Frontiers in Immunology最新文献

Rosacea is a chronic inflammatory cutaneous disorder predominantly affecting the centrofacial region, whose pathogenesis is complex and not yet fully understood. In this review we summarized the latest significant advances in the pathogenesis of rosacea in recent years. In genomic studies, the application of bioinformatics techniques such as whole-genome sequencing has identified novel susceptibility genes and linked multiple pathogenic mechanisms. Neurovascular dysfunction resulting from abnormal neuropeptides expression and dysregulated amino acid metabolism constitutes an important pathogenic factor in rosacea. The TLR2/LL-37/mTORC1 signaling axis, as a core regulatory pathway in innate immunity has been elucidated in detail. In addition, the dysbiosis of skin and gut microbiota, together with the impairment of skin barrier function, is also closely associated with the onset and progression of this disease. The deeper understanding of the pathogenesis of rosacea will benefit the development of new drugs and promote individualized diagnosis and treatment.

Introduction: Hyperuricemia is a prevalent metabolic disorder primarily induced by purine dysregulation. Current therapies face limitations due to systemic side effects and inadequate efficacy, necessitating novel treatment strategies.

Methods: In this study, a biomimetic nanodrug, SZF@PDA‑RM, was synthesized by hybridizing the traditional medicine Shizhifang (SZF) with polydopamine (PDA), followed by erythrocyte membrane coating. Its physicochemical properties and reactive oxygen species (ROS)-responsive release were characterized. In vitro, a hyperuricemia cell model using uric acid (UA)-stimulated renal tubular cells (NRK‑52E) assessed cellular uptake, biosafety, ROS scavenging, and mitochondrial protection. Molecular mechanisms were probed via immunofluorescence, western blot, and inhibitor studies. In vivo efficacy and safety were evaluated in a hyperuricemic mouse model by measuring serum/urinary biomarkers, renal histopathology, and tissue ROS.

Results: The synthesized SZF@PDA‑RM exhibited a spherical morphology, demonstrating good stability and significant ROS-responsive drug release properties. The erythrocyte membrane coating effectively prolonged its systemic circulation. In the cellular model, SZF@PDA‑RM efficiently reduced UA-induced intracellular and mitochondrial ROS levels, restored mitochondrial membrane potential, mitigated mtDNA damage, and inhibited the activation of the NLRP3 inflammasome and the expression of downstream cytokines. Mechanistically, the nanoformulation negatively regulated mitochondrial ROS generation by promoting the interaction between SHP2 and ANT1, an effect that was reversed by SHP2 inhibitors. In the animal model, treatment with SZF@PDA‑RM significantly lowered serum uric acid, creatinine, and multiple urinary renal injury biomarkers in hyperuricemic mice. It also alleviated renal inflammatory infiltration and fibrosis, cleared renal tissue ROS, and showed no systemic toxicity.

Conclusion: The erythrocyte membrane-camouflaged SZF@PDA‑RM nanocomposite achieves long circulation and targeted delivery. It exerts a multi-target synergistic therapeutic effect by directly scavenging ROS, maintaining mitochondrial homeostasis via the SHP2/ANT1 pathway, and inhibiting NLRP3-mediated inflammation, thereby effectively improving uric acid metabolism and alleviating renal injury.

The development of an effective HIV-1 vaccine is of paramount importance to global health. Here, we compared the influence of two adjuvants, Escherichia coli double-mutant heat-labile toxin (dmLT) and alum, on the protective immunity induced by a cyclically permuted trimeric HIV-1 envelope gp120 protein (CycP-gp120) boost. Two groups of rhesus macaques received two modified vaccinia Ankara (MVA)/SHIV C.1086 primes followed by a CycP-gp120 protein boost adjuvanted with either dmLT (n = 9) or alum (n = 10). A group of unvaccinated macaques (n = 8) served as controls. All animals were intrarectally challenged with heterologous SHIV.CH505.375H.dCT weekly for 7 weeks. Following the challenge, dmLT-adjuvanted animals showed significant protection with a vaccine efficacy of 60.8% per exposure (p = 0.0246). Alum-adjuvanted animals did not show significant protection (p = 0.1575). Both adjuvants induced comparable envelope-specific binding antibody in serum and rectal secretions with broad V1V2 scaffold-binding specificity. IL-6 plasma concentration correlated positively with V1V2 scaffold-binding and increased after vaccination with both adjuvants. With respect to CD4 T cells, dmLT induced higher frequencies of proliferating central memory (T_CM) and ICOS⁺ cells in blood compared to alum. However, these proliferating CD4 T_CM cells showed a decrease in the proportion of gut-homing receptor α4β7-expressing cells in the dmLT group compared to the alum group at week 2 post-protein boost. The V1V2 scaffold-specific IgG, proliferating T_CM and ICOS⁺ CD4 T-cell frequencies, and plasma IL-6 concentration associated positively with protection. These data demonstrate that the vaccine adjuvants dmLT and alum differentially modulate protective helper T-cell responses induced by the CycP-gp120 protein, highlighting the importance of an appropriate adjuvant for eliciting a protective immune response against HIV-1.

