课程文献中心 更多>>

摘要： Objective We have previously shown that HLA-B27 was negatively associated with remission status eight years after the onset of juvenile idiopathic arthritis (JIA). We now aimed to study the associations of HLA-B27 with clinical features and disease outcomes 18 years after the onset of JIA. Methods We studied 434 patients from the population-based Nordic JIA cohort. Demographic and clinical data, including remission status, were collected consecutively at baseline, eight years after disease onset, and 18 years after disease onset and presented in relation to HLA-B27 status. Results The HLA-B27 status was available for 416 of the 434 participants (96%) and was positive for 93 participants (22.4%), more often in men (P = 0.01). The sacroiliac, hips, and subtalar joints were more frequently involved in individuals who were HLA-B27 positive than in individuals who were HLA-B27 negative. In almost half of the individuals with HLA-B27 positivity and uveitis, the uveitis was asymptomatic. Uveitis, inflammatory back pain, sacroiliitis, arthritis in hip, tarsal, and subtalar joints, and enthesitis during the disease course were all associated with a lower rate of remission off medication. HLA-B27 positivity was significantly associated with a higher risk of not being in remission off medication after 18 years (odds ratio [OR] 2.6), especially in men (OR 5.6). Conclusion Clinical features related to spondylarthropathies were more common in patients who were HLA-B27 positive and associated with worse outcomes and nonremission 18 years after disease onset, particularly in men. Our results underline the adverse impact of having HLA-B27 positivity on long-term outcomes in individuals with JIA.

关键词： Interleukin-2   Cytokine   Protein engineering  

摘要： The pleotropic nature of interleukin-2 (IL2) has allowed it to be used as both a pro-inflammatory and antiinflammatory therapeutic agent, through promotion of regulatory T cell (Treg) responses via the trimeric IL2RABG receptor or promotion of CD8 T cell responses via the dimeric IL2RBG receptor, respectively. However, the utility of IL2 as a treatment is limited by this same pleiotropy, and protein engineering to bias specificity towards either Treg or CD8 T cell lineage often requires a trade-off in protein production or total bioactivity. Here we use SolubiS and dTANGO, computational algorithm-based methods, to predict mutations within the IL2 structure to improve protein production yield in muteins with altered cellular selectivity, to generate combined muteins with elevated therapeutic potential. The design and testing process identified the V106R (murine) / V91R (human) mutation as a Treg-enhancing mutein, creating a cation repulsion to inhibit primary binding to IL2RB, with a post-IL2RA confirmational shift enabling secondary IL2RB binding, and hence allowing the trimeric receptor complex to form. In human IL2, additional N90R T131R aggregation-protecting mutations could improve protein yield of the V91R mutation. The approach also generated novel CD8 T cell-promoting mutations. Y59K created a cation-cation repulsion with IL2RA, while Q30W enhanced CD8 T cell activity through potential it-stacking enhancing binding to IL2RB, with the combination highly stimulatory for CD8 T cells. For human IL2, Y45K (homolog to murine Y59K) coupled with E62K prevented IL2RA binding, however it required the aggregation-protecting mutations of N90R T131R to rescue production. These muteins, designed with both cellular specificity and protein production features, have potential as both biological tools and therapeutics.

关键词： Nonalcoholic steatohepatitis   Exosomes   Macrophage   TNF antisense oligodeoxynucleotide   2-Deoxy-D-glucose   Sod1  

摘要： Inflammatory mediators tumor necrosis factor (TNF) and interleukin 1 beta (IL1(3), primarily derived from hepatic macrophages in the liver, play a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Meanwhile, intravenously injected exosomes are mainly distributed in the liver and predominantly taken up by hepatic macrophage. Herein, we aimed to evaluate the feasibility of targeted inhibition of TNF and IL1(3 expression in hepatic macrophages via exosomes as a potential therapeutic strategy for NASH. In this study, we demonstrated that antisense oligodeoxynucleotide targeting TNF (ASO-TNF) or 2-deoxy-D-glucose (2DG) effectively suppressed the expression of TNF and/or IL1(3 in macrophages. Exosomes loaded with ASO-TNF or 2DG were able to suppress the expression of TNF and/or IL1(3 in macrophages in vitro or in vivo. Furthermore, infusion of Exo/ASO-TNF or Exo/2DG significantly attenuated experimental steatohepatitis in choline deficient amino acid-defined (CDAA) or methionine and choline deficient (MCD) diet-fed mice. RNA-seq results showed that treatment with Exo/ASO-TNF or Exo/2DG significantly inhibited pro-inflammatory signaling pathways. Mechanistically, we observed that administration of Exo/ASO-TNF or Exo/2DG could attenuate NASH progression by up-regulating the expression of superoxide dismutase 1 (Sod1). Combined, our findings demonstrated that infusion of exosomes loaded with ASO-TNF or 2DG alleviated experimental steatohepatitis in murine models. Thus, infusion of exosomes loaded with anti-inflammatory agents holds promise as a potential therapeutic strategy for NASH treatment.

