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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： 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...

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： cilia   Joubert syndrome related disorders   nephronophthisis   CEP290   IL-6   FOSL1  

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.

关键词： biofilm-infected diabetic ulcers   core-shell microneedle   macrophage polarization   spatiotemporal immunomodulatory  

摘要： Macrophage phenotypic dysregulation, spatially by biofilm and dynamically in time, impedes the healing of diabetic ulcers (DUs). Effective treatment requires enabling spatiotemporal regulation of macrophage polarization, balancing the M1 pro-inflammatory antimicrobial response with the M2 anti-inflammatory tissue-regeneration response. Here, a core-shell microneedle system (LM-MG@MN) is proposed with spatiotemporal immunomodulation features, designed to spatially disrupt biofilm barriers and sequentially induce macrophage polarization from M0 to M1 and subsequently to M2 by regulating the NLRP3/IL-1 beta pathway. Glucose oxidase (GOX)-loaded 2D MXene nanosheets (MG) are encapsulated in a hyaluronic acid-beta-cyclodextrin (HA-beta-CD) matrix as the MN shell layer. The rapid dissolution of this shell triggers MG to induce pro-inflammatory polarization of macrophages from M0 to M1, aiding in clearing biofilm infections. Liposomes (LM) carrying the NLRP3 inflammasome inhibitor MCC950 are embedded within a methacrylate hyaluronic acid (HAMA) matrix in the MN core. In the later stages of wound healing, LM is released gradually from the core, promoting the anti-inflammatory polarization of macrophages from M1 to M2 and accelerating tissue regeneration by enhancing crosstalk with fibroblasts and endothelial cells. Additionally, RNA sequencing indicates that LM-MG@MN regulates macrophage metabolic reprogramming to enhance DUs healing. This spatiotemporal immunomodulation strategy offers a promising approach for clinical DUs treatment.