Recurrent pregnancy loss (RPL), particularly its unexplained form (URPL), represents a formidable challenge in reproductive medicine. Although traditionally attributed to local immune imbalances at the maternal-fetal interface, this perspective may not fully account for the condition's upstream etiological drivers and recurrent nature. This review transcends this limitation by proposing and systematically substantiating an integrative 'gut-systemic-decidual' model of immunometabolic dysregulation. We posit that a key pathological cascade in many URPL cases may originate with distal gut dysbiosis, which, through imbalanced metabolite profiles and the leakage of inflammatory molecules such as lipopolysaccharide (LPS), triggers systemic 'metabolic endotoxemia' and fundamentally reprograms the metabolic state of circulating immune cells. This systemic 'first hit' is compounded when these 'pre-sensitized' cells migrate to an equally metabolically stressed and 'hostile' decidual microenvironment-a 'second hit' characterized by hypoxia and high lactate. This culminates in the functional collapse of the core sentinels of maternal-fetal tolerance, namely regulatory T (Treg) and decidual natural killer (dNK) cells, due to profound metabolic misprogramming. Ultimately, this integrated model elevates the etiological understanding of URPL from a 'local conflict' to that of a 'systemic disease,' paving the way for the development of dynamic warning systems that integrate multi-omics data and for the design of multi-level precision intervention strategies targeting patient stratification and preventive approaches for the gut, systemic metabolism, and the local microenvironment.

Objective: To investigate whether immune-related adverse events and pretreatment neutrophil-to-lymphocyte ratio can serve as predictive biomarkers of treatment response and survival in patients with gynecologic cancer receiving pembrolizumab immunotherapy.

Methods: This retrospective study included 94 patients with gynecologic malignancies treated with pembrolizumab at Kaohsiung Chang Gung Memorial Hospital between May 2017 and July 2024. Detailed clinical and laboratory data including the occurrence of immune-related adverse events, pretreatment neutrophil-to-lymphocyte ratio, mismatch repair (MMR) status, treatment response patterns, and patient demographics were collected. Progression-free survival and overall survival were analyzed using Kaplan-Meier curves and Cox regression models. The optimal neutrophil-to-lymphocyte ratio cut-off value for predicting the prognosis was determined using receiver operating characteristic curve analysis.

Results: Overall, immune-related adverse events occurred in 55.3% of the patients and were associated with a significantly higher objective response rate (ORR; 84.6% vs. 15.4%, p < 0.001), longer progression-free survival (p < 0.001), and improved overall survival (p < 0.001). Similarly, low neutrophil-to-lymphocyte ratio (<4.07) also predicted longer progression-free survival (HR: 0.537, p = 0.043) and improved overall survival (HR: 0.328, p = 0.001). Multivariate analysis confirmed that both immune-related adverse events and low neutrophil-to-lymphocyte ratio were robust independent predictors of progression-free survival and overall survival. MMR-deficient tumors were associated with a significantly higher ORR (60.9% vs. 28.9%, p = 0.011), although MMR status was not independently associated with survival in the final multivariate models.

Conclusion: The development of immune-related adverse events and low pretreatment neutrophil-to-lymphocyte ratio independently predicted improved therapeutic response and prolonged survival in gynecologic cancer patients treated with pembrolizumab. Their integration with tumor molecular profiling may optimize monitoring frequency, adjust supportive care measures, and consider treatment modifications based on individual patient risk profiles, thereby enhancing the delivery of immunotherapy in gynecologic cancers without limiting treatment access.

