Immunologic Research最新文献

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.

Arthritis is a common condition that causes articular cartilage damage, joint tissue destruction, and ligament involvement, representing one of the leading causes of disability worldwide. This study aimed to analyze long-term trends and characterize seasonal patterns in global online information-seeking behavior related to arthritis and its associated terms using Google Trends data. We retrieved monthly relative search volume (RSV) data for the search terms "arthritis", "ankylosing spondylitis (AS)", "gout", "juvenile idiopathic arthritis (JIA)", "osteoarthritis (OA)", "psoriatic arthritis (PsA)", "rheumatoid arthritis (RA)", and "systemic lupus erythematosus (SLE)" from Jan 2004 to Dec 2022. Long-term trends were visualized using time-series plots, and seasonal patterns were assessed using cosinor analysis. Analysis of global RSV from 2004 to 2022 revealed distinct and divergent long-term trends across arthritis-related terms. The general term "arthritis," along with "OA" and "RA," displayed an initial decline until around 2010-2011, followed by a sustained recovery and gradual increase. In contrast, "AS," "gout," and "PsA" exhibited consistent upward trends throughout the period, while "JIA" progressively declined and "SLE" remained stable. More importantly, cosinor analysis confirmed statistically significant seasonal patterns (all P < 0.05) for "arthritis", "JIA", "OA", "PsA", and "RA", with amplitudes ranging from 2.28 to 4.22. These rhythms were characterized by a reproducible peak in late winter to early spring (acrophase: Feb 5-Apr 5) and a trough in late summer to early autumn. Thematic analysis of rising queries highlighted public focus on disease classification, clinical manifestations, and treatment-related information. Global online interest in arthritis, as measured by RSV, demonstrated significant long-term and seasonal patterns. The changes in the public's interest in arthritis-related terms can reflect the public awareness and potential medical needs. Our findings underscore the importance of infodemiology in public health monitoring.

Whole glucan particles (WGP) enhance macrophage immune function, while serine protease inhibitor B9 (SerpinB9)-a molecule known to promote tumor immune escape-has an unclear role in WGP-induced macrophage function. In this study, we found that SerpinB9 knockout in WGP-induced bone marrow-derived macrophages (BMDMs) significantly downregulated surface MHC-II expression, reduced TNF-α secretion, and impaired their ability to induce Th1 cell differentiation. Transcriptome analysis revealed that CIITA, the core regulator of MHC-II transcription, was markedly downregulated in SerpinB9-knockout BMDMs. Further experiments confirmed that CIITA knockdown decreased BMDM surface MHC-II expression, whereas CIITA overexpression rescued MHC-II expression in SerpinB9-knockout BMDMs and restored their capacity to induce Th1 cell differentiation. In conclusion, this study demonstrates that under WGP induction, SerpinB9 regulates macrophage MHC-II expression and Th1 differentiation-inducing ability by maintaining CIITA expression, providing new insights into macrophage immune regulation mechanisms.

Recombination-activating gene (RAG) 1-2 deficiencies have a phenotype spectrum from severe combined to combined immunodeficiency (CID). We presented a comprehensive immunologic/genetic/radiologic/pathological, and virologic evaluation results of a patient with granuloma and reviewed the medical literature in 2022-2025 period for rubella virus (RuV)-associated granulomas in inborn errors of immunity (IEI). We evaluated a 17-year-old male patient with a necrotic, ulcerated, and exudative lesion extending over the right foot and leg at the edge of amputation. He had a history of recurrent pneumonia and bronchiectasis. Further evaluation revealed systemic granulomas (skin, spleen) in addition to the extremity lesions and low T- and B-, and naive CD4 + T cell numbers. In addition to a defined heterozygous RAG1 mutation(c.1421 G > A, R474H) detected with NGS PID-panel analysis, Sanger sequencing analysis confirmed patient`s CID diagnosis by revealing another heterozygous mutation(c.1181 G > A, R394Q). Histopathology demonstrated necrotizing granulomas with vasculitis and RT-PCR study from the splenic granulomas revealed RuV. The ulceration and exudative extremity lesions regressed with a scar within two months after the initiation of the anti-TNF therapy. In addition to CID therapy, hematopoietic stem cell transplantation was planned from his HLA-matched sibling donor. RuV-associated granuloma usually develop in the first 12 years and accompany gene defects related to Griscelli disease and familial hemophagocytic lymphohistiocytosis (HLH) in the medical literature. Early, comprehensive diagnostic workup for granuloma could further reveal the RuV's role in granulomatous inflammation in IEI, leading to targeted therapy to improve outcomes. Thorough genetic investigation in the presence of granuloma is crucial.

