Immunologic Research最新文献

In their recent study, Jedlička et al. demonstrate that glutaminase (GLS) activity is indispensable for sustaining human natural killer (NK) cell cytotoxicity, positing it as a key metabolic regulator of effector function. While this work provides a valuable foundation for understanding NK cell immunometabolism, our analysis identifies several critical areas requiring deeper exploration. This letter offers a prospective critique, highlighting the incomplete delineation of the downstream metabolic mechanisms-specifically regarding energy production, biosynthetic precursor synthesis, and redox homeostasis-that link GLS activity to the cytolytic machinery. Furthermore, we question the physiological relevance of these in vitro findings within the nutrient-deprived and competitive tumor microenvironment (TME), where NK cells must exhibit metabolic flexibility. A paramount concern is the translational double-edged sword of GLS inhibition, which may inadvertently suppress anti-tumor immunity. We conclude that future research must employ integrated multi-omics and in vivo models to resolve these complexities, which is essential for harnessing NK cell metabolism without compromising its therapeutic potential.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Genetic factors play a key role in its pathogenesis and may also influence therapeutic response. This study aimed to investigate the association of the STAT4 rs7574865-T and PTPRC rs10919563-A polymorphisms with RA susceptibility and response to TNF inhibitor (TNFi) treatment in a Brazilian population. A case-control study was conducted including 295 RA patients treated with TNFi and 303 healthy controls. Genotyping of rs7574865 (STAT4) and rs10919563 (PTPRC) was performed. Associations with RA susceptibility, TNFi treatment response, and therapy discontinuation due to adverse events were evaluated under different genetic models. A meta-analysis integrating our results with previously published studies was also conducted. The rs7574865-T allele was associated with increased RA risk (OR: 1.43; 95% CI: 1.03-1.99; p = 0.036; p perm = 0.042), reduced response to TNFi (OR: 0.28; 95% CI: 0.07-0.99; p = 0.047; p perm = 0.058), and higher likelihood of treatment discontinuation due to adverse events (OR: 1.89; 95% CI: 1.01-3.58; p = 0.047;p perm = 0.034). After permutation-based correction (1,000 iterations), all associations remained consistent except for the recessive model in TNFi response, which became non-significant (p_perm = 0.058). The meta-analysis confirmed a 40% increased RA susceptibility in T allele carriers. No significant association was observed for rs10919563-A regarding RA risk or TNFi response. A genetic interaction between STAT4 (G/T) and PTPRC (A/A, p = 0.008; G/G, p = 0.017) genotypes was observed, suggesting an increased RA risk for these genotype combinations, without significant correlation with TNFi treatment outcomes. Our findings reinforce the role of STAT4 rs7574865-T in RA susceptibility and TNFi treatment outcomes and highlight the potential for personalized therapeutic strategies based on genetic profiles.

With the rapid increase in the severity and mortality of OSCC, the potential for new and effective therapies has increased significantly. Therefore, studying the immunological model of this disease will serve as a basis for developing new treatment approaches. In OSCC, Th17 cells play a crucial role in controlling the outcome of the disease and modulating the response to treatment. This review focuses on Th17 cells, their differentiation and characterization, and the role these lymphocytes play in the occurrence and recovery of OSCC. The prognosis of OSCC may depend on the profile of immune cells infiltrating the tumor and the cytokines they release, as well as the dynamics of transient expression of genes such as PD-1 (Programmed cell death protein-1). The balance between Treg and Th17 cells is crucial for health; Disruption of this balance can lead to autoimmune diseases and disrupt normal body function. The Treg/Th17 axis plays a role not only in the inflammatory cascade but also in bone resorption. One of the factors that most influences the growth of OSCC tumors is the tumor microenvironment. Made up of cytokines, lymphocytes, macrophages, chemokines, growth factors, and similar substances, this tumor milieu significantly controls the course of disease progression. Lifestyle factors, such as smoking and drinking, significantly impact Th17 cell activity and distribution in OSCC patients, influencing their immune profile and treatment outcomes. This highlights the need for personalized approaches. Through this review, we aim to provide data on the factors that make OSCC so deadly and also provide an immune profile of this disease.

Macrophage migration inhibitory factor (MIF) is one of several pivotal cytokines that contribute to orchestrate immune regulation, inflammation, and cell survival, acting as both a mediator of host defense and a factor that viruses can exploit. This comprehensive review delineates MIF's multifaceted roles across diverse viral families-including Retroviridae, Herpesviridae, Hepadnaviridae, Orthomyxoviridae, Flaviviridae, Paramyxoviridae, and Picornaviridae-highlighting the mechanisms by which viruses manipulate MIF signaling to promote replication, evade immune responses, and induce tissue damage. Viral strategies often involve upregulating MIF expression or leveraging its receptor pathways, such as CD74, CXCR2, and CXCR4, to enhance viral persistence, disrupt barrier integrity, and skew immune polarization toward pro-viral or immunosuppressive states. Conversely, MIF-driven inflammation can worsen pathogenic processes, including cytokine storms, neuroinvasion, and fibrosis, contributing to disease severity. Notably, pharmacologic inhibition of MIF has shown promise in preclinical models, reducing viral replication and mitigating tissue damage, thereby positioning MIF as one of the compelling targets for host-directed antiviral therapies. Understanding the complex, context-dependent functions of MIF in viral infections provides transformative insights for innovative treatment strategies that aim to disrupt virus-host interactions, control inflammation, and improve clinical outcomes in infectious diseases. Future research exploring MIF's molecular interactions, genetic variations, and therapeutic modulation will be crucial for harnessing its potential for personalized, effective antiviral interventions.

