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关键词： Acute psychiatric disorder   Pediatrics   T-helper 17   Streptococcus   Interleukin   Cerebral spinal fluid  

摘要： Background: Acute neuropsychiatric disorders are heterogeneous conditions resulting from interaction between genetic and environmental features. Among these, post infectious forms like Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) are common. Preclinical studies suggest a role of CNS T-helper-17/interleukin-17 (IL-17) inflammatory mediated response in the pathogenesis of these disorders. We analyze serum and cerebral-spinal fluid (CSF)-IL-17 concentrations in a cohort of patients with acute neuropsychiatric disease. Methods: We retrospectively included patients <14 years with acute neuropsychiatric symptoms from 2016 to 2020. IL-17 was determined on serum and CSF by means of quantitative sandwich enzyme immunoassay technique, and values were compared to serum and CSF controls. Variables were identified using univariate analysis with Pearson's regression test and X-2 test. Results: 58 subjects were included (67.8 % males, average age: 8.5 years). 50.8 % were classified as PANDAS, 11.8 % as PANS. Mean concentrations of serum IL-17 were higher in the study group compared to controls (p < 0.0001). We observe a trend of increasing IL-17 in post-pubertal children both on serum (p = 0.05) and on CSF (p = 0.04). Coupled IL-17 concentration were higher in the CSF than in serum (p = 0.003), with a marked significance in the PANDAS and PANS group (p < 0.001). Conclusion: IL-17 is elevated in children and adolescents with acute neuropsychiatric conditions, both on serum and CSF. IL-17 could be involved in the pathogenesis of acute neuropsychiatric disorders in childhood. Further studies are necessary to validate its potential role as a diagnostic or prognostic biomarker.

关键词： Available online xxx   Adventitial injection   Hydrogel   IL-33   Local drug administration   Neointimal hyperplasia   Vascular injury   Wire injury  

摘要： Introduction: Neointimal hyperplasia is one of the persistent complications after vascular interventions, and is the major cause of treatment failure. Interleukin-33 (IL-33) emerges as a crucial factor in many biological processes and plays an important role in vascular diseases. Adventitial injection is catching attention for its effectiveness and fewer side effects. We hypothesize that targeting IL-33 by adventitial injection can be a therapeutic method to inhibit neointimal hyperplasia. Method: IL-33 expression was examined in human vein graft. The hydrogel was fabricated by the interaction of hyaluronic acid, sodium alginate, and CaCO3;and phosphate buffered saline (PBS) or IL-33 antibody or recombinant IL-33 was mixed within the hydrogel uniformly. A rat aortic wire injury-induced neointimal hyperplasia model was developed;rats were divided into three groups and received an adventitial injection of a hydrogel loaded with PBS or IL-33 antibody or recombinant IL-33 after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with PBS, IL-33 antibody, or IL-33 was also used in a mouse carotid artery ligation neointimal hyperplasia model. Result: There was a high expression of IL-33 in human vein graft neointima. Hydrogel can be successfully injected into the aortic wall and is encapsulated by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection and was partly degraded at day 21. There was a significantly thinner neointimal thickness and less proliferation and inflammation in the IL-33 antibody group compared to the control group. On the contrary, the IL-33 group has a thicker neointima, increased proliferation, and inflammation. The mouse carotid artery ligation model showed similar results. Conclusions: IL-33 plays a role in arterial neointimal hyperplasia in both human and rodent models;adventitial injection of hydrogel loaded with IL-33 antibody can effec

关键词： Apical periodontitis   Genetic polymorphisms   Immune-inflammatory response   Bone metabolism   Genetics  

摘要： Objectives: To investigate the association between genetic polymorphisms in suppressor of cytokine signaling-1 ( SOCS-1 ) , tumor necrosis factor-alpha ( TNF-alpha ) and its receptors 1 and 2 ( TNFRSF1A and TNFRSF1B), receptor activator of nuclear factor kappa-b (RANK), receptor activator of nuclear factor-kappa B ligand ( RANKL ) and osteoprotegerin (OPG), and persistent apical periodontitis (PAP). Methods: Patients with pulp necrosis and apical periodontitis at the time of non-surgical root canal treatment were followed up for at least one year. A total of 423 subjects were included, 172 with signs/symptoms of PAP and 251 with apical periodontitis healed. DNA was extracted from saliva and used for genotyping polymorphisms in SOCS1 (rs243327 and rs33977706), TNF-alpha (rs1800629), TNFRSF1A (rs1800693), TNFRSF1B (rs1061622), RANK (rs1805034), RANKL (rs1054016) and OPG (rs1032128) by real-time PCR. The frequency of genotypes and alleles was assessed using chi-squared test or Fisher's exact test and odds ratio. Interactions were also tested using multifactor dimensionality reduction (alpha = 5 %). Results: In the polymorphism rs1800629 in TNF-alpha, carrying at least one A risk allele significantly decreased the risk to develop PAP (OR=0.47;95 %CI: 0.28-0.79;p =0.004). For the polymorphism rs1054016 in RANKL carrying both T risk alleles significantly decreased the risk to develop PAP (OR=0.47;95 %CI: 0.24-0.92;p =0.027). None of the other polymorphisms evaluated were associated with PAP (p>0.05). A strong interaction was observed among rs1800629, rs1061622 and rs1054016. Conclusions: Genetic polymorphisms rs1800629 ( TNF-alpha) and rs1054016 ( RANKL) had a strong interaction and were associated with a lower risk to develop PAP.

