Immunological Investigations最新文献

Background: Cardiomyopathies contribute substantially to heart failure, arrhythmias, and sudden cardiac death. Innate immune activation-particularly via Toll-like receptors (TLRs)-is increasingly recognized as a driver of pathological cardiac remodeling.

Objective: To evaluate how TLR expression and downstream signaling pathways (MyD88 and TRIF) shape distinct cardiomyopathy phenotypes and to assess therapeutic strategies targeting these mechanisms.

Methods: Evidence from studies of ischemic, viral, septic, diabetic, drug-induced, hypertrophic, and obesity-associated cardiomyopathies was surveyed to determine the roles of TLR subtypes and the impact of modulating their signaling pathways.

Results: Activation of TLR2, TLR3, TLR4, TLR7, and TLR9 consistently amplifies myocardial inflammation, fibrosis, and functional decline. However, context-dependent protective effects in certain settings highlight the complexity of uniformly suppressing TLR activity. Preclinical investigations demonstrate favorable outcomes from selective pathway modulation, including TLR4 antagonists (such as TAK-242 and eritoran), MyD88 pathway inhibitors, and nucleic-acid-directed TLR9 strategies.

Conclusions: Targeting TLR signaling has strong potential to limit inflammation, curb fibrotic remodeling, and preserve cardiac function across diverse cardiomyopathies. The most promising therapeutic direction involves developing subtype-specific and cell- or pathway-targeted interventions, supported by translational research to bridge preclinical findings with clinical application.

Background: Asthma and chronic obstructive pulmonary disease (COPD) - two common airway diseases - have drawn greater attention lately because of their increasing occurrence and mortality rates. The main inflammatory types - type 2 and non-type 2, which include type 1 and type 3 inflammation - are distinguished by the presence of discrete immune cells, that coordinate the recruitment and activation of inflammatory cells, resulting in various pathological presentations, clinical symptoms, therapeutic responses, and prognoses. Despite significant differences, COPD and asthma share many inflammatory commonalities. In recent years, the type 2 inflammatory phenotype in COPD has steadily emerged as the focus of COPD research. Understanding the differences between COPD and asthma with type 2 inflammatory phenotypes is critical for designing individualized treatment strategies.

Methods and results: This review systematically searched for Chinese and English literature on COPD and asthma in the field of type 2 inflammation, and conducted a comprehensive review and analysis of the relevant content. It explored the similarities and differences between type 2 inflammatory phenotypes in COPD and asthma, with particular emphasis on their inflammatory mechanisms, clinical features, biomarkers, therapeutic targets, and treatment responses.

Conclusion: This review investigates the similarities and differences between type 2 inflammatory phenotypes in COPD and asthma, with the aim of better addressing their diversities, gain deeper insights into their underlying cellular and molecular mechanisms, develop novel therapies in unmet areas, explore more effective treatment directions, reduce the disease burden, and enhance patient outcomes.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune manifestation characterized by persistent chronic inflammation and joint damage. B cells play pivotal roles in the immune system, recognize antigens, and facilitate subsequent immune responses. Recent advancements in single-cell resolution techniques and immunogenomics have provided unprecedented insights into deciphering the complex mechanisms underlying B-cell dysregulation in RA.

Methods and results: This review article aims to articulate the current knowledge on how aberrant B cell activation and BCR signalling contribute to the development and perpetuation of self-reactive B cells in RA. Furthermore, this article explores immunogenomic insights that have shed light on the impaired B cell expansion and genetic variations in B cell-specific genes observed in RA patients, unveiling new layers of complexity in the underlying mechanisms driving autoimmune processes.

Conclusion: This article focused on abberant B cell activation and immunogenomics aspects of B cells in rheumatoid arthritis. Precise identification of abberant BCR signalling pathways, abberant genetic variats and extensive abnormalities in DNA can provide detailed insights to direct structural and therapeutic interventions against autoimmune and hypersensitive disorders.

Background: Periodontal disease is a prevalent chronic inflammatory condition of the tooth-supporting tissues characterized by progressive loss of connective attachment and alveolar bone. The IL-12 cytokine family-comprising IL-12, IL-23, IL-27, and IL-35-plays key yet divergent roles in shaping periodontal immune responses through heterodimeric subunits and distinct JAK-STAT signaling pathways. These cytokines differentially regulate inflammation, microbial interactions, and bone resorption.

Methods: This review integrates experimental and clinical evidence assessing IL-12 family members in saliva, gingival crevicular fluid, and periodontal tissues. Studies examining cytokine expression profiles, their correlation with disease activity, microbial dysbiosis, and treatment response were analyzed. Mechanistic data elucidating how IL-12 family signaling modulates inflammatory cascades and osteoclastogenic pathways were also evaluated.

Results: IL-12 and IL-23 predominantly amplify pro-inflammatory responses by promoting Th1/Th17 polarization, enhancing neutrophil recruitment, and driving osteoclastogenesis, thereby linking dysbiotic biofilms to tissue destruction. In contrast, IL-27 and IL-35 exhibit context-dependent immunoregulatory properties, inducing IL-10-mediated anti-inflammatory signaling and expanding regulatory T and B cell compartments to support the resolution of inflammation. Across clinical samples, cytokine levels consistently reflect disease severity and demonstrate modulation following periodontal therapy, underscoring their potential as adjunctive biomarkers.

Conclusion: Members of the IL-12 cytokine family exert both pathogenic and protective influences in periodontal disease. Therapeutic strategies that suppress IL-12/IL-23-driven inflammation while augmenting IL-27/IL-35-mediated regulation show promise as host-modulatory approaches in periodontal treatment. A deeper understanding of these immunologic dynamics may advance precision-based periodontal therapies.

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: Treating traumatic spinal cord injury (SCI) requires mitigating microglia-mediated inflammation and nerve damage. Phillyrin (phi) shows neuroprotective potential, but its effects on SCI are unknown. We investigated phi's impact on microglial activation, inflammation, neuronal apoptosis, and pyroptosis in mice after SCI.

Methods: A mouse contusion SCI model was used to assess phi efficacy. Functional recovery was assessed with BBB and LSS scales. Histological and TUNEL staining were used to evaluate tissue damage and neuronal survival. Microglial phenotypes, inflammation, pyroptosis, oxidative stress and Nrf2/HO-1 pathway were analyzed.

Results: Phi treatment accelerated motor function recovery, improved tissue pathology, increased live cells, and reduced apoptosis. Phi treatment showed a decrease in the proportion of M1 pro-inflammatory microglia characterized by iNOS, an increase in the proportion of M2 anti-inflammatory microglia characterized by Arg1 and a reduction in inflammatory factors. Phi enhanced Nrf2 expression in neurons and microglia, activated HO-1 and NQO1 expression, weaken oxidative stress, and improved pyroptosis.

Conclusion: Phi alleviates SCI by activating the Nrf2/HO-1 pathway, suppressing microglial activation-mediated neuroinflammation, neuronal apoptosis, oxidative stress and pyroptosis. This study provides the first evidence of the therapeutic effect of phi on traumatic SCI, providing theoretical support for its future clinical application in SCI.

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: 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.