Multiple myeloma (MM) is an incurable hematologic malignancy with high heterogeneity and poor prognosis. Lactylation, a novel post-translational modification, drives tumor progression and immune dysregulation, yet its prognostic value in MM remains uncharacterized. To explore the prognostic value of lactylation-related genes in multiple myeloma, our study aims to construct and validate a lactylation-related multigene signature, which can provide integrated prognostic stratification, immune landscape profiling, and therapeutic guidance for MM patients. This study integrated 1,417 MM patients (859 from the TCGA-MMRF training cohort; 558 from the GSE24080 validation cohort) and 121 normal controls. Differential expression identified lactylation-related genes, and a prognostic model was constructed via LASSO-Cox regression. The model was validated in an independent cohort and we assessed immune infiltration and drug sensitivity. We finally identified four lactylation-associated prognostic genes (SLC19A1, KIF23, TOP2A, and XK) and categorized the patients into high-risk/low-risk groups, which differed in survival rates (P < 0.0001). The model showed robust accuracy (3-year AUC = 0.764) and validation (P = 0.0018). Low-risk patients exhibited enhanced anti-tumor immunity (activated dendritic cells↑, CD8⁺ T cells↑) and heightened sensitivity to bortezomi/venetoclax, etc. We established the lactylation-derived gene signature for MM, providing a clinical tool for risk stratification, immune profiling, and personalized therapy.

The development and stability of induced regulatory T cells (iTregs) are essential for their immunosuppressive function and therapeutic potential in inflammatory diseases. Although Treg-based immunotherapy offers promise for restoring immune tolerance, clinical application is limited by the instability and reduced potency of iTregs. STAT6 signaling has been implicated in destabilizing Foxp3 expression, a key marker of Treg identity. Here, we investigated the impact of pharmacological STAT6 inhibition on iTreg differentiation, stability, and function both in vitro and in vivo. Naïve CD4⁺ T cells were differentiated into iTregs under standard conditions or expanded with IL-2 in the presence of the STAT6 inhibitor AS1517499 (AS-iTregs). STAT6 inhibition enhanced iTreg stability, maintaining high expression of Foxp3, CD25, PD-1, and CTLA-4 for up to 10 days, even in inflammatory conditions. AS-iTregs also showed increased mRNA levels of Foxp3, IL-10, TGF-β, and PD-1, and reduced IL-6, IL-1β, and DNMT1 expression-suggesting improved functional and epigenetic stability. In the DSS colitis model, adoptive transfer of AS-iTregs alleviated disease severity, preserved mucosal architecture, and increased goblet cell numbers. Histopathological analysis showed reduced epithelial damage and inflammation compared to controls. Importantly, AS-iTregs did not promote tumor growth in a colitis-associated cancer model. Furthermore, in vivo administration of AS1517499 during acute colitis enhanced Treg expansion, activation, and suppressive function. These findings establish STAT6 inhibition as a promising approach to boost iTreg stability and efficacy, advancing the potential of Treg-based therapies for inflammatory disorders.

This study aimed to determine the current prospective strategies for diagnosing and treating cold urticaria based on the history of its research since the 19th century. The study analysed relevant scientific sources, and the main historical milestones of cold urticaria research were identified. Based on the results, a chronology of scientific events was established that formed the modern understanding of the pathogenesis of cold urticaria and contributed to the development of diagnostic and treatment methods used in contemporary clinical practice. Throughout the 19th century, scientists formulated the concept of cold urticaria as an allergic reaction, identifying a causal relationship between exposure to cold and a patient's skin reaction. They expanded this understanding by describing the symptoms, triggers, and mechanism of development, and establishing the hereditary nature of the disease. The technological capabilities of the 20th century significantly improved the level of research. The results obtained have demonstrated the scientific processes that have become the basis for the introduction of existing approaches to the treatment of cold urticaria and have expanded the potential for the development of fundamentally new therapeutic strategies in this area.