Early detection of latent tuberculosis (TB) is crucial for prevention. However, there is a debate over the effectiveness of QuantiFERON tests versus tuberculin skin tests. This meta-review critically evaluated QuantiFERON (QFT) tests for latent TB detection. This diagnostic meta-analysis reviewed studies from January 2015 to July 22, 2024, sourced from Medline/PubMed. Rigorous selection and data extraction ensured robust results. Diagnostic test results were organised into 2 × 2 tables, and statistical analysis was performed using Stata versions 14 and 16. Statistical significance was set at p < 0.05. Data from 35 studies with 23,383 participants were analysed. Males represented 46.7% of the sample. QFT tests were positive in 22.5% and negative in 77.5% of cases. The pooled sensitivity was 49% (range: 3% to 92%), indicating a risk of false negatives, and its pooled specificity was 86% (range: 31% to 98%), reflecting good performance in ruling out non-TB cases. Sensitivity was moderate in HIV (60%) and HCWs (55%), low in TB contacts (48%), children (43%), and RA (39%), and lowest in IBD (15%). Specificity was highest in IBD (94%), children (91%), HCWs (84%), RA (82%), TB contacts (80%), and moderate in HIV (74%). The positive predictive value (PPV) was 61% (range: 5% to 97%) and the negative predictive value (NPV) was 72% (range:13% to 98%). PPV was moderate in TB contacts (70%), RA (64%), HCWs (63%), HIV (51%), children (50%), and low in IBD (42%), and NPV was high in children (88%), HIV (84%), IBD (79%), HCWs (73%), RA (72%), and moderate in TB contacts (63%), with substantial heterogeneity across populations. Despite high specificity, the lower sensitivity suggests QFT tests may miss some latent TB infections. The diagnostic odds ratio was 5.73 (SE ± 1), indicating strong yet highly variable performance (I² = 96.2%). This highlighted the need to combine QFT tests with other diagnostics. QFT tests had high specificity and NPV, ensuring reliable negative results. However, lower sensitivity reduces PPV, making positive results less definitive. The results also revealed moderate sensitivity in HIV, lowest in IBD, highest specificity in IBD, lowest in HIV, highlighting heterogeneous performances.

The cellular immune response is not only affected by endogenous cytokines or mediators but also affected by exogenous chemical products from food. Human blood leukocytes express members of chemosensory taste receptors such as sweet and umami taste receptors (TAS1Rs) and bitter taste receptors (TAS2Rs). These ectopic taste receptors have been found to sense irritants or bacterial lipopolysaccharides and activate innate immunity. Saccharin, an artificial sweetener, can modulate the cellular immune response via the leukocytic taste receptors. The study aimed to investigate the in vitro effect of saccharin on the function of isolated polymorphonuclear neutrophils (PMNs) in the blood by stimulating sweet taste receptors. Chemotaxis and transmigration assays were measured along with transcriptional profiling of selected neutrophil inflammatory chemokines (CXCL1, CCL2 and CCL26) and chemokine receptors (IL8R and CCR4) following in vitro stimulation by saccharin through siRNA knockdown and RT-qPCR. Saccharin was found to activate chemotaxis in isolated human leukocytes and also to activate PMN migration in a concentration-dependent manner. It was found that siRNA against TAS1R2 or TAS1R3 suppressed PMN migration towards saccharin. On the other hand, no loss of migration occurred in PMN transfected with siRNA against TAS1R1 or in non-siRNA transfected PMNs. Incubation of PMNs with saccharin resulted in a significant upregulation of chemokine and chemokine receptor transcript levels. Our study indicates that saccharin can orchestrate innate immunity by stimulating their cognate taste receptors in the peripheral blood PMNs by signaling chemokines and their receptors.