Immunological Investigations最新文献

Background: Psoriasis is increasingly recognized as a systemic immuno-metabolic disorder in which chronic inflammation interacts with alterations in cellular energy metabolism.

Objective: To summarize current evidence on immunometabolic dysregulation in psoriasis and highlight emerging metabolic-targeted therapeutic strategies.

Methods: A narrative review of recent literature examining metabolic pathways, immune responses, and therapeutic interventions involved in psoriasis pathogenesis was conducted.

Results: Psoriatic keratinocytes, T cells, dendritic cells, and macrophages undergo significant metabolic reprogramming characterized by increased glycolysis, altered lipid metabolism, mitochondrial dysfunction, and excessive reactive oxygen species production. These metabolic disturbances contribute to keratinocyte hyperproliferation and sustain Th17-driven inflammation, linking skin pathology with systemic comorbidities such as obesity, insulin resistance, dyslipidaemia, and endothelial dysfunction. Key nutrient-sensing regulators, including mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), hypoxia-inducible factor-1α (HIF-1α), sirtuin-1 (SIRT1), and PGC-1α, integrate metabolic status with inflammatory signaling. Additionally, adipokine imbalance and metabolic stress promote chronic metaflammation.

Conclusion: Targeting immunometabolic pathways through glycolysis inhibitors, AMPK activators, mTOR modulators, mitochondrial-targeted antioxidants, and lipid-regulating agents may restore metabolic homeostasis and reduce inflammation. Advances in multi-omics approaches may further facilitate biomarker discovery and precision-based therapeutic strategies in psoriasis management.

Background: Despite the high diversity of the αβ T cell receptor (TCR), sharing of identical TCR chains between individuals is common. This shared repertoire consists mainly of chains with few non-germline nucleotide additions. Many of these chains recognize conserved viral peptides, but it is unclear whether the number of nucleotide additions is similar regardless of specificity.

Methods: We studied shared human TCR α chains associated with the recognition of viral antigens. The chains were retrieved from published databases. In sets of 6 thymus and 10 blood samples we identified these chains and analyzed their frequency and properties in the pre-immune and peripheral repertoire.

Results: For all but one virus, the identified TCR α sequences conformed to the conventional public repertoire, with a high frequency of germline rearrangements and few nucleotide additions. Surprisingly, TCR α sequences associated with Herpes simplex virus 2 (HSV-2) displayed a bimodal division, with one group of sequences having a high number of inserts, while the other group was close to germline.

Conclusion: Our results identify a novel type of shared TCR repertoire, likely to be generated by selection instead of convergent recombination. Whether this reflects features exclusive to the immune response against HSV-2 remains to be studied.

Introduction: Propofol is the preferred anaesthetic for asthma patients due to its bronchodilatory effects, yet its protective mechanisms remain unclear. This study investigated its effects both in vivo and in vitro.

Methods: An asthmatic mouse model was induced using ovalbumin (OVA). Airway responsiveness, lung histopathology, and inflammatory biomarkers (IgE, IL-4, IFN-γ) were assessed. TGF-β1-stimulated airway smooth muscle (ASM) cells were used for proliferation, migration, and apoptosis assays via MTT, Transwell, and flow cytometry. ECM production was analyzed by immunohistochemistry and immunofluorescence. The SAPK/JNK signaling pathway was evaluated by western blot.

Results: Propofol dose-dependently attenuated airway hyperresponsiveness and lung histological damage in OVA-induced asthmatic mice, while reversing abnormal inflammatory biomarker expression. In vitro, propofol inhibited ASM cell proliferation and migration and promoted apoptosis. It also suppressed ECM synthesis and restored TIMP-1 expression to rebalance ECM homeostasis. Mechanistically, propofol inhibited SAPK/JNK pathway activation in both in vivo and in vitro models.

Discussion: These findings clarify the molecular mechanisms underlying Propofol's protective effects, providing a foundation for its potential therapeutic use in asthma treatment.

Background/objective: Sepsis remains a leading cause of mortality worldwide, with immune dysfunction serving as a central driver of adverse outcomes. While early hyperinflammation contributes to organ damage, subsequent immunoparalysis characterized by T-cell exhaustion, monocyte deactivation, and impaired pathogen clearance accounts for late deaths and susceptibility to secondary infections. Immune checkpoint molecules have emerged as critical mediators of sepsis-induced immunosuppression.

