Immunological Investigations最新文献

Background: Multiple sclerosis (MS) is an autoimmune disorder driven by myelin autoantigen-specific autoreactive T cells, yet the most effective disease-modifying therapies (DMTs) target B cells. The mechanism underlying this paradox remains unclear. Here, we identify dual-expressor cells (DEs) -a novel lymphocyte population with hybrid T and B cell characteristics, including co-expression of the T cell receptors (TCRαβ) and surface B cell receptors (BCRs), primarily IgM-as potential contributors to MS pathogenesis and inadvertent targets of anti-CD20 DMTs.

Methods: DEs were examined in the peripheral blood and cerebrospinal fluid (CSF) of patients with relapsing-remitting MS (RRMS) compared to healthy controls. Their phenotype and functional properties were characterized, including responses to myelin autoantigens and susceptibility to depletion in a pilot cohort of seven RRMS patients treated with ocrelizumab.

Results: DEs were found at significantly higher frequencies in the peripheral blood of patients with RRMS compared to healthy controls and were further enriched in CSF, where up to 95% expressed CD20, versus ~60% in blood. Furthermore, most of DEs in CSF express CXCR3, indicating involvement of CXCR3-CCL-9, 10 and 11 in their recruiting and maintenance in the CSF of MS patients. Functionally, DEs exhibited robust responses to myelin autoantigens, supporting their relevance in disease. In a pilot cohort of seven RRMS patients, ocrelizumab significantly reduced circulating DE frequencies, confirming their susceptibility to CD20-mediated depletion.

Conclusions: These findings implicate DEs in MS and provide insight into the efficacy of anti-CD20 therapies in a traditionally T cell-driven disease.

Introduction: The persistent presence of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) contributes significantly to joint damage, yet the anti-apoptotic mechanisms involved are not well understood. This study investigates how the interleukin-21 (IL-21)/IL-21 receptor (IL-21R) pathway affects RA-FLS survival during endoplasmic reticulum stress (ERS).

Methods: Clinical data, in vitro, and in vivo experiments were comprehensively used.

Results: RA patients with moderate-high disease activity and anti-CCP antibodies have high serum IL-21 levels. IL-21 enhances HFLS-RA cell survival and prevents apoptosis under ERS by upregulating IL-21R. It activates autophagy, shown by increased LC3II/I; ratio and p62 degradation, and inhibits ERS-mediated apoptosis by downregulating GRP78 and CHOP. Overexpressing IL-21R boosts autophagy and suppresses ERS. Transcriptome analysis identified USP18 as a key downstream effector of IL-21R. Silencing USP18 increased GSDMD expression and negated IL-21R's protective effects. In vivo, silencing IL-21R reduced joint inflammation and cartilage degradation in RA mouse models, reversing excessive autophagy and ERS marker expression in synovial tissue.

Discussion: This study elucidates, for the first time, the mechanism by which IL-21/IL-21R synergistically modulates the survival of RA-FLS through the "autophagy-ERS balance" and the USP18/GSDMD axis.

Background: Nonalcoholic steatohepatitis (NASH) involves liver inflammation and fibrosis. Monocytes, key immune cells differentiating into macrophages and dendritic cells, are understudied in NASH using single-cell RNA sequencing (scRNA-seq).

Methods: Liver nonparenchymal cells from NASH and control mice underwent scRNA-seq to identify monocyte subsets and transcriptional profiles. Findings were validated via transfection, coculture, immunofluorescence, and qPCR.

Results: scRNA-seq analysis revealed that Ly6c^hi monocytes in Cluster 0 appeared to be converted into macrophages in the liver, potentially contributing to the progression of NASH inflammation. Similarly, Ly6c^lo monocytes in Cluster 1 seemed to differentiate into dendritic cells, possibly mediating T-cell immune responses in NASH. Notably, Sdc4 was uniquely abundant in Cluster 0. Sdc4⁺ monocytes were elevated in NASH patients and mice versus controls. Under lipotoxic conditions, Sdc4-deficient (sh-Sdc4) monocytes exhibited upregulated expression of CD206 (an M2 marker) and IL-10. When cocultured with sh-Sdc4 monocytes under palmitic acid stimulation, HepG2 cells accumulated fewer lipid droplets and produced less TNF-α protein, along with increased IL-10 genes, compared to controls.

Conclusion: Our study elucidates the heterogeneity and functional transformation of two major monocyte subsets in NASH. We foundSdc4+ monocytes may exacerbate NASH through pro-inflammatory mechanisms.

