Immunologic Research最新文献

Axial skeletal involvement is central to ankylosing spondylitis, yet the in situ interplay between immune effectors (especially cytotoxic T lymphocytes) and the bone matrix microenvironment remains poorly resolved. Prior single-cell studies in peripheral compartments revealed exhaustion-resistant CTLs and dysregulated transcriptional regulators (e.g. NFKB, FOS, JUN) in AS patients, but lacked spatial and stromal context. We obtained axial skeletal tissue (vertebral bone marrow, enthesial fibrocartilage, adjacent endplate stromal tissue) from 24 AS patients with active disease and 12 age-matched controls undergoing spine surgery (total 108,752 single cells). We performed joint single-cell RNA-seq and ATAC-seq on matched samples, followed by integrative clustering, differential gene expression, chromatin accessibility analysis, pseudotime trajectories, and ligand-receptor network inference. Correlations with clinical indices (BASDAI, MRI inflammation scores) and imaging structural progression were assessed. We identified a discrete CTL subset in axial tissues with high expression of checkpoint molecules (PD-1, TIM-3), cytotoxic genes (GZMB, PRF1), and chromatin accessibility favoring NFKB/FOS motif enrichment, consistent with resistance to exhaustion. This subset increased by about 2.8 times in AS compared to controls (p < 0.001). Simultaneously, enthesial stromal fibroblasts displayed the upregulation of matrix remodeling genes (MMP9, COL1A1, COL3A1) and osteogenic drivers (RUNX2, BMP2). Ligand-receptor modeling demonstrated robust interactions between CTLs and stromal fibroblasts via TNF, TGFβ, integrin, and Notch signaling pathways. It is important to note that CTL-stromal interaction scores were related to MRI inflammation grade (r = 0.62, p = 0.003) and structural progression (r = 0.54, p = 0.01). This integrated single-cell atlas identifies a pathogenic CTL-stromal axis in the axial skeleton of AS patients, linking immune cytotoxic mechanisms with matrix remodeling and osteogenesis. These findings delineate actionable molecular crosstalk nodes that could inform precision therapeutic strategies aimed at immune-matrix interactions in situ.Clinical trial numberNot applicable.

Messenger RNA (mRNA)-encoded antibodies represent a transformative therapeutic platform with the potential to rapidly combat emerging infectious diseases by enabling in situ expression of potent neutralizing antibodies directly in the patient's body. Unlike conventional monoclonal antibody (mAb) therapies, which rely on labor-intensive and time-consuming cell culture production, mRNA-encoded antibodies offer a faster, scalable, and cell-free approach that bypasses protein purification and cold-chain constraints. This strategy has demonstrated considerable promise during the COVID-19 pandemic, where Moderna's mRNA-1940, an mRNA-based neutralizing antibody targeting the SARS-CoV-2 spike protein, entered preclinical and early-phase trials within months of viral emergence, underscoring the potential for rapid response in outbreak settings. The platform leverages advances in nucleoside-modified mRNA, codon optimization, and lipid nanoparticle (LNP) delivery systems to achieve transient, high-level expression of functional antibodies with reduced innate immune activation. Beyond COVID-19, mRNA-encoded antibody approaches have been explored in preclinical models of Zika virus, Ebola virus, and rabies, where a single intramuscular dose provided prophylactic and therapeutic benefits in animal models. As the world faces recurrent viral threats, the development of mRNA-encoded antibodies as a plug-and-play system offers a compelling, adaptable, and clinically feasible strategy for infectious disease preparedness. This review explores the mechanistic foundation, delivery technologies, translational progress, case studies, safety considerations, and future clinical potential of mRNA-encoded antibodies in combating both pandemic and endemic infections.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder with a high prevalence among postmenopausal women (PMW), and it is associated with substantial functional impairment and reduced quality of life. To inform targeted prevention strategies for high-risk populations in the U.S., a comprehensive and up-to-date assessment of disease burden in this population is needed. We conducted a quantitative analysis of the prevalence, years lived with disability (YLDs), and disability-adjusted life years (DALYs) of RA among PMW (PMWRA) in the U.S. from 1990 to 2021. In addition, disease trends were projected for 2022-2035 using data from the Global Burden of Disease Study (GBD) 2021. We extracted state-level estimates of prevalence, YLDs, and DALYs for PMWRA across 51 U.S. states from 1990 to 2021. Temporal trends were summarized using the average annual percent change (AAPC), and geographic and age-specific differences were assessed. Major risk factors contributing to state- and age-specific YLDs and DALYs were analyzed. Future projections were forecast using autoregressive integrated moving average (ARIMA) and exponential smoothing state-space (ETS) models. All analyses were conducted using R version 4.4.2 and the Joinpoint Regression Program. From 1990 to 2021, prevalence, YLD, and DALY rates among U.S. PMWRA showed upward trends, with AAPCs of 0.55, 0.50, and 0.04, respectively; the corresponding total percent changes in numbers were 1.13, 1.10, and 0.82. In 2021, Montana exhibited the highest prevalence (2,235.76), YLD (277.29), and DALY rates (362.62) among all states nationwide. The disease burden increased with the rising sociodemographic index up to a threshold and then declined. Age-stratified analyses indicated increasing prevalence, YLD, and DALY rates across nearly all age groups. Smoking emerged as the principal risk factor for PMWRA-related YLDs and DALYs across ages and regions. Forecasts based on ARIMA and ETS models indicated continued increases in prevalence and YLDs, whereas DALY rates were projected to decline. The burden of PMWRA among U.S. women is projected to continue rising, with concentration in specific states and age groups, which emphasizes the need for targeted public-health interventions to mitigate the burden in this population.