Methods: We reviewed current literature on inhibitory checkpoint pathways including PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, TIGIT, and BTLA in sepsis-induced immune dysfunction. Cell-type-specific expression patterns, dual protective and pathological roles of checkpoint signaling depending on timing and tissue context, and convergence with metabolic and epigenetic reprogramming sustaining immunoparalysis were analyzed. Myeloid checkpoints such as CD47-SIRPα and MerTK contributing to innate immune dysfunction were evaluated.

Results: Checkpoint molecules exhibit context-dependent roles with protective and pathological effects varying by timing and tissue microenvironment. Monocyte HLA-DR and ferritin were identified as actionable biomarkers for patient phenotyping. The ImmunoSep trial provides proof-of-concept evidence demonstrating improved outcomes with phenotype-guided immunotherapy.

Conclusions: Successful translation of checkpoint-based immunotherapies requires precision medicine frameworks matching the right intervention to the right patient at the right time. Combination immunotherapies hold promise when guided by biomarker-driven stratification.

Background: Thyroid-associated ophthalmopathy (TAO)is a common autoimmune inflammatory disorder that compromises visual function and quality of life. It is characterized by orbital tissue inflammation and ocular surface injury. Although immunosuppressive pulse therapy has shown clinical efficacy, its underlying molecular mechanisms remain incompletely understood.

Methods: Tear samples were collected from 30 healthy controls and 30 patients with TAO before and after immunosuppressive pulse therapy. Proteomic profiling was performed using label-free quantitative liquid chromatography - tandem mass spectrometry (LC-MS/MS), and key proteins involved in FGA expression and complement-coagulation cascade signaling were validated by ELISA. Primary orbital fibroblasts (OFs) were isolated from TAO patients and subjected to FGA overexpression and immunosuppressant treatment. Fibrosis and adipogenic differentiation were assessed using a multidimensional approach, including CCK-8 assay, flow cytometry, Oil Red O staining, qRT-PCR, and Western blotting.

Results: Immunosuppressive pulse therapy significantly alleviates ocular surface injury in TAO patients, primarily through FGA-mediated regulation of the complement and coagulation cascade pathway. Our findings identify FGA as a promising therapeutic target in TAO. Restoration of FGA expression synergizes with immunosuppressive therapy, highlighting a potential combinatory treatment strategy.

Conclusion: FGA represents a potential therapeutic target for TAO. Enhancing FGA expression may augment the efficacy of immunosuppressive therapythrough synergistic modulationof inflammatory and fibrotic pathways.

Clinical trial number: Not applicable.

Background: Organ transplantation faces challenges of chronic rejection and infection due to immunosuppression. Inducing long-term immune tolerance is a key goal, with anti-CD45RB antibody being a studied target for decades.

Methods: This review examines its mechanisms-modulating T cells (e.g.promoting Tregs), B cells, and cytokines-and efficacy across transplantation models (e.g.pancreatic, cardiac, cutaneous), including combination therapies.

Conclusions: Efficacy varies by model: monotherapy induced tolerance in certain islet transplants but not skin grafts. Combination with agents like anti-CD40L or rapamycin significantly prolonged graft survival (e.g.to 100% in heart transplants). Dosage, timing, and recipient immune status influence outcomes, with Treg involvement as a common mechanism.

Future directions: Further research should explore synergies with clinical immunosuppressants and mechanisms in large animal xenografts to advance clinical translation.

Background: The interaction between the immune system and fungi has long intrigued researchers, as fungi are among the most common organisms encountered by humans. Myeloid-derived suppressor cells (MDSCs) are specialized immune cells that play a key role in modulating immune responses during fungal infections by inhibiting T-cell activity.

Objectives: This review aims to investigate the mechanisms by which MDSCs influence fungal infections and to explore their potential as therapeutic targets.

Methods: A comprehensive review of existing studies examining MDSC activity in various fungal infections was conducted. Comparative analysis focused on the protective versus non-protective effects of MDSCs across different fungal species.

Results: MDSCs suppress pro-inflammatory T-cell responses, leading to two contrasting outcomes. On one hand, this suppression mitigates disease progression by reducing harmful inflammation. On the other, it can enhance fungal survival by preventing T-cell-mediated damage. Protective effects of MDSCs have been observed in Candida albicans infections, whereas non-protective or detrimental effects have been reported in infections caused by Candida tropicalis, Paracoccidioides, Aspergillus fumigatus, Cryptococcus neoformans, Malassezia, and Mucor species.

