Frontiers in Immunology最新文献

Objective: Parkinson's disease (PD) is a severe neurodegenerative disorder whose pathogenesis is closely linked to gut microbiota dysregulation. However, whether and how modulation of gut homeostasis can ameliorate PD remains unclear. Dietary isoflavones have been associated with neuroprotective effects and show strong potential in shaping the composition of the gut microbiota, yet their underlying mechanisms in PD are poorly understood.

Methods: Microbiomics and non-targeted metabolomics were utilized to characterize microbial community composition and metabolic alterations in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD. Subsequently, both the MPTP-induced PD mouse model and in vitro cell experiments were employed to investigate the effects and underlying mechanisms of the differentially regulated metabolite serotonin on PD pathogenesis.

Results: Here, we show that an isoflavone-enriched diet alleviates motor deficits and dopaminergic neuron loss in an MPTP-induced mouse model of PD. This protective effect is mediated via a gut-brain axis mechanism: isoflavones promote the expansion of intestinal Lactobacillus species, especially Lactobacillus intestinalis, leading to increased 5-hydroxytryptamine (5-HT) production in both serum and brain. Elevated 5-HT activates central 5-HT1A receptor (5-HTR1A), which in turn triggers downstream PI3K-AKT signaling to suppress ferroptosis-a key pathogenic process in PD. Pharmacological inhibition of either 5-HTR1A or the PI3K-AKT pathway abolishes the neuroprotective effects of 5-HT.

Conclusions: Our findings reveal a novel dietary-microbiota-serotonergic pathway that mitigates ferroptosis and neurodegeneration, highlighting the therapeutic potential of isoflavone-based interventions for PD.

Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly recognized adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene. It typically presents in older males with systemic inflammation, hematologic abnormalities, and a relapsing, treatment-refractory course. Reports in younger patients remain rare, and pulmonary involvement is often misdiagnosed as infection.

Case presentation: We present a 30-year-old man with a two-year history of recurrent scleritis, fever, cough, auricular chondritis, rash, and transfusion-dependent macrocytic anemia. Despite multiple immunosuppressants and broad-spectrum antimicrobials, symptoms persisted. Imaging revealed relapsing bilateral ground-glass pulmonary infiltrates, and repeated microbiologic studies were negative. Bone marrow showed vacuolated precursors and cytogenetic abnormalities. A somatic UBA1 mutation (NM_003334 exon3 c.121A>G p.M41V) was detected with high variant allele frequency in blood and marrow, and notably, also in bronchoalveolar lavage cells. The patient was diagnosed with VEXAS syndrome with early myelodysplastic features. Tocilizumab induced transient improvement, but disease relapse followed. He is currently being evaluated for allogeneic hematopoietic stem cell transplantation (AHSCT).

Conclusion: This case represents one of the youngest patients reported with VEXAS syndrome and provides rare evidence of UBA1 mutation in pulmonary cells, supporting the concept of tissue-level clonal inflammation. It highlights the importance of considering VEXAS in younger patients with unexplained systemic inflammation, cytopenias, and non-infectious pulmonary infiltrates, and supports early genetic testing and multidisciplinary management.

[This corrects the article DOI: 10.3389/fimmu.2022.825312.].

Inflammatory bowel disease (IBD) remains a critical unmet medical challenge, with a substantial number of patients experiencing ineffective treatment or therapeutic failure over time. Here, GB20-5A8-31, a novel anti-TNF-like ligand 1A (TL1A) antibody, was engineered for high potency and superior developability. GB20-5A8-31 exhibited ultra-high affinity (KD = 5.11×10-¹¹ M) for human TL1A, potent inhibition of TL1A signaling in vitro. Meanwhile, GB20-5A8-31 demonstrated potent anti-inflammatory effects and anti-fibrotic tendencies in both the 2,4,6-trinitro-benzenesulfonic acid-induced rat and dextran sulfate-induced hTLIA-transgenic mouse acute IBD models. Its favorable pharmacokinetic profile, including an extended half-life (T_1/2 = 248.54 h) in hFcRn-transgenic Sprague-Dawley rats, supports sustained target engagement. Crucially, GB20-5A8-31 exhibits advantageous biophysical properties-including high stability, solubility, and low aggregation-which facilitate the development of high-concentration formulations aimed at improving patient compliance. In summary, these findings indicate that GB20-5A8-31 is a therapeutic candidate for IBD with promising preclinical efficacy and the potential to advance to the Chemistry, Manufacturing and Controls research.