关键词： Donor specific antibodies   Effector function   Kidney transplant   Phagocytosis   NK cells  

摘要： Donor Specific Antibodies (DSAs) are associated with a higher risk of Antibody Mediated Rejection (AMR). However, not all DSAs are pathogenic, and patients that raise DSAs have a wide spectrum of outcomes ranging from the complete absence of graft injury to severe AMR. Hence, characterization of both the qualitative features and titer of DSAs has the potential to predict AMR risk and treatment outcome for sensitized patients. Here, using HLA-A2+ cell-based assays, we investigate the qualitative features of immunoglobulin G (IgG) alloantibodies including Fc receptor binding properties and Fc-mediated effector function over time. Compared to seronegative controls, reactive antibodies in seropositive participants were predominantly IgG1, and exhibited elevated levels of binding to the receptors involved in Antibody Dependent Cellular Phagocytosis (ADCP) and Antibody Dependent Cellular Cytotoxicity (ADCC) activity. Further analysis of seropositive individuals revealed that these activities were predictive of AMR status. Collectively, these results suggest a role for phagocytic and cytotoxic antibody effector functions of DSA in contributing to graft injury.

关键词： HLA-DQB1*05:03:38   next generation sequencing   novel allele  

摘要： The novel HLA-DQB1*05:03:38 allele was first described in a Chinese individual.

关键词： Breathing training   Mycoplasma pneumonia   Serum inflammatory factors   Characteristics and symptoms   Respiratory function test  

摘要： Objective This study aims to investigate the effects of video scenario-based breathing training on interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in children with Mycoplasma pneumonia. Methods A total of 106 children with Mycoplasma pneumonia treated in our hospital from February 2022 to April 2024 were selected. According to different nursing methods, children receiving routine intervention were assigned to the control group, while those undergoing video scenario-based breathing training were assigned to the training group. The serum inflammatory indexes, improvement time of clinical symptoms and lung function recovery were compared between the two groups before training, and at 1 and 2 weeks after training. Results Before training, there was no statistically significant difference in serum inflammatory and lung function indexes between the two groups (p > 0.05). After 1 and 2 weeks of training, the forced expiratory volume in 1 s (FEV1), peak expiratory flow rate (PEF), and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in both groups increased, with higher values in the training group than in the control group, and the difference was statistically significant (p < 0.05). The time for cough disappearance, wheezing disappearance, lung rales disappearance and high fever abatement in the training group was lower than that in the control group, with statistically significant differences (p < 0.05). The levels of IL-4, IL-6, IL-10, TNF-alpha, and IFN-gamma decreased in both groups, with lower levels in the training group than in the control group, and the difference was statistically significant (p < 0.05). Conclusion Video scenario-based breathing training can improve lung function, alleviate clinical symptoms and signs, and reduce serum inflammatory levels of IL-4, IL-6, IL-10, TNF-alpha and IFN-gamma in children with Mycoplasma pneumonia.

关键词： Osteoarthritis   Parecoxib   Ilomastat   IL-17   PI3K   NF-kappa B  

摘要： Background: Osteoarthritis is a degenerative disease, and current drug treatment is to give nonsteroidal antiinflammatory drugs to relieve symptoms. The anti-inflammatory ability of parecoxib and ilomastat has been confirmed, but the synergistic effect of combined administration in osteoarthritis has not been clear. Methods: Mouse primary chondrocytes stimulated with IL-1 beta were cultured. The expression levels of inflammatory cytokines and matrix metalloproteinases were investigated by western blotting, quantitative real-time polymerase chain reaction and ELISA. The effects of parecoxib and ilomastat on chondrocyte apoptosis were evaluated by flow cytometry. In addition, the rat model of osteoarthritis was established by meniscal instability, and the morphological changes of cartilage and the expression levels of related molecules were monitored using Safranin O-Fast green and immunohistochemical staining after intra-articular injection of parecoxib, ilomastat, and the combination of the two. Results: In vitro experiments showed that the combined administration of parecoxib and ilomastat more effectively inhibited the expression of proinflammatory factors and matrix metalloproteinases compared with single drug administration. The combined drug treatment could more effectively inhibit IL-1 beta-induced chondrocyte apoptosis. The combined drug treatment alleviated the progression of osteoarthritis by inhibiting the IL-17/ PI3K/AKT/NF-kappa B pathway. In addition, in vivo experiments showed that the combined administration could improve the further deterioration of the osteoarthritis rat model. Conclusions: The combined administration of parecoxib and ilomastat to inhibit IL-17/PI3K/AKT/NF-kappa B transduction is beneficial to reduce the infiltration of inflammatory factors and matrix metalloproteinases in osteoarthritis.