Dexmedetomidine (Dex), an α2 adrenergic receptor agonist, has been shown to exert protective effects against postoperative neurocognitive disorder (PND) following anesthesia and surgery. This study aimed to investigate the underlying mechanisms, with a focus on the inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-chaperone glucose-regulated protein 75 (GRP75) calcium transport protein complex-mediated mitochondrial dysfunction. An in vitro sevoflurane-induced SH-SY5Y cell injury model and an in vivo PND rat model induced by sevoflurane anesthesia plus laparotomy were established, and both models were pretreated with Dex. Subsequent assessment included cell viability, apoptosis, inflammatory cytokines, reactive oxygen species (ROS), mitochondrial calcium ion (Ca²⁺), mitochondrial membrane potential (MMP), mitochondrial ultrastructure, and ATP production. Cognitive functions including spatial memory, anxiety-like behavior, and recognition memory were evaluated in rats. The expression levels and interactions among IP3R, GRP75, and VDAC1 were examined to elucidate the mechanisms involved. Sevoflurane exposure reduced cell viability, increased apoptosis and inflammation, and induced mitochondrial impairments including ROS overproduction, Ca²⁺ overload, loss of MMP, ultrastructural damage, and reduced ATP production. Dex pretreatment effectively alleviated all these cellular injuries. Furthermore, Dex alleviated cognitive deficits in PND rats and mitigated neuronal loss, histological damage, apoptosis, neuroinflammation, and mitochondrial ultrastructural damage in hippocampal tissues. Mechanistically, Dex reversed sevoflurane-induced upregulation of IP3R, GRP75, and VDAC1 and disrupted their enhanced interaction. VDAC1 exhibited the most pronounced changes in response to both sevoflurane injury and Dex treatment. Rescue experiments suggested that VDAC1 overexpression abrogated Dex-mediated mitochondrial protection. Dex alleviates cognitive deficits in PND rats by preserving mitochondrial calcium homeostasis and mitigating mitochondrial dysfunction through regulating the IP3R-GRP75-VDAC1 complex. This study may provide critical insights into the neuroprotective mechanisms of Dex in PND and identify potential therapeutic targets.

Immunoglobulin G4-related disease (IgG4-RD) neurological involvement typically presents as pachymeningitis. However, there have been reports of neuromuscular manifestations. To review the involvement of the peripheral nerves, neuromuscular junction, and muscles in IgG4-RD, we conducted a systematic review of case reports and case series of patients with IgG4-related disease (IgG4-RD) presenting with neuromuscular manifestations, using the PubMed/MEDLINE, Embase, and Scopus databases. Articles were analyzed for demographic characteristics, neurological presentations, systemic involvement, and investigative findings (laboratory, electrophysiological, and pathological). A total of 38 articles, encompassing 42 cases of neuromuscular manifestations in patients with IgG4-RD, were included. Peripheral nerve involvement was frequently reported (25/42, 60%). The most common clinical presentations were mononeuritis multiplex (48%) and polyneuropathy (20%). Electrodiagnostic studies revealed an axonal pattern in 88% of cases, while nerve biopsies were compatible with vessel and nerve infiltration by IgG4-positive cells in 46% (6/13) of cases. Involvement of the neuromuscular junction was infrequently reported (n = 4), presenting as Lambert-Eaton syndrome (25%) or myasthenia gravis (75%), with all cases being negative for anti-acetylcholine receptor antibodies. Muscle involvement (n = 13) manifested as focal myositis in 53% and a limb-girdle muscle weakness pattern in 47%. Creatine kinase levels were elevated in 53%, and muscle biopsy demonstrated IgG4-positive cell infiltration in all focal myositis cases. Our review suggests that typical neuromuscular manifestations in patients with IgG4-RD include mononeuritis multiplex, polyneuropathy, and focal myopathy. However, comorbid conditions should also be considered as potential contributors to neuromuscular manifestations.

Patients with idiopathic inflammatory myopathies (IIM) are at increased risk for infections. Identifying clinical and immunological biomarkers predictive of infection is essential. We included 169 patients from the MYOTReCSZ cohort, all with ≥ 6 months of follow-up. Clinical data and laboratory parameters were collected, including: (1) low-density granulocytes and monocyte subsets, (2) serum cytokines, and (3) neutrophil extracellular trap (NET) quantification. The primary outcome was infection development. Most patients were female (72.78%), with a median age of 42. At least one infection occurred in 46.7% of patients; 55.6% were severe and 32.9% had recurrent infections. Independent predictors of infection included number of immunosuppressants (OR 1.7, P = 0.023), gastrointestinal activity score, cardiovascular damage-VAS, anti-Jo1 positivity (OR 10.0, P = 0.05), heliotrope rash, alopecia, and mycophenolate mofetil use (OR 11.9, P = 0.026). Severe infections were associated with number of immunosuppressants, low albumin, constitutional activity score, gastrointestinal damage-VAS, and TLR4⁺ intermediate monocytes (OR 1.0, P = 0.038). Recurrent infections correlated with lower TLR2⁺ classical monocytes (OR 0.4, P = 0.045), cumulative prednisone dose, global damage-VAS (OR 2.0, P = 0.0004), and anti-PM/Scl75 positivity (OR 3.8, P = 0.006). In conclusion, IIM patients with higher baseline activity and damage scores, specific autoantibodies, and altered innate immune cell phenotypes are more likely to develop infections. These parameters may serve as early biomarkers to stratify infection risk in clinical practice.