Immunological Investigations最新文献

Background: This review aims to synthesize the structural and functional characteristics of DOCK2, as well as its mechanistic roles in various diseases, in order to provide a theoretical foundation for targeted therapies.

Methods: We systematically reviewed existing literature to summarize the molecular features and expression patterns of DOCK2, its regulation of cellular processes through both Rac-dependent and Rac-independent pathways, and its implications in inflammation, cancer, fibrosis, and related disorders.

Results: DOCK2, a member of the Dock-A subfamily of GEFs, is widely expressed across tissues and prominently in immune cells (e.g., dendritic cells, macrophages, T cells, B cells), where it regulates proliferation, differentiation, migration, and cytokine secretion primarily via Rac activation. Emerging evidence also links DOCK2 to non-immune cell types such as glial cells and vascular smooth muscle cells, highlighting its relevance in immune-related and broader pathological conditions including inflammatory diseases, cancer, atherosclerosis, idiopathic pulmonary fibrosis, and obesity.

Conclusion: As a critical GEF, DOCK2 plays a central role in immune and non-immune cellular processes through Rac and non-Rac signaling pathways. Dysregulation of DOCK2 is closely associated with multiple diseases. Further elucidation of its regulatory networks may reveal novel therapeutic targets for treating related disorders.

Background: Macrophage polarization is widely involved in the progression of acute lung injury (ALI). Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have been reported to participate ininflammatory diseases by regulating macrophage polarization. This study aimed to investigate the role of BMSC-Exos in ALI through the regulation of macrophage polarization.

Methods: LPS-induced ALI mouse models and RAW264.7 cell injury models were established. Lung injury was assessed through HE staining and assessment of bronchoalveolar lavage fluid (BALF) protein contents, the lung wet/dry weight ratios, and lung myeloperoxidase (MPO) activities. The expression of protein was detected via Western blotting and immunofluorescence. Exosomes were characterized using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA).

Results: BMSC-Exos significantly alleviated pathological lung injury in ALI mice; reduced the lung wet/dry weight ratio, BALF protein content, MPO activity. BMSC-Exos inhibited LPS-induced macrophage M1 polarization and reduced proinflammatory cytokine expression. The molecular mechanism revealed that the BMSC-Exos delivered miR-451a to the macrophages and that inhibition of miR-451a expression attenuated the suppressive effect of the BMSC-Exos on M1 polarization. Furthermore, miR-451a targeted MIF to inhibit the MIF/CD74 signaling pathway.

Conclusion: BMSC-Exos inhibit MIF/CD74 signaling by delivering miR-451a, thereby suppressing LPS-induced M1 macrophage polarization and alleviating ALI.

Objective: To elucidate the role of the polypyrimidine tract-binding protein 1 (PTBP1)-tumor necrosis factor receptor-associated factor 6 (TRAF6) pathway in chronic obstructive pulmonary disease (COPD), with a particular focus on its regulatory effects on macrophage polarization and clearance of neutrophil extracellular traps (NETs).

Methods: A COPD-like mouse model was established via cigarette smoke (CS) exposure. Lung injury, macrophage polarization, and levels of NETs were assessed. The role of TRAF6 in macrophage polarization and NETs clearance was assessed through lentiviral modulation of TRAF6 expression. RNA immunoprecipitation-quantitative polymerase chain reaction (RIP-qPCR), RNA stability assays, and Western blotting were performed to investigate the regulatory mechanism of PTBP1 on TRAF6 expression.

Results: The COPD-like mouse model exhibited increased M1 and decreased M2 macrophage populations, along with elevated NETs formation. Both PTBP1 and TRAF6 were upregulated in lung tissues of the COPD-like mouse model and cigarette smoke extract (CSE)-treated macrophages. Mechanistically, PTBP1 bound to and stabilized TRAF6 mRNA, enhancing TRAF6 expression. Inhibition of the PTBP1-TRAF6 pathway alleviated lung injury, restored macrophage polarization balance, and promoted NETs clearance.