Among all malignant tumors, liver cancer is highly common, and hepatocellular carcinoma (HCC) stands as its most frequently seen pathological form. The majority of HCC patients are difficult to be detected or treated at an early stage. Concurrently, the postoperative recurrence rate remains relatively high, leading to a poor clinical prognosis of HCC. Recently, immunotherapy has made it promising to treat HCC. tumor microenvironment (TME) matters considerably in HCCprogression and metastasis. Neutrophils belong to the innate immune system's essential elements, and their role as key regulators in the HCC-TME is becoming more widely recognized. By studying neutrophils ' pro-tumor and anti-tumor mechanisms in HCC, it is expected to gain a deeper comprehension of the functions of neutrophils and further reveal their biological characteristics. In addition, we analyze the crosstalk between neutrophils and other cellular constituents of the TME, and discuss emerging therapeutic strategies that target neutrophil-centric pathways. A deeper understanding of neutrophil biology will both illuminate the complexity of immune networks in liver cancer and offer a theoretical framework for HCC prevention and treatment.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), has an important pathogenesis that lies in the self-amplifying inflammatory circuit formed by bidirectional interactions between dendritic cells (DCs) and T follicular helper (TFH) cells. This review elucidates that specific mature DC subsets in the intestinal inflammatory microenvironment drive TFH cell differentiation through synergistic co-stimulatory signals (CD80/CD86-CD28, OX40L-OX40) and cytokine networks (IL-12/STAT4/BCL-6, TGF-β/c-Maf/CXCR5); conversely, TFH-derived Lymphotoxin alpha 1 beta 2 (LTα1β2) activates stromal cell LTβR/NF-κB signaling pathway, inducing chemokine (CXCL13, CCL19, CCL21) production, thereby recruiting CCR7⁺ DC and CXCR5⁺ lymphocytes to form structural lymphoid clusters. Within these clusters, sustained DC-TFH cell interactions enhance TFH pathological effector functions (e.g., excessive IL-21 secretion), promote Th1/Th17 differentiation and weaken regulatory T cell inhibitory capacity, ultimately causing barrier destruction and tissue damage. Notably, while this pathogenic axis is active in both CD and UC, its cellular dynamics and microenvironment may exhibit disease-subtype distinctions. Current therapeutic strategies targeting this axis-including JAK inhibitors (e.g., upadacitinib), cytokine biologics (e.g., ustekinumab) and integrin blockers (e.g., vedolizumab)-achieve efficacy by interfering with DC-dependent TFH differentiation or TFH-mediated DC aggregation. Emerging evidence indicates traditional Chinese medicine active components (e.g., ginsenoside Rh2, curcumin) may intervene in this interaction through multi-pathway immunoregulation. However, utilizing single-cell and spatial transcriptomics to analyze spatial characteristics and disease-subtype-specific profiles of DC-TFH cell interactions remains key to developing next-generation therapies. While this axis provides a novel perspective for understanding immune dysregulation in IBD, its temporal role in disease initiation, crosstalk with other immune pathways, and translation from animal models to human disease remain challenges and future directions for the field.

Background: Properdin and factor H (FH), the two regulatory proteins of the alternative complement pathway, oppose each other to maintain the complement system's activation. While properdin upregulates, FH downregulates the complement alternative pathway. The current study evaluated the expression of properdin and FH transcripts and proteins in the placental tissues and umbilical cords (UC) of preeclampsia (PE), gestational diabetes mellitus (GDM), and recurrent pregnancy loss (RPL) compared to normal healthy pregnancy (N).

Methods: The tissue histology of PE, GDM and RPL were observed using haematoxylin-eosin and Masson's trichrome staining. To understand the expression and distribution of properdin and FH, RT-qPCR, western blot, and immunohistochemistry were carried out. The expressions of two additional complement components, C3 and C5, were also detected by western blot.

Results: The placentae from PE and GDM showed substantial collagen and fibrinoid deposition, thicker foetal blood capillaries, and a considerable number of syncytial knots. There was a significant rise in the level of properdin and significant decline in the level of FH at both mRNA and protein levels in the placentae and umbilical cord of PE compared to N; in GDM placentae, both properdin and FH were significantly elevated compared to N. In the case of RPL placentae, similar to PE, properdin expression was high while FH expression level was low. In both PE and RPL placentae, C3 and C5 levels were high, suggesting possibility of overactivation of complement proteins in the placenta.

Discussion: The observed elevated properdin level can contribute to the heightened inflammatory response in PE, GDM and RPL placentae. Low FH and high C3 and C5 in the placenta possibly suggests dysregulated complement activation in PE and RPL.

Introduction: β-Cell replacement therapy offers a potential cure for type 1 diabetes, but its success is limited by rapid graft rejection. While genome-wide CRISPR screens have recently identified RNLS and HIVEP2 as candidate genes capable of protecting β-cells from autoimmune destruction, their efficacy against the distinct mechanisms of allogeneic and xenogeneic rejection remains unknown. This study aimed to test the hypothesis that single-gene ablation of RNLS or HIVEP2 protects β-cell spheroids from allo- and xenorejection in immunocompetent hosts.