关键词： Lung adenocarcinoma   Fructose 1   6-diphosphatase 1   Dendritic cells   IL33   Lactate   cGAS/STING  

摘要： Fructose 1,6-diphosphatase 1 (FBP1) is an enzyme involved in gluconeogenesis and glycolysis inhibition. Dendritic cells (DCs) are antigen-presenting cells, and antigens presented to T cells activate the immune response. FBP1 inhibits the development of several tumors, and high FBP1 expression inhibits the proliferation, migration, and invasion of lung cancer cells. However, the mechanism through which FBP1 mediates the tumor immune microenvironment is unclear. This study mainly analyzed the role of FBP1 in regulating the function of DCs through metabolic reprogramming and immune microenvironment using in vitro and in vivo experiments. The positive association of FBP1 with DCs was found by bioinformatic analysis. The in vitro experiments revealed that the extracellular acidification rate and lactate level were lower in the FBP1 overexpression cells than in the control cells and that the lower lactate level reduced the inhibition of DC function. In addition, high FBP1 expression promoted the secretion of IL33 by activating the cGAS/STING/NF-kappa B/IL33 pathway, which was identified and verified via high-throughput sequencing and in vitro experiments. FBP1 activated the cGAS/ STING pathway by increasing the degree of DNA damage, as revealed by the level of gamma H2AX and comet assay. IL33 enhanced the expression of the DC costimulatory molecules CD86 and HLA-DR as well as that of the functional factor IL-1 beta. The results demonstrated that FBP1 promoted the activation and maturation of DCs by inhibiting glycolysis and promoting the secretion of IL33 as well as by further activating the function of CD8+T cells. Finally, the humanized immune system mouse models confirmed the above role of FBP1. Thus, FBP1 may serve as a new target to cure lung adenocarcinoma, and IL33 may improve the efficiency of immune therapy in lung adenocarcinoma.

关键词： Interleukin-2   CD25   Soluble receptors   Glycosylation   Proteolysis  

摘要： The cytokine interleukin-2 (IL-2) is a critical regulator of immune responses, with an especially wellcharacterized role in regulating T-cell homeostasis. IL-2 signaling involves three distinct receptor subunits: the IL-2R alpha (CD25), IL-2R beta, and IL-2R gamma. The intracellular transduction of IL-2-induced signals is strictly dependent on IL-2R beta and IL-2R gamma, while the IL-2R alpha is not directly involved in signaling. Instead, it has the highest affinity towards IL-2 and is thus responsible for regulating the affinity of a cell for IL-2. In addition to the membrane-bound IL-2R alpha, a soluble form of the receptor (sIL-2R alpha) has been described, which is present in the blood of healthy individuals, increased under various pathological conditions, and able to bind IL-2 and thus modulate its function. The sIL-2R alpha is generated by proteolytic cleavage of the membrane-bound receptor. Here, we analyze whether glycosylation of the IL-2R alpha regulates its proteolysis. We find that constitutive IL-2R alpha shedding is affected by glycosylation and discover distinct roles for N- and O-glycosylation. Furthermore, we show that induced shedding by the metalloproteases ADAM10 and ADAM17 is also differentially regulated by distinct types of glycans. Finally, we identify a specific role for an N-glycan at an exosite in ADAM17-mediated proteolysis that does not affect ADAM10, indicating distinct substrate recognition mechanisms. These results further the understanding of the mechanisms leading to sIL-2R alpha generation, and thus offer the opportunity to specifically modulate the generation of the soluble receptor.

关键词： Streptococcus pyogenes   Strep a   Vaccine   IL-8 cleavage   SpyCEP   Functional assay  

摘要： Exposure to Group A Streptococcus leads to a broad spectrum of disease and sequelae, as the bacterium employs a wide range of virulence factors to facilitate colonization of the host, propagation and onward transmission, disrupting both innate and adaptive immune responses. The protease SpyCEP has a crucial role in contributing to bacterial immune evasion by impairing neutrophil recruitment and killing of bacteria through the cleavage of interleukin-8 (IL-8). Given this critical function, SpyCEP represents a key vaccine antigen and quantifying functional anti-SpyCEP antibodies represents not only an important marker of vaccine efficacy, but also a tool to dissect the natural immune response. Here, we report the development and characterization of an IL-8 cleavage inhibition assay to measure the function of anti-SpyCEP antibodies in human sera. The assay was demonstrated to be sensitive, highly specific, linear and reproducible, and suitable for evaluating the function of anti-SpyCEP antibodies induced in humans in vaccine clinical trials and in observational studies of natural immunity.

