BMC Immunology最新文献

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major global health burden due to latent infection, multidrug resistance, and the limited efficacy of the BCG vaccine. To address this challenge, we computationally designed and evaluated a circular mRNA-based multi-epitope vaccine candidate, TZ1391. Five experimentally validated M. tuberculosis antigens (ESAT-6, CFP-10, Ag85B, PPE18, and HspX) were used to predict immunodominant cytotoxic T lymphocyte (CTL), helper T lymphocyte (HTL), and B-cell epitopes. Three vaccine constructs (MTB-C1, MTB-C2, and MTB-C3) were assembled by integrating 20 CTL, 20 HTL, and 20 B-cell epitopes with appropriate linkers, PADRE sequence, and innate immune adjuvants. Structural modeling using AlphaFold2 and GalaxyRefine confirmed stable, native-like conformations for all constructs, with MTB-C3 showing the highest structural quality (GDT-HA = 0.8782; RMSD = 0.646 Å) and the greatest number of stabilizing disulfide bonds. Molecular docking against TLR3, TLR4, and TLR8 identified two top-performing candidates. MTB-C3 exhibited the strongest interaction with TLR3, achieving the lowest HDock score (- 480.53) and highest confidence score (0.9987), while MTB-C2 showed optimal binding to TLR4 (ClusPro score - 1488.6; confidence 0.9700). Despite favorable TLR4 engagement by MTB-C2, MTB-C3 was prioritized as the lead candidate (TZ1391) due to its superior structural stability, reduced conformational fluctuations during molecular dynamics simulations, and stronger TLR3 binding free energy (ΔG_bind = - 173.25 ± 7.9 kcal/mol). Immune simulations further predicted that TZ1391 elicits a robust Th1-biased response, characterized by sustained IgG production, strong IFN-γ and IL-2 induction, and durable immune memory. Overall, the strong TLR3-mediated interaction, combined with enhanced structural stability and favorable immunogenic profiles, establishes TZ1391 as a promising multi-epitope vaccine candidate for further experimental validation against tuberculosis.

Background: T lymphocyte dysfunction is closely associated with immunosuppression in sepsis, whereas the underlying mechanisms are not fully understood.

Results: In this study, we established a mouse model of cecal ligation and puncture (CLP)-induced sepsis and observed immunometabolic alterations in splenic T cells. Serum energy metabolites related to glycolysis and the tricarboxylic acid (TCA) cycle were imbalanced. Splenic T cells from septic mice showed a shift in subset distribution, with decreased naïve T cells and increased effector populations, along with concurrent activation and exhaustion phenotypes. Notably, mitochondrial mass and mitochondrial membrane potential were significantly diminished in both CD4⁺ and CD8⁺ T cell, correlated with increased programmed cell death protein 1 (PD-1) expression. Transmission electron microscopy further confirmed mitochondrial morphological alterations in CLP-derived CD3⁺ T cells. Furthermore, seahorse assays demonstrated impaired metabolic reprogramming capacity in activated CLP splenic CD3⁺ T cells, with suppressed glycolytic and oxidative phosphorylation responses. This impairment was coupled with reduced fold-increases in mitochondrial mass and mitochondrial membrane potential levels upon activation in both CD4⁺ and CD8⁺ T cell compared to controls. Clinically, peripheral T cells from septic patients showed elevated CD69 and PD-1 expression, a significant increase in CD39 and a decrease in CD73, increased mitochondrial mass and decreased mitochondrial membrane potential, particularly in those with septic shock.

Conclusions: Our findings provide several layers of T cell dysfunction in sepsis, linking subset redistribution, an exhausted phenotype, mitochondrial impairment, and reduced proliferative capacity, suggesting that future therapeutic interventions aiming to reverse sepsis-induced immunosuppression may require a combinatorial approach.

Background: Anti-interferon (IFN)-gamma (γ) autoantibody positivity (AIGA) is a rare cause of adult-onset immunodeficiency, leading to severe disseminated opportunistic infections with varying outcomes. Due to its rarity, the diagnosis of AIGA is often missed or delayed.

Methods: We used the hospital information system of the First Affiliated Hospital of Wenzhou Medical University to retrospectively analyze the data of patients with AIGA between January 2018 and March 2024. Clinical, laboratory, and outcome data were collected and analyzed.

Results: Six patients with AIGA were included in this study. A retrospective review of the clinical characteristics and laboratory results showed that all patients had recurrent opportunistic infections, and five patients had hypergammaglobulinemia before receiving the diagnosis of AIGA. All six patients presented with pneumonia and recurrent cough; two patients presented with recurrent skin abscesses, two presented with recurrent penile ulcers, and two presented with severe bone destruction. Of these, five patients were infected with Talaromyces marneffei (T. marneffei). After being diagnosed with AIGA, all six patients received routine anti-infection therapy. As the disease progressed, all patients presented with recurrent infections. Notably, five patients exhibited elevated serum immunoglobulin G (IgG) (median 25.06 g/L; interquartile range, 17.73-38.22) during a previous admission. One succumbed to respiratory failure at follow-up, while five survived.

Conclusion: The diagnosis of AIGA is often delayed and should be considered as a differential diagnosis in patients with recurrent opportunistic infections and hypergammaglobulinemia.

Introduction: Asthma is a complex and heterogeneous disease that significantly impacts quality of life. Eosinophilic asthma, characterized by elevated eosinophil levels, leads to inflammation and hypersensitivity. Many patients remain inadequately managed, resulting in frequent exacerbations and hospitalizations despite standard treatment options. Depemokimab, a long-acting monoclonal antibody that targets IL-5, could offer a novel approach for managing severe eosinophilic asthma.

Methods: A systematic search was conducted across the PubMed, Cochrane Library, Embase, ClinicalTrials.gov, and Scopus databases up to January 2025. Dichotomous outcomes were pooled as risk ratios (RR), and continuous outcomes were represented as mean differences (MD) from baselines, with 95% confidence intervals (CIs), using a random-effects model. Statistical analysis was performed using RevMan (version 5.4).

Results: Two randomized controlled trials (n = 762) were included. Depemokimab significantly reduced the annualized rate of exacerbations (MD -0.59, 95% CI [-0.76 to -0.42], P < 0.00001) and improved the St. George's Respiratory Questionnaire (SGRQ) score (MD -2.93, 95% CI [-5.48 to -0.38], P = 0.02). It also significantly decreased the annualized rate of exacerbations requiring hospitalization or emergency department visits (RR 0.33, 95% CI [0.15 to 0.75], P = 0.008). No significant differences were observed in changes to the Asthma Control Questionnaire (ACQ-5) score, pre-bronchodilator FEV1, or asthma-related diaries. Safety outcomes indicated significantly lower risks for pneumonia, nasopharyngitis, rhinitis, and back pain in the Depemokimab group. However, an increased risk of allergic rhinitis was noted (RR 2.71, 95% CI [1.22 to 6.02], P = 0.01). No significant differences were observed in serious adverse events or other adverse events.

Conclusion: Depemokimab demonstrates promising efficacy in reducing clinically significant exacerbations and improving quality of life measures in patients with severe eosinophilic asthma, with a generally favorable safety profile. However, the current evidence is limited to two trials with relatively short follow-up periods. Further research with larger, more diverse patient populations and extended long-term follow-up is needed to establish the drug's definitive place in therapeutic algorithms and to comprehensively evaluate potential long-term safety concerns before widespread clinical implementation can be recommended.