Methods: Murine β-TC-6 and human EndoC-βH1 β-cell lines were genetically edited using CRISPR-Cas9 to knockout RNLS or HIVEP2. Editing efficiencies were confirmed via T7 endonuclease I assay and Tracking of Indels by Decomposition (TIDE) analysis. Cells were aggregated into uniform, size-controlled spheroids using an optimized agarose suspension culture. Functional integrity was assessed via glucose-stimulated insulin secretion (GSIS). To evaluate immune evasion in vivo, luciferase-labeled spheroids were transplanted subcutaneously into immunocompetent CD-1 mice, modelling allogeneic (murine-to-murine) and xenogeneic (human-to-murine) rejection, with graft survival monitored longitudinally by bioluminescence imaging.

Results: Robust editing efficiencies were achieved for both targets. Functional characterization indicated that Rnls deletion modestly impaired GSIS in murine cells, whereas HIVEP2 deletion showed no functional alterations in either cell line. In vivo assessment revealed no protective effects of RNLS or HIVEP2 deletion; grafts from both knockout groups displayed rejection kinetics indistinguishable from non-targeting controls. While allogeneic grafts survived longer than xenogeneic grafts, both were ultimately cleared by the host immune system regardless of genotype.

Discussion: These data indicate that single-gene deletions of RNLS or HIVEP2 are insufficient to protect β-cell grafts from the barriers of allo- or xenorejection. By defining the limitations of these targets in isolation, our findings highlight the necessity for combinatorial genome editing strategies or complementary integration with immunomodulatory biomaterials to achieve effective and sustained β-cell graft survival.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of lung cancer, yet the heterogeneity in their efficacy and toxicity among different patients remains a significant clinical challenge. Obesity, as a global epidemic associated with chronic low-grade systemic inflammation and complex immunometabolic disturbances, has been identified as a crucial regulatory factor in cancer immunotherapy response. This review aims to systematically and deeply explore the intricate network of interactions between obesity, lung cancer, and immunotherapy. We not only examine the molecular and cellular mechanisms by which obesity-related inflammation influences ICI efficacy through remodeling the tumor microenvironment, altering systemic immune status, and modulating the gut microbiota, but also comprehensively assess its complex impact on clinical outcomes of ICI (including the controversial "obesity paradox" phenomenon) and immune-related adverse events (irAEs), particularly those uniquely associated with endocrine toxicity. Simultaneously, we systematically review novel biomarkers centered around obesity-related inflammatory parameters and body composition (such as circulating adipokines and radiomic features) and their application in integrative predictive models. Finally, based on available evidence, we propose multidisciplinary, longitudinal clinical management strategies tailored for obese lung cancer patients and envision novel combination treatment directions targeting the obesity-inflammation axis, aiming to provide theoretical support and practical guidance for achieving more precise, individualized immunotherapy.

Background: N6-methyladenosine (m⁶A) is a dynamic mRNA modification influencing transcript fate and cellular identity, especially in cancer. While oncogenic roles of m⁶A regulators in AML cells are known, their impact on the leukemic immune microenvironment is unclear.

Methods: In this study, we constructed a single-cell atlas of macrophages in AML by integrating publicly available scRNA-seq datasets from 129 patient cohorts. Data were batch-corrected using Seurat and Harmony. Macrophage subpopulations were identified, and the expression and activity of 29 m⁶A regulators were analyzed. Pseudotime analysis (Monocle3), cell-cell communication (CellChat), and pathway enrichment (Metascape) analyses were performed to explore m⁶A-related functional programs. Survival analysis was conducted using Kaplan-Meier curves. RT-qPCR was used to verify the correlation between m⁶A regulatory molecules and prognosis.

Results: Our findings indicated that m⁶A regulators are associated with macrophage fate. Writer-high macrophages showed enhanced proliferation and differentiation, maintaining monocyte-like features. Eraser-high macrophages remodeled macrophage function toward an M1-like, pro-inflammatory and antigen-presenting state. Reader-high macrophages drove macrophages toward an immunosuppressive, M2-like phenotype, while m⁶A-deficient cells exhibit features of functional exhaustion. Survival analysis based on bulk RNA-seq data further revealed that m⁶A-regulated macrophage profiles were associated with distinct prognostic stratification in AML patients. RT-qPCR analysis of macrophages isolated from clinical AML samples further validated these findings, showing that patients with favorable prognosis exhibited significantly higher expression levels of erasers compared to those with poor prognosis.

Conclusion: These results highlight m⁶A system's role in macrophage reprogramming and suggest that targeting m⁶A regulators in macrophages may serve as a potential basis for prognostic stratification and a promising therapeutic strategy in AML.