Conclusions: MDSCs play a dual role in fungal infections, balancing protective immune regulation with facilitation of fungal persistence. Understanding their mechanisms offers promising avenues for the development of targeted immunotherapies against fungal pathogens.

Introduction: The immunosuppressive microenvironment of hepatocellular carcinoma (HCC) is shaped by multiple oncogenic pathways, but howosteopontin (OPN), a molecule frequently overexpressed in HCC, regulates anti-tumor immunity remains unclear.

Methods: To define the mechanism by which OPN modulates the HCC immune microenvironment, with a focus on its regulation of CD155 and its impact on CD8⁺ T-cell - mediated anti-tumor responses.

Results: We identified that OPN activates the p65/NF-κB - c-Myc/CD155 signaling axis, leading to robust upregulation of CD155 and impaired intratumoral CD8⁺ T-cell infiltration and effector activity. These immunosuppressive effects occurred independently of changes in tumor stemness markers or Treg accumulation. Genetic suppression of p65 abrogated OPN-induced CD155 expression and mitigated tumor progression in vivo, demonstrating the pathway's functional requirement.

Discussion: OPN drives HCC progression by suppressing CD8⁺ T-cell immunity through the NF-κB (p65)/c-Myc/CD155 axis. Targeting this pathway may enhance anti-tumor immunity and represents a promising therapeutic strategy for HCC.

Background: Obesity-induced metabolic stress impairs the efficacy of immune checkpoint blockade (ICB) therapy, but the mechanisms linking a high-fat diet (HFD) to immune suppression remain unclear.

Objective: To investigate how HFD-induced metabolic changes modulate the tumor immune microenvironment through the STAT3/CD155 axis.

Methods: Murine colorectal cancer models using control, CD155-overexpressing (CD155 OE), and STAT3 knockdown CT26 cells were established under normal or HFD conditions with anti - PD-L1 treatment. Tumor growth, immune infiltration, and gene expression were analyzed by flow cytometry, Western blotting, and chromatin immunoprecipitation.

Results: HFD impaired anti - PD-L1 efficacy and accelerated tumor growth. Mechanistically, HFD promoted STAT3 nuclear translocation and CD155 upregulation, reducing CD8⁺ T cell infiltration and enhancing regulatory T cell accumulation. Chromatin immunoprecipitation confirmed direct STAT3 binding to the CD155 promoter, while STAT3 knockdown reversed these effects and restored antitumor immunity in HFD-fed mice.

Conclusion: HFD-induced metabolic stress drives immune evasion via the STAT3/CD155 axis. Targeting this pathway may improve ICB efficacy in obesity-related cancers.

Background: The gut microbiota plays an important role in systemic immune homeostasis and is increasingly implicated in autoimmune thyroid disease (AITD). Evidence suggests that gut dysbiosis, impaired intestinal barrier function, and altered microbial metabolites particularly short-chain fatty acids contribute to immune imbalance along the gut-thyroid axis. Although molecular mimicry between microbial and thyroid antigens has been proposed, current human evidence remains associative rather than causal.

Methods: This review synthesized current observational, translational, and preclinical studies evaluating microbial composition, barrier integrity, microbial metabolites, and immune pathways relevant to AITD. Mechanistic insights into T-lymphocyte regulation and microbial-host interactions were integrated with emerging interventional data.

Results: Gut dysbiosis in AITD is linked to reduced regulatory T-lymphocytes, expansion of Th17 cells, increased intestinal permeability, and the loss of short-chain-fatty-acid-producing taxa. Observational studies consistently report disease-associated taxonomic alterations, while preclinical models support causal pathways through barrier disruption and microbiota-driven immune activation. Early interventional approaches such as high-fiber dietary patterns, probiotics, prebiotics, and experimental fecal microbiota transplantation show modest reductions in thyroid autoantibodies in small trials, though effects are strain-specific, short-term, and not disease-modifying.

Conclusion: Despite largely associative human evidence, converging mechanistic findings highlight the gut microbiota as a modifiable contributor to thyroid autoimmunity. Future priorities include clarifying causality, identifying keystone microbial taxa and metabolites, and establishing standardized interventional frameworks to facilitate translation into endocrine practice.