关键词： Macrophage   Immune regulation   IL-10   Epigenetics   Ubiquitination   Airway allergy  

摘要： The pathogenesis of many immune disorders is linked to regulatory macrophage dysfunction. The mechanism underlying it is unclear. The objective of this study is to examine the mechanism by which the PRKN ubiquitin protein ligase (PRKN) inhibits the development of regulatory macrophages (Mreg). In this study, dust mite antigens were used as the specific allergens to establish an airway allergy (AA) mouse model. Flow cytometry cell sorting was used to isolate macrophages from the airway tissues. According to the results, the Prkn gene inhibition led to an increase in the number of Mregs in macrophages. Mregs demonstrated the capacity to suppress Th2 polarization, in which IL-10 played a critical role. Pan macrophages isolated from Prkn-deficient mice were more capable of suppressing the activities of other immune cells. PRKN was required for maintaining the hyperubiquitous status of signal transducer and transcriptional activator-3 (STAT3) in macrophages. Exposure to dust mite antigen increased the expression of PRKN in macrophages. IL-10 suppressed PRKN in macrophages by inducing its promoter hypermethylation. PRKN inhibition mitigated the experimental AA. To sum up, PRKN maintains the hyper ubiquitous status of STAT3 and restricts the expression of IL-10 in macrophages, which compromises their immune suppressive functions. Inhibition of PRKN increases Mreg development and mitigates AA. The data suggest that the regulation of Mreg has translation potential to be used in the treatment of immune disorders such as AA.

关键词： humanized mouse   liver cancer   precision medicine   tumor immune microenvironment   HCC mouse models  

摘要： Background & Aims: Response to immunotherapy in hepatocellular carcinoma (HCC) is suboptimal with no biomarkers to guide patient selection. "Humanized" mice represent promising models to address this deficiency but are limited by variable chimerism and underdeveloped myeloid compartments. We hypothesized that expression of human GM-CSF and IL-3 increases tumor immune cell infiltration, especially myeloid-derived cells, in humanized HCC patient-derived xenografts. Material and Methods: NOG (NOD/Shi-scid/IL-2Rcnull) and NOG-EXL (huGM-CSF/huIL-3 NOG) mice conditioned with busulfan underwent i.v. injection of human CD34+ cells. HCC patient-derived xenograft tumors were then implanted subcutaneously or orthotopically. Following serial blood sampling, mice were euthanized at defined tumor sizes. Tumor, blood, liver, and spleen were analyzed by flow cytometry and immunohistochemistry. Results: Humanized NOG-EXL mice demonstrated earlier and higher levels of human chimerism compared to humanized NOG mice (82.1% vs. 43.8%, p <0.0001) with a greater proportion of human monocytes (3.2% vs. 1.1%, p = 0.001) and neutrophils (0.8% vs. 0.3%, p = 0.02) in circulation. HCC tumors in humanized NOG-EXL mice exhibited greater human immune cell infiltration (57.6% vs. 30.2%, p = 0.04) with higher proportions of regulatory T cells (14.6% vs. 6.8%, p = 0.04), CD4+ PD-1 expression (84.7% vs. 32.0%, p <0.01), macrophages (1.2% vs. 0.6%, p = 0.02), and neutrophils (0.5% vs. 0.1%, p <0.0001). No differences were observed in tumor engraftment or growth latency in subcutaneous tumors, but orthotopic tumors required implantation at 2 rather than 4 weeks post-humanization for successful engraftment. Finally, utilizing adult bone marrow instead of fetal livers enabled partial HLA-matching to HCC tumors but required more CD34+ cells. Conclusions: Human GM-CSF and IL-3 expression in humanized mice resulted in features more closely approximating the immune microenvironment of human disease, providing