Clinical and experimental immunology最新文献

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.

Our group previously demonstrated that NETs were involved in interstitial lung diseases (ILD) among patients with idiopathic inflammatory myopathies (IIM) and the experimental autoimmune myositis (EAM) mouse model and that NETs activated lung fibroblasts through the TLR9-miR7-Smad2 axis. This study aimed to establish a novel mouse model of myositis-associated interstitial lung disease (MAILD) by using a TLR9 agonist (ODN2395). ODN2395 and muscle homogenate were used to induce MAILD in BALB/c mice. MAILD was evaluated using histopathology, immunohistochemistry, serum NETs determination, and myositis-specific antibody profile. Furthermore, TLR9 and IRF3 were examined in a lung biopsy tissue from a dermatomyositis patient with ILD. MAILD mice developed inflammatory myopathy with positive expression of myositis-specific antibodies. ILD occurred in all mice of the MAILD group. ODN2395 at doses of 5 μg, 10 μg, or 20 μg induced ILD, with increasing severity as the dose increased, but 20 μg ODN2395 was not recommended due to non-specific damage to the lungs. ILD could occur as early as one week after immunization and was most pronounced by the fourth/fifth week. MAILD process was accompanied by NETs infiltration and TLR9 activation. TLR9 activation was demonstrated in the patient with DM-ILD. Serum levels of Cit-H3 were elevated in the MAILD group. Skeletal muscle homogenate and ODN2395 induced neutrophils to form NETs in vitro. Combined with muscle homogenate, ODN2395 induced a novel MAILD mouse model with NETs infiltration and TLR9 activation, which are similar to pathogenesis of IIM-ILD, suggesting that MAILD model could replace EAM model in IIM-ILD research.

Introduction: Cladribine is a deoxyadenosine analogue that can penetrate the blood-brain barrier. It is used to treat multiple sclerosis (MS). However, the mechanistic understanding of the effect of this highly effective therapy on B cells and plasma cells in the central nervous system compartment is limited. The CLADRIPLAS study examined the effect of cladribine on peripheral and intrathecal B and plasma cell biology in people with MS.

Methods: Thirty-eight people with progressive MS ineligible for- or rejecting-treatment with licenced therapies were recruited and supplied a baseline lumbar puncture. Those exhibiting gadolinium-enhancing or new/enlarging T2 magnetic resonance imaging lesions and/or elevated neurofilament levels were offered subcutaneous cladribine (Litak®). Seven people were eligible; one person died before treatment, and only five completed the first year of treatment. Twenty-two ineligible people were willing to provide a repeat lumbar puncture 12 months later.

Results: The CLADRIPLAS study found no evidence of a difference in the odds of a positive cerebrospinal fluid oligoclonal band result between the cladribine-treated and untreated group. This is probably explained by microarray and in vitro studies, which demonstrated that plasmablasts and notably long-lived plasma cells are relatively resistant to the cytotoxic effect of cladribine compared with memory B cells at physiological concentrations. This was consistent with the loss of intracellular deoxycytidine kinase during antibody-secreting cell differentiation.

Conclusion: CLADRIPLAS indicates that cerebrospinal fluid oligoclonal bands are not rapidly eliminated in most people with MS. This may be explained by the relative lack of direct cytotoxic action of cladribine on long-lived plasma cells.

Neutrophils are key effector leukocytes of the innate immune system and play a pivotal role in defending the host against microbial infections. Recent studies have identified a crucial link between glycolysis and neutrophil cellular functions. Using human neutrophils, we have investigated the intricate relationship between glycolysis, extracellular glucose availability, and the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), in the regulation of reactive oxygen species (ROS) and neutrophil extracellular trap (NET) production. We have identified that PFKFB3 is elevated in rheumatoid arthritis (RA) neutrophils and that the small molecule PFKFB3 inhibitor 3PO is a key regulator of neutrophil ROS and NET production. 3PO blocked the production of ROS and NETs in a dose-dependent manner in both RA and healthy neutrophils (P < 0.01), and RA neutrophils were more sensitive to lower concentrations of 3PO. Bacterial killing was only partially inhibited by 3PO, and the proportion of live neutrophils after 24 h incubation was unchanged. Using NMR metabolomics, we identified that 3PO increases the concentration of lactate, phenylalanine, and L-glutamine in neutrophils, as well as significantly decreasing intracellular glutathione (adj. P-value < 0.05). We also demonstrated that RA neutrophils produce ROS and NETs in culture conditions which mimic the low glucose environments encountered in RA synovial joints. Our results also suggest that 3PO may have molecular targets beyond PFKFB3. By dissecting the intricate interplay between metabolism and neutrophil effector functions, this study advances the understanding of the molecular mechanisms governing pro-inflammatory neutrophil responses and identifies 3PO as a potential therapeutic for conditions characterized by dysregulated neutrophil activation.