Conclusion: PTBP1 enhances TRAF6 expression by stabilizing its mRNA, promoting M1 macrophage polarization and impairing NETs clearance, ultimately aggravating COPD.

Introduction: Colorectal Cancer has been a significant health issue at a global level in terms of increasing incidence, high metastatic capacity, and inadequate treatment reactions in most patient groups. Though chemotherapy and targeted agents have given better survival chances, resistance to treatment, avoidance of the immune system as well as systemic toxicity still limit long-term efficacy. Immunotherapeutic strategies have developed as effective methods in the past few years to address these shortomings.

Methods: A comprehensive literature search was conducted across different electronics databases including Web of Science, PubMed, Scopus, and ScienceDirect utilizing keywords colorectal cancer immunotherapy, PD-1 / PD-L1, CAR-T cells, viral vector vaccines, carcinoembryonic antigen alone and in combinations.

Results: PD-1/PD-L1, CTLA-4, immune checkpoint inhibitors have shown long-term responses, especially in mismatch repair-deficient and microsatellite instability-high tumours, and cell-based therapies such as CAR -T cells and dendritic cell vaccines provide other opportunities of personalised immune modulation.

Discussion: This critical review summarizes the current developments in terms of immunotherapy and interventions of CRC with a focus on the mechanistic understanding of the issue, clinical outcomes, and combinatorial strategies aimed to improve antitumor immunity and surmount therapy resistance. Specific attention is paid to the optimization of the checkpoint blockade, innovations with vaccines and CAR-T engineering to accumulate and release tumor-specific cells and control the microenvironment. Finally, key translational challenges current clinical trials, and future perspectives are identified to promote the development of the next-generation multimodal therapies in the efficient and customized management of CRC.

Background: The Igκ locus undergoes multiple molecular processes during B cell development, including V(D)J recombination and epigenetic regulation, which are influenced by cis-regulatory regions within the locus. A novel cis-regulatory region, termed the Dm element, has been identified. It functions in coordination with the 3'Eκ and Ed enhancers and has been implicated in Igκ demethylation and somatic hypermutations (SHM). The Dm element is characterized by a high density of CpG dinucleotides, a hallmark of region subject to DNA methylation. Our previous work demonstrated that RAG2, but not RAG1, contributes to the Igκ locus demethylation. However, whether RAG proteins influence the epigenetic state of the Dm element remains unknown.

Methods: Here, we investigated the epigenetic state of the Dm element using bisulfite sequencing and chromatin immunoprecipitation (ChIP).

Results: We found that the Dm element was hypermethylated in pre-B cells but partially demethylated in splenic B cells. Furthermore, it was marked by active histone modifications, including H3K27Ac and H3K9Ac, and was bound by B cell-specific transcription factor Pax5 in pre-B cells.

Conclusion: Our findings provide evidence that the Dm element undergoes DNA methylation remodeling in mature B cells, potentially contributing to Igκ allelic expression.

Background: Adjuvants potentiate adaptive immunity by enhancing antigen-specific immune responses, yet many exhibit high toxicity for clinical use. Naloxone (NLx) and naltrexone (NLt) opioid receptor antagonists have emerged as promising adjuvants in preclinical vaccination models against intracellular pathogens.

Objective: This narrative review synthesizes evidence from 2000 to 2025 evaluating NLx/NLt as adjuvants against bacterial, viral, and parasitic infections, while examining proposed immunoregulatory mechanisms.

Methods: A comprehensive search of Web of Science, PubMed, Scopus, ScienceDirect, and ProQuest employed Boolean operators combining: (vaccine OR vaccination) AND (adjuvant) AND (naloxone OR naltrexone OR NLx OR NLt OR "opioid receptor antagonist") AND ("immune response" OR "cellular immunity" OR "Th1").

Results: Key findings demonstrate that NLx/NLt monotherapy or combinatorial use with Alum consistently, enhanced Th1 polarization and cellular immunity, Elevated pathogen clearance and protection rates, synergistically overcame Alum's Th2 bias. Mechanistically, μ-opioid receptor (MOR) antagonism disrupts tonic immunosuppression, reversing opioid-mediated inhibition of dendritic cell maturation, IL-12 production, and cytotoxic T-cell function.