Objective: Familial Mediterranean Fever (FMF) is the most prevalent monogenic autoinflammatory disorder. In the present study, we investigated whether HLA-B polymorphisms contribute to familial Mediterranean fever (FMF) susceptibility and phenotypic variability.

Methods: We enrolled 50 familial Mediterranean fever (FMF) patients, 40 asymptomatic Mediterranean FeVer (MEFV) mutation carriers, and 50 healthy controls. HLA-B genotypes were determined by the PCR-SSO technique. Allele frequencies were compared using chi-square or Fisher's exact tests.

Results: HLA-B*51 and HLA-B*35 alleles were enriched among FMF patients compared with controls (p = 0.01 and p = 0.03, respectively). HLA-B*27 was moderately increased in patients (p = 0.04), while HLA-B*44 tended to be more common in carriers (p = 0.07). Odds ratio (OR) and confidence interval (CI) analyses indicated an elevated FMF risk for carriers of HLA-B*51 and HLA-B*35.

Conclusion: HLA-B variants, particularly B*51 and B*35, may act as immunogenetic modifiers of FMF, supporting the concept of MHC class I linked inflammatory pathways contributing to disease heterogeneity.

SALL4 is aberrantly reactivated in multiple malignancies, including breast cancer (BC), where it promotes tumor progression and therapy resistance. However, its therapeutic targeting remains underexplored. This study investigates the antitumor efficacy of a novel SALL4-inhibitory peptide, PEN-FFW, and its regulatory impact on the PI3K/AKT/PD-L1 axis and CD8⁺ T cell-mediated cytotoxicity in BC. SALL4 expression in BC was assessed using public databases and validated in cell lines by RT-qPCR and western blot. The interaction between SALL4 and the NuRD complex was evaluated by co-immunoprecipitation assay. Functional assays were conducted to assess the effects of PEN-FFW in vitro. Co-culture systems were used to evaluate CD8⁺ T cell-mediated cytotoxicity. Mechanistic studies investigated the involvement of the PTEN/PI3K/AKT/mTOR signaling axis. In vivo efficacy was tested in allograft mouse models, including combination therapy with anti-PD-L1 antibody. SALL4 was significantly upregulated in BC and associated with poor prognosis. PEN-FFW disrupted the SALL4-NuRD interaction, restored PTEN expression, and suppressed PI3K/AKT/mTOR signaling. This led to a reduction in PD-L1 expression and increased apoptosis, while inhibiting the proliferation and migration of BC cells. PEN-FFW also enhanced CD8⁺ T cell cytotoxicity by reducing PD-L1-mediated immune evasion. Furthermore, combination treatment with PEN-FFW and anti-PD-L1 antibody showed superior tumor suppression and increased CD8⁺ T cell infiltration compared to either treatment alone. PEN-FFW is a potent SALL4-inhibitory peptide that suppresses BC progression by downregulating PD-L1 through PI3K/AKT pathway inactivation and promoting CD8⁺ T cell-mediated tumor killing. These findings highlight a promising strategy for enhancing immunotherapy in SALL4-positive BC.

The lectin pathway, activated by ficolins, contributes to systemic lupus erythematosus (SLE) pathogenesis, but ficolin data remain inconsistent across populations. Present muti-centric cross-sectional study assessed serum ficolin-1, -2, and - 3 levels and their associations with clinical features and disease activity among SLE patients from five Indian regions (Mumbai, Assam, Meghalaya, Manipur, and Nagaland). Serum levels of ficolin-1, ficolin-2, and ficolin-3 were measured using ELISA. Disease activity was assessed using the SELENA-SLEDAI score. Statistical analyses were performed using non-parametric tests, with p < 0.05 considered significant. Serum ficolin levels differed significantly by region. Ficolin-1 and ficolin-2 levels were positively correlated with the renal involvement in SLE patients from Mumbai (r = 0.218; p < 0.001 and r = 0.199; p = 0.001, respectively), while ficolin-1 levels were also correlated with lupus nephritis (LN) in SLE patients from Manipur (r = 0.247; p = 0.040). In Assam, ficolin-2 levels were significantly reduced in patients with mucocutaneous manifestations (r=-0.258; p = 0.014), and ficolin-3 levels showed a negative correlation with musculoskeletal manifestations (r=-0.217; p = 0.040). In Mumbai, ficolin-1 levels were positively associated with disease activity (r = 0.139; p = 0.018), and ficolin-3 levels correlated positively with anti-dsDNA autoantibodies (r = 0.172; p = 0.004). Conversely, ficolin-3 levels showed a negative correlation with anti-dsDNA (r=-0.470; p < 0.001) in Assam. The present study demonstrated significant regional variations in ficolin levels among SLE patients across India. Association of ficolin-1 and ficolin-3 with specific organ involvement suggested their potential as possible immunological indicators in SLE. These findings suggested the importance of considering regional and ethnic differences in SLE management and warranted further validation through larger, longitudinal studies.

