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关键词： RAG deficiency   anti-IFN-a autoantibodies   viral infection  

摘要： Background: Autoantibodies against IFN-alpha (anti-IFN-alpha) have been reported in recombinase activating gene (RAG) deficiency, attributed to impaired central and peripheral T-cell/B-cell tolerance. However, the clinical features, especially viral infections, associated with these autoantibodies at baseline, their kinetics over time, and their response to hematopoietic cell transplantation are not well defined. Objective: We described the clinical and immunologic findings linked to anti-IFN-alpha IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation. Methods: We measured anti-IFN-alpha IgG by enzyme-linked immunosorbent assay in 80 RAG-deficient patients with curated clinical and immunologic data from a multinational collaboration. Results: Forty-eight patients (60.0%) had positive anti-IFN-alpha at baseline;these patients were typically older at time of testing, fulfilled the phenotype of delayed-onset combined immunodeficiency with granuloma and/or autoimmunity (70.8% vs 31.3%, P = .001), and had a history of more frequent viral infections, mainly from the Herpesviridae family (62.5% vs 21.9%, P < .001). These patients also showed higher levels of serum immunoglobulins and expanded populations of peripheral blood autoreactive-prone (CD19(hi)CD21(lo)) (14.3 vs 5.2%, P = .016) and double-negative (IgD(-)CD27(-)) B cells (12.8 vs 5.8%, P = .001). In cases with longitudinal evaluation, anti-IFN-alpha titers were largely stable, although an increase was observed with concurrent active cytomegalovirus infections. Despite some decline after transplantation, these autoantibodies persisted during follow-up. Conclusions: Anti-IFN-alpha autoantibodies reflect immune dysregulation in partial RAG deficiency. Their production is likely aggravated by environmental factors, especially frequent viral infections. Further studies are needed to define their pathogenic role in RAG deficiency.

关键词： IL-23 receptor   leukopenia   Mulberroside C   neutrophil   RASGRP1  

摘要： Chemotherapy- and radiotherapy-induced leukopenia is a common challenge in cancer treatment, with a significant dearth of effective therapeutic options. IL-23 receptor (IL-23R) signaling holds the potential for promoting neutrophil generation and maturation, yet the underlying mechanisms remain elusive. This study investigates the molecular mechanism and efficacy of Mulberroside C (MC) in alleviating leukopenia via IL-23R signaling. In vitro, flow cytometry, nitroblue tetrazolium reduction assay, and Giemsa staining were employed to evaluate MC's impact on neutrophil differentiation in NB4 and HL-60 cell lines. The antibacterial activity of MC was assessed using an agar plate assay. In vivo, leukopenia models induced by irradiation and cyclophosphamide were established in zebrafish and mice to determine MC's effect on neutrophil recovery. Mechanistic studies involved RNA sequencing, network pharmacology analysis, molecular docking, quantitative real-time PCR (qRT-PCR), and Western blotting to explore the associated signaling pathways. Cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to identify MC's targets. MC significantly enhanced neutrophil maturation in a dose-dependent manner, facilitating leukopenia recovery. Mechanistically, MC binds to IL-23R, upregulating G-CSF, GM-CSF, and RASGRP1 and activating the RAS/ERK signaling pathway. Notably, the upregulation of RASGRP1 by MC supports the generation of fully functional neutrophils, compared to those induced by G-CSF and GM-CSF alone. This study provides the first evidence that MC promotes neutrophil generation and antimicrobial activity through the IL-23R-mediated pathway, offering a promising therapeutic strategy for leukopenia.

关键词： THRIL   TNF-alpha   FTO   HuR   NSCLC  

摘要： Tumor necrosis factor-alpha (TNF-alpha) is a crucial cytokine involved in cancer progression, affecting the proliferation and survival of tumor cells. However, the exact mechanisms underlying its action remain poorly understood. Here we found that high concentration of TNF-alpha decreased TNF-alpha and heterogenous nuclear ribonucleoprotein L related immunoregulatory LncRNA (THRIL) expression, thereby inhibiting non-small cell lung cancer (NSCLC) cells proliferation while facilitating apoptosis. Clinically, the expression of THRIL was upregulated in NSCLC cells and tissues. THRIL knockdown resulted in decreased proliferation and increased apoptosis in NSCLC cells. Mechanistically, TNF-alpha diminished the m6A methylation of the THRIL transcript by enhancing the expression of FTO in A549 cells, which was subsequently recognized and degraded by YTHDF2. Furthermore, we identified that THRIL specifically interacted with HuR, forming a functional THRIL-HuR complex that enhanced TNF-alpha mRNA stability, thereby influencing endogenous TNF-alpha expression. Collectively, our findings reveal a novel regulatory feedback loop between TNF-alpha and THRIL, demonstrating that TNF-alpha inhibits the proliferation of NSCLC cells via the FTO/YTHDF2/THRIL axis. This highlights THRIL as a potential biomarker and therapeutic target in NSCLC.