Introduction: Interleukin-33 (IL-33) is a multifunctional cytokine from the interleukin-1 family that plays a pivotal role in modulating macrophage responses during infection. Functioning both as an extracellular alarmin and as a nuclear transcriptional regulator, IL-33 orchestrates a dynamic balance between autophagy and apoptosis, crucial for immune homeostasis.Methods: A systematic literature search was conducted in PubMed, Web of Science, and Scopus for studies published between January 2010 and April 2025. Search terms combined "Interleukin-33" with keywords related to autophagy, apoptosis, macrophages, and infection.Results: It enhances autophagy by activating AMP-activated protein kinase (AMPK), inhibiting mechanistic target of rapamycin (mTOR), and interacting with Beclin-1 to promote autophagosome formation and LC3 lipidation. Concurrently, IL-33 suppresses apoptosis by upregulating Bcl-2 and Mcl-1, inhibiting Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), and blocking caspase activation. Recent studies also highlight the importance of post-translational modifications (PTMs) and the nuclear domain of IL-33 in fine-tuning these responses. Furthermore, IL-33-based combination therapies with immune checkpoint inhibitors (ICIs) are emerging as promising immunotherapeutic strategies.Discussion: This review synthesizes current insights into IL-33-mediated regulation of macrophage fate and identifies key research gaps. A better understanding of the context-dependent roles of IL-33 will be critical for translating these mechanisms into effective, targeted therapies for infectious and inflammatory diseases.

Background: Tertiary lymphoid structures (TLSs) function as ectopic immune centers in non-lymphoid tissues and are a key area of research in tumor immunology, particularly in hepatocellular carcinoma (HCC). However, the role of TLSs in HCC shows significant heterogeneity; intratumoral TLSs (iTLSs) are linked to favorable outcomes and immune therapy responses, while peritumoral TLSs may be dysfunctional or promote tumor progression. This spatial paradox is a core scientific question for understanding and leveraging TLSs in HCC treatment. The liver's unique immunosuppressive and fibrotic microenvironment, influenced by hepatic stellcell-derived cancer-associated fibroblasts (CAFs) and local signals like tryptophan metabolism, profoundly regulates TLSs formation and functional polarization.

Methods: This review integrates current research on TLSs in HCC, focusing on their functional heterogeneity based on spatial localization and the regulatory mechanisms involving the liver's microenvironment. It identifies major bottlenecks in TLSs clinical translation, including inconsistent assessment standards and the lack of non-invasive dynamic monitoring methods. Cutting-edge technological paradigms such as spatial multi-omics, AI-driven computational pathology, and multi-modal liquid biopsy are explored as feasible pathways for precise decoding and standardized assessment of TLSs functional states.

Results: Existing evidence highlights the differential impact of iTLSs (favorable outcomes, improved immunotherapy response) versus peritumoral TLSs (dysfunctional or pro-tumorigenic) in HCC. The regulation of TLSs is shown to be deeply intertwined with the liver's unique microenvironment, particularly CAFs and tryptophan metabolism. The analysis points to the potential for integrating advanced technologies to overcome current assessment and monitoring challenges, paving the way for a more precise understanding of TLSs functional states.

Conclusion: Addressing the functional paradox of TLSs based on spatial localization in HCC is crucial for guiding treatment. Overcoming current assessment and monitoring bottlenecks through the integration of spatial multi-omics, AI-driven computational pathology, and multi-modal liquid biopsy offers a pathway for precise decoding and standardized evaluation of TLSs functional states. Future research should shift towards active therapeutic interventions targeting TLSs function and location to optimize personalized immunotherapy strategies for HCC patients.

Background: Pulmonary neuroendocrine cells (PNECs) are specialized airway epithelial cells with dual sensory and secretory functions. They release bioactive mediators --including neuropeptides such as calcitonin gene-related peptide (CGRP) and gastrin-releasing peptide (GRP), and neurotransmitters such as 5-hydroxytryptamine (5-HT) and γ-aminobutyric acid (GABA) --that regulate airway smooth-muscle tone, mucus production, and immune responses. In chronic obstructive pulmonary disease (COPD), these PNEC-derived mediators contribute to airway inflammation, remodeling, and smooth-muscle dysfunction. Chronic inflammation and oxidative stress in COPD are closely linked to PNEC activity.

Methods: We conducted a narrative review summarizing evidence on PNEC biology, their principal secretory mediators, and mechanistic links to key pathological processes in COPD, including inflammation, oxidative stress, and airway remodeling.

Results: PNEC-derived mediators (CGRP, GRP, 5-HT, GABA) participate in COPD-relevant processes by modulating airway tone, mucus production, and immune responses. In COPD, dysregulated PNEC activity is associated with persistent inflammation, heightened oxidative stress, airway remodeling, and smooth-muscle dysfunction. PNECs also contribute to epithelial repair and regeneration, indicating a role in maintaining -and, when perturbed, disrupting -airway homeostasis.

Conclusion: PNECs integrate sensory inputs with secretory signaling to shape multiple COPD-related pathways. Clarifying the mechanisms and context dependence of PNEC activity may inform therapeutic strategies targeting PNEC-derived mediators and support the development of novel interventions for COPD.

Background: T cell malignancies represent a broad, highly heterogeneous subset of lymphomas with poor prognosis. Chimeric antigen receptor (CAR)-T cell therapy holds great promise in treating B cell lymphoma and multiple myeloma. However, understanding its efficacy in treating T cell lymphoma remains challenging, primarily due to the lack of tumor-specific targets and intra-tumor heterogeneity.