IHP is a rare inflammatory disorder characterized by dural thickening. Its nonspecific presentation often leads to diagnostic challenges and potential misdiagnosis as a neoplasm. Literature review and illustrative case example. PubMed search using terms related to IHP yielded 272 candidate citations, 50 of which met study criteria and were included. A 40-year-old woman presented with headache, dizziness, and blurred vision. Surgical intervention via right craniotomy was recommended due to diagnostic uncertainty, symptomatic mass effect, and the potential for a malignant diagnosis. A near-total resection of the mass and its dural base was performed given the involvement of the transverse-sigmoid sinuses; histopathology revealed dense fibrous tissue with chronic inflammatory cell infiltration. Immunohistochemistry was positive for CD3 and CD20, and negative for EMA, SSTR2, IgG, and IgG4, confirming the diagnosis of IHP. Review of the literature identified 117 patients presenting at a median age of 51 years with slight female predominance. Headache was the most common symptom (94%), followed by cranial nerve deficits (49%). MRI was used in all cases, with the tentorium being the most frequent site of involvement (48%). Treatment typically involved biopsy (47%), resection (11%), long-term steroids (56%), or steroid taper (44%). Radiographic recurrence was observed in 35%. Based on the experience from our case and supportive summative evidence from the literature, we developed a clinical decision-making schema to assist clinicians in recognizing and managing IHP. IHP remains a diagnostic challenge due to its rarity, nonspecific presentation, and potentially confounding radiographic features.

Current biologics and small-molecule inhibitors for autoimmune diseases often provide symptomatic relief but fail to restore immune tolerance, necessitating lifelong treatment with associated risks. Triptolide, a natural compound from Tripterygium wilfordii Hook F, exhibits a unique capacity for immune reprogramming, simultaneously suppressing pathogenic immunity while enhancing regulatory functions, positioning it as a potential 'immune reset' agent. However, its clinical translation is plagued by a narrow therapeutic window due to mechanism-based toxicity, creating a critical challenge of decoupling efficacy from toxicity. This review moves beyond a descriptive cataloguing of triptolide derivatives to provide a critical appraisal of the field's progress in achieving this decoupling. We systematically evaluate the most promising candidates (e.g., LLDT-8, Minnelide, ZT01), not only examining their mechanisms but also analyzing why most stall in early development. By integrating mechanistic insights with clinical progress data, we dissect the structural determinants of toxicity and efficacy and propose a concrete future roadmap focused on rational drug design (e.g., novel targets like TAK1), targeted delivery systems, and biomarker-driven precision medicine to advance safe and effective triptolide-based therapies to the clinic.

This systematic review and meta-analysis assess the immunogenicity and maternal-fetal safety profile of RSV prefusion F (RSVpreF) vaccination during pregnancy. PubMed, Scopus, Embase, Cochrane, and Web of Science databases were searched for relevant studies. Only randomized controlled trials (RCTs) evaluating the safety, efficacy, and immunogenicity of RSVpreF vaccination in pregnant women were included. Six RCTs, involving 17,212 participants, were analyzed. The vaccine significantly boosted maternal anti-RSV neutralizing antibody levels, with a standardized mean difference (SMD) of 1.40 for RSV-A and 1.11 for RSV-B, both with high statistical significance. Infants born to vaccinated mothers had a 49% reduced risk of RSV-associated lower respiratory tract illness within 180 days post-vaccination (OR = 0.51, 95% CI: 0.40-0.64). Preterm birth rates did not differ significantly between the vaccine and placebo groups (OR = 1.09, 95% CI: 0.87-1.37). The vaccine was not associated with increased risks of serious adverse events or perinatal complications. Maternal RSVpreF vaccination significantly elevates neutralizing antibody levels against RSV subtypes A and B without increasing the risk of serious adverse events or preterm delivery. These findings support the safety and immunogenicity of RSV vaccination in pregnant women, reinforcing its potential utility in protecting neonates against RSV-related morbidity.