关键词： Anthemis   Sesquiterpene lactone   IL6   TNF   Carbonic anhydrase   Network pharmacology  

摘要： The present study investigated the phytochemical composition and biological activities of extracts from the aerial parts of Anthemis austriaca, A. cretica subsp. albida, A. pauciloba, A. tinctoria and A. wiedemanniana. About 150 compounds belonging to hydroxybenzoic acids, hydroxycinnamic acids, phenylethanoid glycosides, acylquinic acids, acylhexaric acids, flavonoids and sesquiterpene lactones were identified. A. tinctoria also displayed significant antiradical activity, obtained from its MeOH and 70 % MeOH extracts. EtOAc and MeOH extracts of A. pauciloba revealed the highest anti-acetylcholinesterase activity (3.51 and 3.50 mg GALAE/g;p > 0.05). Extracts had a higher affinity towards human carbonic anhydrase isoenzymes I (CAI) than CAII, and the best inhibition effect was exerted by EtOAc extract of A. wiedemanniana a (IC50 7.02 mu g/mL). Network pharmacology analysis identified IL6 and TNFa as key targets of these plant-derived molecules, underscoring their multi-target potential. Anthemis extracts' efficacy in blunting LPS-induced IL6 and TNF alpha gene expression in isolated mouse colon has confirmed these predictions. Molecular docking studies further confirmed that these compounds interact with multiple transcription factors (TFs), suggesting broad pharmacological activity. These results indicated that the five Anthemis species could be a promising source of bioactive molecules.

关键词： Inflammation   3D cultures   Study models   Disease models   Intervertebral disc  

摘要： Chronic inflammation plays a key role in intervertebral disc (IVD) herniation contributing to extracellular matrix (ECM) disorganization, annulus fibrosus (AF) tissue fibrosis, and consequent failure. Despite its importance, the impact of chronic inflammatory environment has been poorly explored in 3Dmodels. This study establishes a relevant 3D human-derived model to investigate the progression of inflammation in human AF cells. For that, cells from herniated IVD of patients with low back pain were cultured in 3D collagen type I hydrogels under basal and inflammatory (IL-1n) conditions for 7 days, in a transient (2 days) or continuous (7 days) periods. In parallel, 2D cultures were conducted in the same conditions. The 3D model recapitulated key pathological features of AF degeneration/failure, as actin filament alterations and reduced collagen type I deposition under continuous inflammation, which led to increased fibronectin production. Continuous inflammation also increased proinflammatory mediators in 3D cultures and enhanced immune cell infiltration in vivo. These findings validate collagen type I hydrogels with continuous inflammation, as a valuable model for replicating in vitro the AF pathomechanisms, offering insights into potential biomarkers and therapeutic targets for IVD herniation prognosis. Statement of significance: This study evaluates the effects of continuous versus transient inflammation in a 3D model of annulus fibrosus (AF) cells, providing insights on how sustained inflammatory conditions impact tissue components and inflammatory response in intervertebral disc (IVD) herniation. While previous research has focused on transient inflammation, this work uses a collagen-based 3D model to replicate prolonged inflammatory states, evaluating extracellular matrix alterations, inflammatory mediators' production and immune response. This work is of broad scientific interest, presenting a valuable approach for studying AF tissue pathology and inflammatio

关键词： Primary central nervous system lymphoma   TNF-alpha   IFN-gamma   NF-kappa B   PD-L1  

摘要： AIDS-related primary central nervous system lymphoma (AR-PCNSL) differs from immunocompetent PCNSL (ICPCNSL) due to its immune function and higher mortality rates, emphasizing the urgent need for new treatment targets. This study aimed to investigate the role of the NF-kappa B p65/PD-L1 signaling pathway in AR-PCNSL. A total of 56 PCNSL tissue samples, including 32 AR-PCNSL cases and 24 IC-PCNSL cases, were analyzed for clinicopathological and imaging features. Histopathological examination was conducted using hematoxylin and eosin (HE) staining, PD-L1 immunohistochemistry and Epstein-Barr encoding region (EBER) in situ hybridization. Differentially expressed molecules (DEMs) were identified via bulk RNA-Seq analysis, while functional pathways were explored through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. MYD88 L265P and CD79B mutations were detected using sanger sequencing. Additionally, RT-PCR was used to measure the mRNA expression levels of TNF-alpha and IFN-gamma in frozen tissues, while western blotting assessed the protein expression levels of p-NF-kappa B p65, NF-kappa B p65, and PD-L1 in cell lines. Compared with IC-PCNSL tissues, AR-PCNSL tissues demonstrated significantly more necrosis (p = 0.001). Imaging analysis showed that AR-PCNSLs had lower ADC (Apparent Diffusion Coefficient, ADC) values (p = 0.000) and more frequent annular enhancement signals (p = 0.007) on DWI (diffusion weighted imaging, DWI). The PD-L1 and EBER positivity rates were higher in ARPCNSL patients. Co-occurring mutations in MYD88 L265P and CD79B were rare in AR-PCNSL, and were found in only 6.7 % (1/15) of samples, while these mutations appeared in 60.0 % (9/15) of the IC-PCNSL patients (p = 0.005). The RNA levels of TNF-alpha and IFN-gamma were significantly higher in AR-PCNSL patients than in IC-PCNSL patients (p = 0.001). Western blot analysis after TNF-alpha and IFN-gamma treatment revealed increased expression of pP65 protein and PD-L1. This study provides new