关键词： Ulcerative colitis   Modified Jiaoqi Powder   Intestinal barrier   Autophagy   Apoptosis   Tumor necrosis factor  

摘要： Background: A vicious cycle of dysregulated intestinal epithelial cell death, intestinal barrier defect, and subsequent inflammation response is core to chronic ulcerative colitis (UC). Modified Jiaoqi Powder (MJQP), a traditional Chinese medicine formula, has been clinically applied to treat chronic relapsing and chronic persistent types of UC. Nevertheless, the underlying mechanisms of MJQP in chronic UC remains unknown. Purpose: The present study aimed to demonstrate the favorable effects and potential molecular mechanisms of MJQP in chronic UC. Methods: The chemical components of MJQP and MJQP drug serum were identified by LC-MS/MS. The curative effects of MJQP were evaluated in a well-established DSS-induced chronic UC mice model by measuring body weight, colon length, disease activity index (DAI) and histological scores. Serum cytokines, including interleukin (IL)-1 beta, IL-12, IL-13, IL-4, tumor necrosis factor-alpha (TNF-alpha), and IFN-gamma were measured using enzyme-linked immunosorbent assay. Western blotting, immunofluorescence, and MTT assay were used to analyze the effects of MJQP on colonic barrier function in chronic UC mice and human epithelial cell lines. TUNEL assay, western blotting, and flow cytometry were used to examine the related apoptosis indicators. An electron microscope was used to observe autophagosomes and autolysosomes, while western blotting and immunofluorescence were used to detect autophagy-associated proteins. Network pharmacology was used to predict potential targets and pathways of MJQP in UC. Finally, the TNF pathway-related proteins were detected by immunohistochemistry and western blotting. Results: MJQP administration prevented the UC progression, as evidenced by faster weight gain, longer colon length, lower histological scores and DAI, and up-/down- regulation of inflammatory factors. The expression of tight junction proteins, ki67, and E-cadherin increased dose-dependently after MJQP intervention. Moreover, MJQP treatm

关键词： Cirrhosis   Bacterial infections   HLA evolutionary divergence   Cirrhosis decompensation   Liver transplantation  

摘要： Bacterial infections are common in cirrhosis patients, increasing the risk of decompensation and death. The impact of HLA evolutionary divergence (HED) on infection risk hasn't been studied in humans before. We conducted a retrospective study on cirrhosis patients awaiting liver transplantation (LT) from January 2019 to February 2022, examining class I and II-HED effects on bacterial infections and cirrhosis decompensation. We included 269 cirrhosis patients. Among them, 98 experienced 153 bacterial infections. Multivariable analysis after variable selection revealed that higher class II-HED was linked to fewer bacterial infections (p = 0.034), while class I-HED showed no effect (p = 0.074). Independent risk factors for bacterial infections included invasive procedures (p < 0.001), ICU hospitalization (p < 0.001), recent antibiotic treatment (p = 0.046), rifaximin use (p = 0.043), and cirrhosis decompensation (p = 0.002). Neither class I nor II-HED affected decompensation risk.
This pioneering study shows that high class II-HED levels may protect against bacterial infections in cirrhosis patients awaiting LT, suggesting an immunological mechanism at play.

摘要： *** patients with circulating donor-specific antibodies (DSAs) before transplantation are at risk for antibody-mediated rejection (AMR). Peritransplant desensitization mitigates but does not eliminate the alloimmune response. We examined the possibility that subthreshold AMR activity undetected by histology could be operating in some early *** of kidney allograft biopsies performed within the first month in presensitized patients (DSA+) who had received desensitization and did not develop active/probable AMR by histology (R-) was compared with biopsies showing active/probable AMR (R+/DSA+). As negative controls, biopsies without rejection by histology in patients without DSA at transplantation were used (R-/DSA-). RNA sequencing from biopsies selected from the biobank was used in cohort 1 (n = 32) and microarray, including the molecular microscope (Molecular Microscope Diagnostic System [MMDx]) algorithm, in recent cohort 2 (n = 30).*** transcriptome of R-/DSA+ was similar to R+/DSA+ as these groups differed in 14 transcripts only. Contrarily, large differences were found between both DSA+ groups and negative controls. Fast gene set enrichment analyses showed upregulation of the immune system in both DSA+ groups (gene ontology terms: adaptive immune response, humoral immune response, antigen receptor-mediated signaling, and B-cell receptor signaling or complement activation) when compared with negative controls. MMDx assessment in cohort 2 classified 50% of R-/DSA+ samples as AMR and found no differences in AMR molecular scores between R+ and R- DSA+ groups. In imlifidase desensitization, MMDx series showed a gradual increase in AMR scores over *** kidney transplant recipients exhibited frequent molecular calls of AMR in biopsy-based transcript diagnostics despite desensitization therapy and negative histology.