VEXAS syndrome is a rare, adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. Patients may present with symptoms similar to IgG4-related disease (IgG4-RD) or systemic vasculitis. We report the case of a 70-year-old man who presented with periorbital swelling, fever, and elevated serum IgG4. However, a biopsy of the lacrimal gland did not show histological evidence of IgG4-RD. Consecutively, the patient developed progressive pulmonary infiltrations, bicytopenia and leukocytoclastic vasculitis. Chest-CT showed organizing pneumonia, which was histologically proven by transbronchial lung cryobiopsy (TBLC), again excluding IgG4-RD. PET/CT revealed hypermetabolic bone marrow and bone marrow aspiration biopsy showed vacuolization of granulocytic precursor cells. Finally, genetic testing for UBA1 mutation confirmed the diagnosis of VEXAS syndrome. Treatment with ruxolitinib in addition to steroids, led to temporary stabilization but long-term prognosis was unfavorable. This case highlights the importance of considering VEXAS syndrome a relevant differential diagnosis of vasculitis and IgG4-RD in men. Furthermore, we present valuable insights into the pathophysiology of VEXAS through transmission electron microscopy (TEM) of TBLC samples.

Lung cancer remains one of the most prevalent and lethal malignancies globally and its treatment has consistently been a focal point of research in the medical field. The emergence of immunotherapies such as immune checkpoint inhibitors has brought about a new understanding of vaccine treatment for tumors. Tumor vaccines induce anti-tumor immune responses by targeting tumor-associated antigens or specific neoantigens. In recent years, advancements in vaccine technology, such as neoantigen screening, refinement of vector systems, and optimization of adjuvants, have significantly propelled the development of personalized tumor vaccines, thereby endowing lung cancer vaccines with substantial therapeutic potential. Furthermore, studies have demonstrated that the integration of tumor vaccines with immune checkpoint inhibitors, chemotherapy, and other therapeutic modalities can produce synergistic anti-tumor effects. This article reviews the latest progress in lung cancer vaccines, elucidates current combination treatment strategies supported by preclinical and clinical evidence, and explores their translational potential for clinical application.

Inflammatory bowel disease (IBD) is pathologically characterized by dysregulated inflammation and compromised intestinal barrier integrity. While multi-component herbal formulations hold promise for IBD management, the combined potential of specific phytochemical combinations remains underexplored. This study investigates the cooperative therapeutic effects of Berberine and Taxifolin, two anti-inflammatory phytochemicals, in a murine colitis model. Multi-omics network pharmacology initially identified their shared anti-inflammatory and anti-apoptotic targets in IBD pathogenesis. Experimental validation demonstrated that combined treatment with berberine and taxifolin produced stronger protective effects against Dextran Sulfate Sodium (DSS)-induced colitis than either compound alone. Specifically, the combination significantly alleviated body weight loss and colon shortening, reduced macrophage infiltration and the expression of pro-inflammatory cytokines (IL-1β and TNF-α), and preserved intestinal barrier integrity by restoring tight junction proteins (occludin and ZO-1). In addition, the combined treatment attenuated caspase-3-mediated epithelial apoptosis. Molecular docking analysis suggested that berberine and taxifolin may interact with multiple inflammation-related targets, including NF-κB, NLRP3, PPARγ, and STAT3, providing a potential mechanistic basis for the observed effects. These findings establish Berberine-Taxifolin co-administration as a novel multi-target therapeutic strategy that concurrently addresses inflammatory dysregulation, barrier repair, and apoptosis control in IBD, and may provide a phytochemical blueprint for complex inflammatory disorders.

Background: Oxidative stress and endoplasmic reticulum stress (ERS) are critical for crustaceans' stress responses. Genome-wide identification of superoxide dismutase (SOD) genes in Procambarus clarkia is essential for understanding its stress adaptation and aquaculture disease control.

Methods: Five PcSOD genes were identified, with analyses of their structure, motif, chromosomal distribution and phylogeny. Their tissue-specific expression, expression under Vibrio parahaemolyticus challenge, correlation with ERS-related genes, and changes in T-AOC/SOD activity were detected, along with the effect of heat shock pretreatment.

Results: PcSOD genes showed structural diversity and tissue specificity, with time-dependent expression under bacterial challenge. Heat shock pretreatment regulated their expression timing and intensity. Significant correlations between PcSOD and ERS genes were observed in hemocytes under NLHS + V. parahaemolyticus treatment, supported by NLHS-induced Hsp70.

Conclusion: These findings suggest a potential coordinated SOD-ERS response in P. clarkia, providing insights for aquaculture disease control strategies.