关键词： inflammation   lipid mediators   regulatory B cells   RvD5  

摘要： It is well known that regulatory B cells (Breg), especially IL-10-producing regulatory cells (B10), play an important role in immune regulation during inflammatory and infectious diseases. Although it has been revealed that the immune regulatory function of B10 can be exerted through cognate cell-cell contact with T cells, more research is needed to delineate its impact on other key cellular immune components within the immune microenvironment. In this study, we evaluated the effect of B10 on the phenotypic change of macrophages and their pro-resolving functional activities using various co-culture systems. The roles of cell-cell contact and the IL-10 secretion by B10 on macrophage differentiation and function were determined. Splenocyte-derived B10 cells from wild-type or IL-10 knockout (KO) mice were co-cultured with RAW 264.7 cells in the presence or absence of trans-well inserts. Macrophage polarization, programmed cell death 1 (PD-1) expression, production of specialized pro-resolving mediators (SPMs), and phagocytic activity were evaluated. The results showed that direct B10-macrophage co-culture enhanced the macrophage polarization towards a pro-resolving phenotype and their PD-1 expression, which was diminished when the cultured B10 and macrophages were separated by trans-well inserts, or when B cells from IL-10 KO mice were used for the co-culture. In addition, B10 was found to promote the release of specific SPM [resolvin D series 5 (RvD5)] and phagocytic activity by macrophages after co-culture. These effects were compromised in trans-well co-culture or co-cultures with IL-10-deficient B cells. Our results suggest that B10 promotes pro-resolving macrophage differentiation and function through direct cell-cell contact and IL-10 secretion.

关键词： Multiple sclerosis   Neuroinflammation   Cytokines   Autoantibodies   TWEAK  

摘要： Multiple sclerosis (MS) is a complex, chronic inflammatory disease of the central nervous system, where immune dysregulation plays a critical role. We sought to explore the modulation of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF alpha) and TNF-like weak inducer of apoptosis (TWEAK), along with their respective autoantibodies, TNAb and TWAb, and to decipher potential associations between these and clinical characteristics which could assist personalized therapy in MS. We also assessed the complementarity to leading candidate biomarkers in MS patient monitoring, namely, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL). Serum levels of these cytokines and their autoantibodies were measured in 150 MS patients and 186 healthy controls (HC) by ELISA. We found that sTWEAK levels were significantly higher, while sTNF alpha levels were lower in MS patients compared to HC. Additionally, we detected TWAb in 10% of MS patients, a prevalence significantly higher than in HC (4%) and TNAb in only one patient. TWAb-positive patients were significantly younger, had lower EDSS scores, a shorter disease duration, and predominantly presented with the relapsing-remitting form of MS. Together, these results provide new actors to be considered in the development of a biomarker profiling panel to be used in MS patient management. Further research is warranted to elucidate the clinical significance of these autoantibodies and their role in MS neuroinflammatory modulation.

关键词： Chemical activation  

摘要： CEP290 gene mutations are linked to Joubert syndrome-related disorders (JSRD) which present with various symptoms, including brain malformation, retinal degeneration, and kidney disorders. It remains unclear how patients with JSRD having CEP290 gene mutations lead to kidney disorders, particularly polycystic kidney disease including nephronophthisis (NPH). To address this question, Xenopus CEP290 (xCEP290) was depleted using morpholino oligonucleotides against xCEP290 in Xenopus embryos. xCEP290 morphants exhibited edema and dilated pronephric tubule, indicative of renal dysfunction. Next, RNA-seq analysis was performed to explore which signals and molecules are important for the formation of dilated pronephric tubule observed in the xCEP290 morphant kidney. The hallmark gene set associated with the IL-6/JAK/STAT3 signaling pathway was upregulated in xCEP290 morphant kidney, and inhibition of this signaling by JAK inhibitor ruxolitinib suppressed the dilated pronephric tubule in xCEP290 morphants. Furthermore, the expression level of transcription factor Xenopus FOSL1 (xFOSL1), whose gene expression is regulated by IL-6 signaling, was upregulated in xCEP290 morphant kidney, and overexpression of xFOSL1 induced pronephric tubular dilation. These results together revealed that abnormal activation of IL-6/JAK/STAT3/FOSL1 signal axis is responsible for dilated pronephric tubule resembling cystic lesions observed in polycystic kidney disease of JSRD patients with CEP290 gene mutations. © 2025 The Authors

关键词： maternal microchimerism   umbilical cord blood   monoclonal HLA antibodies   spectral flow cytometry sorting   T cells  

摘要： OBJECTIVE: Maternal microchimerism is the transmission of small quantities of maternal cells to the fetus. It has been found that maternal microchimeric cells can home to fetal lymph nodes where they exert influence on the fetal immune system. Thi...