examine the effects of programed death ligand 1 (PD-L1) on HCC progression and to verify the correlations among HIF-1α, WNT/β-catenin, and PD-L1. The mechanisms underlying hypoxia-induced PD-L1 overexpression were studied using chromatin immunoprecipitation (ChIP). We found that the median post-TACE serum sPD-L1 and HIF-1α concentrations in HCC patients were significantly higher compared to pre-TACE levels, with a significant correlation observed between sPD-L1 and HIF-1α. In vitro studies demonstrated that hypoxia promoted WNT/β-catenin activation and PD-L1 expression. HIF-1α silencing significantly inhibited WNT/β-catenin activation. In vivo, hypoxia-induced PD-L1 overexpression significantly promoted HCC progression. WNT/β-catenin activation increased PD-L1 promoter luciferase activity, and ChIP confirmed that LEF1 bound to the PD-L1 promoter in hypoxic hepatoma cells. Therefore, we concluded that the post-TACE hypoxia-induced activation of HIF-1α/WNT/β-catenin signaling could promote HCC progression by upregulating PD-L1 expression.

Melanoma is currently the fifth most common cancer in the UK, and its incidence is rising. Although surgery is curative for many early-stage tumours, advanced disease which is inoperable has historically also been considered incurable. Recent and rapid advances in cancer immunotherapy, particularly immune checkpoint inhibitors, have now revolutionized the management of advanced melanoma with many patients likely being cured. Here, we review the immunobiology of melanoma, the growing list of standard-of-care immunotherapies and the considerations around which treatment regimen to use. We also review evidence from recent clinical trials of promising novel immunotherapies which will hopefully help patients who do not benefit from current treatments.

Periodontitis is a frequent local inflammatory disease. The microbiota and repeated exposure to bacterial endotoxins triggers excessive inflammation through oral mucosal immunity and sometimes leads to a destructive effect on the supportive mucosal tissues around the teeth. Elimination of the pathogens and increasing the tolerance of the cellular immune response is crucial in addition to standard dental therapies like mechanical debridement. Based on our experience with immune-mediated diseases, especially primary immunodeficiency diseases, we wrote this review to discuss the treatment alternatives for severe periodontal disease. Risk factors are malnutrition, vitamin deficiencies, smoking, systemic inherited and acquired immune-mediated diseases, infections, endocrinological diseases, and pharmacological agents that may accompany periodontitis. The diagnosis and treatment of dietary deficiencies, as well as the addition of nutritional supplements, may aid in epithelial regeneration and immune system function. Recently, modifications to the therapeutic option for severe periodontitis have been made depending on the fact that the immune response against bacteria may modify the severity of periodontal inflammation. The anti-inflammatory therapies support or inhibit the host's immune response. The clinical approach to severe periodontitis should extend beyond classical therapies. There is a need for a diverse therapeutic strategy that supports the epithelial barrier, which is the crucial component of innate immunity against microbiota. Leukocytes are the main cellular component in periodontal inflammation. Anti-inflammatory therapeutic options directed at leukocytes, such as IL-17 and IL-23-targeted therapies, could be the candidates for the treatment of severe periodontitis. Therapy against other inflammatory cytokines, IL-1, IL-6, IL-12, IL-23, TNF-alpha, PGE2, and cytokine receptors, could also be used in periodontal inflammation control.

Eosinophilic Esophagitis (EoE) is a chronic disease primarily driven by immune-mediated pathogenesis, characterized by eosinophil-driven inflammation of the oesophagus, leading to organ dysfunction and fibrosis. Although initially considered a rare disorder, EoE is now recognized as one of the leading causes of food impaction and dysphagia. Advances in knowledge and diagnostic techniques have contributed to its increased detection; however, epidemiologic data suggest that the surge in incidence represents an actual rise in disease prevalence rather than solely increased awareness. The pathogenesis of EoE remains largely unclear, but it is believed to involve a complex interplay of genetic predisposition, environmental factors, diet-derived allergens, and immune dysregulation. A significant role in the pathogenesis of EoE is attributed to environmental and, particularly, food allergens, with mechanisms that extend beyond IgE-mediated pathways, as evidenced by the lack of efficacy of anti-IgE therapies such as omalizumab in clinical trials. A key pathogenic feature is the dysregulated activation of pathways mediated by T-helper type 2 (Th2) lymphocytes. Supporting the role of the Th2 system in EoE inflammation is the demonstrated efficacy of monoclonal inhibitors of interleukin 4 and 13 (i.e. dupilumab), currently the only approved biological therapy for this condition. Additionally, the role of autophagic processes in EoE pathogenesis is becoming increasingly evident. This review aims to provide a concise overview of the key pathogenic mechanisms of EoE and the currently available diagnostic approaches, both invasive and non-invasive, for managing this disorder.