Conclusions: This immunorestorative action positions NLx/NLt as strategic adjuvants for vaccines targeting intracellular pathogens requiring robust cell-mediated immunity. Future horizons include combinatorial platforms (e.g. DNA vaccines + low-dose naltrexone) and clinical translation.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory, T cell-mediated autoimmune disorder which commonly affects the tiny joints of the hands and feet.

Objectives: To develop and evaluate novel topical gel containing combinatorial aceclofenac (ACF) and quercetin (QCT) nanoemulsion (NE) for management of RA.

Methods: NE components (oil, surfactant, and cosurfactant) were selected based on solubility. Pseudo ternary phase diagrams were constructed using titration method. Carbopol bases were screened to produce NE-gel. Drug loaded NE-gels were characterized for transmission electron microscopy and in-vitro drug release. Further evaluated for ex-vivo drug release, retention-permeation studies, in-vivo studies using Wistar rat model.

Results: Optimized NE showed approximate globule size 79nm, zeta potential of -28.1 ± 1.20 mV and polydispersity index 0.22. The NE-gel showed in-vitro drug release of ACF=75.56 ± 0.318% and QCT=74.72 ± 0.715% after 12h, depicting sustained zero order release kinetics in contrast to marketed gel (release of ACF=95.33 ± 0.449% after 9h). Ex-vivo study on porcine ear skin revealed improved permeation and minimum retention. In-vivo studies showed 50.89% reduction in paw volume (p<0.0001) with better anti-arthritic effects.  .

Conclusion: The study substantiated combinatorial NE-gel formulation with advanced permeation characteristics which can be an efficient alternative for topical delivery in RA.

Background: Recent advancements in cancer therapy have focused on blocking immune checkpoint receptors (ICRs) to restore anti-tumor immunity. Despite these developments, a significant proportion of patients remain unresponsive to currently available immune checkpoint inhibitors (ICIs), highlighting the urgent need for novel therapeutic targets. T-cell immunoglobulin mucin-3 (TIM-3) has emerged as a new immune checkpoint molecule implicated in tumor immune evasion and cancer progression.

Methods: This review synthesizes data from recent epidemiological and molecular studies examining the role of TIM-3 in lung cancer. The literature related to the genetic mutations, expression patterns, and immunological mechanisms of TIM-3 was systematically analyzed to explore its clinical and therapeutic significance.

Results: The findings indicate that mutations in the TIM-3 gene are correlated with increased susceptibility to lung malignancies. TIM-3 expression is consistently elevated in both tumor cells and immune cells of patients with lung cancer. Evidence further demonstrates that TIM-3 contributes to impaired immune responses, impacts prognostic outcomes, and influences resistance to existing ICIs. These observations suggest that TIM-3 functions as a critical modulator of tumor-immune interactions.

Conclusion: TIM-3 represents a promising therapeutic target for overcoming resistance to current immunotherapies and improving clinical outcomes in lung cancer. Understanding the regulatory mechanisms of TIM-3 expression provides valuable insights that may guide the development of future therapeutic strategies and precision medicine approaches.

Introduction: Systemic Lupus Erythematosus (SLE) is an incurable autoimmune disease. The remarkable success of Chimeric Antigen Receptor T-cell (CAR-T) therapy in oncology has prompted its investigation for autoimmune conditions, particularly SLE.

Methods: This review synthesizes current evidence, primarily from the last five years, to elucidate the pathological basis, mechanisms, advancements, and future directions of CAR-T therapy for SLE.

Results: Evidence indicates that CAR-T therapy, which targets pathogenic B cells or restores immune tolerance, is a promising intervention for SLE. Preclinical and early clinical data suggest it can effectively mitigate symptoms and may induce sustained, drug-free remission, representing a shift from chronic management.

Discussion: CAR-T cell therapy represents a transformative potential for SLE treatment. Future efforts should focus on target optimization, safety enhancement, and validation of long-term efficacy in larger clinical trials.