Methods: In this proof-of-concept study, we developed and characterized three distinct CAR-T cells targeting tumor-associated glycoprotein 72 (TAG-72), C-C chemokine receptor type 4 (CCR4) and tumor necrosis factor receptor CD30 respectively and assessed their anti-tumor efficacy against T cell malignancies in vitro.

Results: TAG-72 and CD30 CAR-T cells each demonstrated comparable expansion potential and eliminated tumor cells expressing their respective target antigens. Subsequently, we explored the advantages of targeting two antigens through the pooling of these CAR-T cells. In instances where target antigen expression was low (as determined by flow cytometry), dual targeting of TAG-72 and CD30 was able to elicit cytotoxic function.

Conclusion: These findings define TAG-72 and CD30-targeting CAR-T cells as a promising strategy against T cell malignancies and highlight the potential of dual or combination CAR-T cell therapies for this aggressive disease.

Background: Bone marrow-derived macrophage (BMDM) is key tool cell for studying biological processes such as immunity and inflammation. It is also known as a cell drug that can be used for cytotherapy of many diseases such as liver fibrosis. Given the high demand for BMDMs in research, this study explored the most cost-effective, high-productivity method and its molecular mechanism for obtaining Macrophage Colony-Stimulating Factor (M-CSF)-induced mouse BMDM.

Methods: A factorial experimental design was employed to examine different induction conditions on BMDM phenotype proportion and productivity, including bone marrow cell (BMC) seeding density, M-CSF concentration, induction time, and removal of bone marrow resident macrophage. Neutral red phagocytosis assay was used to measure phagocytic capacity of BMDM. The mechanism of BMDM proliferation and differentiation was investigated by RNA-seq technology.

Results: The most cost-effective and high-productivity BMDM induction protocol is 2 × 10⁵ cells/cm² BMDM seeding density, 80 ng/ml M-CSF induction for 4 days with medium changing once on day 3. BMDM productivity reaches 75.6%. Furthermore, 4-day BMDM showed the strongest phagocytic capacity. RNA-Seq analysis revealed that Cd4, Smad6, Acta2, and Lrrc32 were key target genes regulating BMDM proliferation. Jun, Smad6, Cd4, Fhl2, Hspb1, Id1, and Inhbb were key target genes regulating BMDM differentiation. MAPK, mTOR, TGF-β, and NF-kappa B signaling pathways were the key proliferation or differentiation-related pathways.

Conclusions: This study proposes an efficient and economical protocol for BMDM induction. Besides, it explores the regulatory mechanism of M-CSF on BMDM proliferation and differentiation.

This review highlights the emerging role of the immune checkpoint receptor T cell immunoglobulin and mucin-domain containing-3 (TIM-3) as a crucial modulator in the prostate's microbiome-immune axis, with significant implications for prostate-related diseases such as prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer. These conditions reflect the prostate's susceptibility to immune dysregulation, which is influenced by microbial communities and their metabolites. TIM-3, already known for its role in immune regulation in cancer and chronic infections, is now recognized for its potential to shape immune responses within the prostate by modulating regulatory T cells (Tregs) and influencing inflammation and tolerance. Microbial metabolites, such as short-chain fatty acids (SCFAs), and pro-inflammatory bacterial components like lipoteichoic acid can alter TIM-3 expression, contributing to immune imbalance. Therapeutic strategies targeting TIM-3 aim to restore immune equilibrium, while complementary microbiome-focused approaches, such as probiotics, dietary interventions, pH modulation, and enhancement of epithelial antimicrobial peptides, may further prevent microbial overgrowth and inflammation. Drawing parallels with therapies for inflammatory bowel disease and other immune-related conditions, the integration of TIM-3 blockade with microbiota modulation presents a promising avenue for managing chronic prostate inflammation and cancer. This review proposes a multi-omics and bioinformatics-driven framework for developing TIM-3-centered diagnostic and therapeutic strategies.

Objective: To examine whether features of the B cell receptor (BCR) IgG repertoire correlate with disease activity and clinical phenotypes in systemic autoimmune diseases (SAIDs).

Methods: High-throughput sequencing was performed on IgG heavy chain repertoires from 138 patients with SAIDs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma (SSc), and idiopathic inflammatory myopathy (IIM), as well as 36 healthy controls (HC). We analyzed V/D/J gene usage, clonal distribution and diversity, CDR3 length distribution and amino acid usage, and the correlation between specific BCR features and clinical features.

Results: SAIDs showed skewed usage of V/D/J genes and V-D-J combinations, with altered CDR3 length distributions and amino acid usage in SLE, RA, SSc, and IIM. Notably, SLE and RA exhibited a pronounced expansion of mid-ranked clones and significantly higher clonal diversity compared to HC. Specific genes, including IGHD2-15, IGHV1-24, IGHV1-69-2, IGHV1-8, and IGHV4 family members, along with increased clonal diversity, were closely associated with disease activity and clinical phenotypes in SLE and RA.

Conclusions: IgG repertoire features reflect disease-related immune perturbations and may serve as potential biomarkers for disease progression, diagnostics and targeted therapies in SAIDs.