Coronary artery involvement (CAI) is a special but not rare manifestation of Takayasu arteritis (TAK). Granzyme B (GzmB) is a multifunctional protease associated with the immune system and coronary artery disease. However, its role in patients with TAK and CAI remains unclear. This study investigates the role of GzmB+ cell subsets in TAK. The study included 105 TAK patients and 58 healthy controls. The percentages of different GzmB+ cells in blood samples were analyzed by flow cytometry. We found that age, age at onset, body mass index, disease duration month, hypertension, and hyperlipidemia were significantly different between TAK patients with and without CAI (P = 0.000, P = 0.038, P = 0.003, P = 0.031, P = 0.039, P = 0.000). The proportions of CD3+CD8+cells (P = 0.001) and CD3+CD4+cells (P = 0.000) in GzmB+ cells were significantly increased, while the proportion of CD3-CD56+cells (P = 0.001) in GzmB+ cells was decreased in TAK patients. The proportions of three types of GzmB+ subsets in lymphocytes (CD3+CD4+GzmB+, CD3+CD8+GzmB+, CD3+CD56+ GzmB+) were higher in TAK patients with CAI compared with those without CAI (P = 0.021, P = 0.007, P = 0.007). The increased proportion of CD3+CD8+GzmB+cells/lymphocytes was an independent risk factor for coronary involvement in TAK (OR = 4.990 [1.766-14.098], P = 0.002). Additionally, patients with a high CD3+CD8+GzmB+cells/lymphocytes ratio had a higher major adverse cardiovascular events rate than those with a low ratio in TAK (P = 0.019). Our results indicate that CD8 cell-derived Gzm B may be a predictor for CAI and major adverse cardiovascular events in TAK patients. Targeting CD3+CD8+GzmB+ lymphocytes or using GzmB inhibitors could be a potential therapeutic approach for the treatment of CAI in TAK.

Recent studies on cancer cells and the immune microenvironment have offered valuable insights into personalized diagnostics, targeted therapies, and individualized prognosis evaluation. A comprehensive understanding of new and existing biomarkers in both healthy and diseased conditions is essential for advancing these goals. CD56, also known as the neural cell adhesion molecule, is a well-established phenotypic marker of natural killer cells. It is also expressed by various immune cells under healthy conditions, such as T cells, dendritic cells, and monocytes. Despite its widespread expression, the functions of CD56 are still poorly understood. In patients with infectious, autoimmune, or malignant diseases, changes in the proportion, phenotype, and function of CD56+ immune cells have been observed. In patients with hematolymphoid disorders, malignant cells may exhibit aberrant CD56 expression, making it a valuable diagnostic and prognostic marker. CD56 also holds potential as a therapeutic target. In this review, we summarize the current understanding of CD56 expression and function across various immune cells in infectious, immune-related, and cancerous conditions. We also explore its diagnostic, prognostic, and therapeutic significance in hematological malignancies. This review aims to present a comprehensive overview of CD56 in hematolymphoid disorders, offering insights into how CD56 and its associated immune cells could inform future immunotherapeutic strategies.

Conventional dendritic cells (cDCs) in the gut express the vitamin A (VA)-converting enzyme retinal dehydrogenase 2 (RALDH2) and produce significant amounts of retinoic acid (RA). RA derived from gut cDCs contributes to the generation of tolerogenic responses by promoting regulatory T-cell (Treg) differentiation while inhibiting Th1 and Th17 cell differentiation. In this study, we investigated whether similar RA-mediated immunoregulatory mechanisms operate in the pancreas using an experimental autoimmune pancreatitis (AIP) model. Our previous studies have shown that activated cDCs and plasmacytoid DCs (pDCs) play crucial roles in the induction and maturation phases of experimental AIP, respectively. Pancreatic cDCs produce IFN-α/β, CXCL9, and CXCL10, which attract CD4+CXCR3+ T cells to the pancreas during the induction phase. These CD4+CXCR3+ T cells, in turn, produce CCL25, recruiting CCR9+ pDCs that secrete IFN-α/β, CXCL9, and CXCL10 during the maturation phase. Under homeostatic conditions, RALDH2 expression was higher in pancreatic cDCs than in pDCs. Pancreatic cDCs isolated from VA-deficient mice promoted CD4+ T-cell production of IFN-γ and CCL25-the latter being a chemokine implicated in AIP pathogenesis. VA deficiency increased susceptibility to experimental AIP through a process dependent on the pancreatic accumulation of CD4+CXCR3+ T cells producing CCL25. Conversely, activation of RA-mediated signaling pathways by Am80 protected mice from severe AIP by reducing the accumulation of CXCR3+ T cells producing CCL25. Collectively, these findings suggest that RA produced by cDCs protects against AIP development by inhibiting the pancreatic accumulation of CD4+CXCR3+ T cells. RA-mediated immunoregulation may serve as a potential therapeutic target for AIP.

Oral keratinocytes are pivotal to the structural and immunological integrity of the oral mucosa, orchestrating mucosal defense through multifaceted immune functions. This narrative review synthesizes mechanistic insights from primary keratinocyte cultures, in vitro infection models, transcriptomic and proteomic profiling, and immunohistochemical analyses to elucidate their roles in pathogen sensing via pattern recognition receptors, antimicrobial peptide production, cytokine secretion, antigen presentation, immune modulation, and tolerance induction. The review highlights their contributions to innate and adaptive immunity, including the secretion of antimicrobial peptides such as β-defensins and the regulation of T-cell responses through major histocompatibility complex molecules. It also examines their dysregulation in chronic inflammatory conditions, such as oral lichen planus, recurrent aphthous stomatitis, and periodontitis, where altered pattern recognition receptors signaling and barrier dysfunction drive disease progression. These insights underscore the therapeutic potential of targeting keratinocyte-mediated immunity to restore mucosal homeostasis.