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关键词： MHC   cattle   high‐throughput sequencing  

摘要： Due to factors such as lower biosecurity, greater wildlife/farm animal interfaces, and environmental challenges, cattle in sub-Saharan Africa are exposed to more diverse and intensive bacterial, viral and protozoan pathogen challenges than cattle in Europe and other high-income regions of the world. Classical class I genes of the major histocompatibility complex (MHC) contribute to protection from diseases caused by these pathogens by refining a huge pool of potential pathogen-derived peptide ligands into a smaller ensemble for presentation to CD8+ T cells. Knowledge of population-prevalent MHC alleles is therefore critical for evidence-based approaches to vaccine design and improved understanding of pathogen resistance. Whereas variation in MHC molecules is understood in most detail for European Bos taurus, the alleles expressed by Africa's cattle remain poorly defined. We have leveraged recent improvements in the accuracy of PacBio high-fidelity (HiFi) circular consensus sequencing (CCS) and adapted stringent sequence filtering algorithms to identify hundreds of as yet uncharacterised fully phased BoLA-I alleles from multiple populations of African taurine (Ankole) and indicine (Zebu) cattle in East Africa. The analysis highlights a convergence of population-prevalent class I MHC allelic repertoires in taurine and indicine cattle, likely due to the similar pathogen-driven selective pressures. Our analysis of the anchor residue accommodating pockets of these prevalent alleles revealed extremely high levels of polymorphism, which contrast with Holstein alleles that exhibit a more limited repertoire of MHC specificity-determining pocket residues, potentially constraining the breadth of peptide presentation. However, in the context of considerable sequence and physicochemical variation in the pocket-forming residues, it was possible to discern overlaps in the predicted peptide binding spectrum. Interrogation of potential differences in peptide binding specificities wi

关键词： 100   CXCL8   CXCR1 Ab   gentamicin   IL-17 Ab   lysozyme   neutrophil degranulation   septic arthritis  

摘要： AimThe main objective of this study is to elucidate the role of CXCR1 Ab, IL-17 Ab, and gentamicin in protecting septic arthritis by regulating neutrophil functional responses while evaluating the contribution of the CXCL8-CXCR1 ***-four experimental swiss albino mice were utilized to study septic arthritis. They were divided into eight groups. After developing sepsis, respective mice groups were treated with CXCR1 Ab, IL-17 Ab, and gentamicin doses. Doses were administered on days 1, 8, and 13 of the experimental schedule. At the early, middle, and late phases of the experiment i.e. at 3, 10, and 15 DPI (Days Post Infection), mice were sacrificed and blood and tissues were collected for further experimental evaluations. Different functional studies were performed on isolated blood neutrophils, spleen, and synovial tissues. Histological evaluation, immunofluorescence study, sepsis profile, and downstream signaling pathway analysis were done to obtain *** mice group exhibited high inflammatory responses while treatment helped to mitigate them. IL-17 neutralization helped to lower bacterial burden, neutrophil ROS activity, MPO activity, and ALP activity. However, the combined neutralization of CXCR1 and IL-17 greatly influenced PMN chemotactic activity and lysozyme activity. At the early phase of the experiment, IL-17 neutralization's impact was more prominent, while later, CXCR1 neutralization gained the upper *** can conclude that IL-17 Ab in combination with gentamicin is potent in modulating neutrophil activities positively to cure sepsis, while CXCR1 Ab, through the CXCL8/CXCR1 pathway, regulates neutrophil functional activities by impacting different downstream signaling cascades.

关键词： Alzheimer's disease   BMAL1   circadian rhythm   DNA methylation   IL-17A  

摘要： Circadian disruptions and neuroinflammation impact nearly all people with Alzheimer's disease (AD), but their relationships with each other and the impact of their interaction on AD remain to be addressed. Here, we found that amyloid (A)-beta treatment downregulated brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL) 1 through the hypermethylation of its promoter region in HT22 cells and that the inhibition of DNA methylation ameliorated circadian rhythm disorders and restored BMAL1 protein expression by reversing its hypermethylation in APPswe/PSEN1dE9 (APP/PS1) mice. Critically, increased levels of interleukin (IL)-17A contributed to BMAL1 downregulation through the hypermethylation of its promoter region, thus leading to circadian disruptions in APP/PS1 mice. Moreover, we revealed that the mitogen-activated protein kinase (MAPK) pathway was responsible for IL-17A-induced DNA methyltransferase (DNMT) 1 upregulation. Taken together, we elucidate a new mechanism connecting IL-17A with altered DNA methylation of Bmal1, which results in circadian disturbances in an AD mouse model.

关键词： HLA   HLA-DRB1*11:343   new allele   NGS   peptide-binding domain  

摘要： HLA-DRB1*11:343 differs from HLA-DRB1*11:03:01 by a single nucleotide substitution in codon 12 in exon 2.

关键词： filgotinib   IL-17A   JAK1   pulmonary fibrosis   SOCS3   STAT3  

摘要： BackgroundRegulatory agencies in Europe and Japan have approved filgotinib, a selective JAK1 inhibitor, for use in treating rheumatoid arthritis, but its effect and mechanism of action in treating pulmonary fibrosis remain unclear. MethodsWe performed an in vivo investigation in rats on filgotinib's effect on pulmonary fibrosis resulting from the intratracheal infusion of bleomycin (BLM). Then, we focused on the mechanisms by which filgotinib inhibits experimentally induced pulmonary fibrosis in vitro by determining its effect on TGF-beta 1-induced proliferation of mouse lung fibroblasts. ResultsContinuous gavage of filgotinib at 20 mg/kg for 14 days elicited protective effects in the BLM-induced rat experimental pulmonary fibrosis model, as reflected in changes in Hounsfield units as an indicator of overall pulmonary function and in the lung coefficient and lung microscopic pathology scores as indicators of gross pulmonary pathology. Protein expression levels of IL-17A, phosphorylated tyrosine kinase (p-JAK1), p-STAT3 and cytokine signal transduction inhibitor 3 (SOCS3) were also changed. In in vitro studies, filgotinib at 1 mu M reduced TGF-beta 1-induced fibroblast proliferation and produced lower levels of IL-17A, p-JAK1 and p-STAT3, but higher SOCS3. ConclusionsFilgotinib appeared to alleviate experimental pulmonary fibrosis by reducing fibroblast proliferation via inhibition of the JAK1/STAT3/SOCS3/IL-17A pathway.

关键词： DM9 domain   Pattern recognition receptor   Complement system   Interleukin 17   Oysters  

摘要： DM9 domain-containing protein (DM9CP) as pattern recognition molecule is involved in regulating the inflammation-related signaling pathway in invertebrates. In the present study, a DM9CP with two tandem DM9 repeats (designated as CgDM9CP-8) was identified from Crassostrea gigas. The mRNA transcript of CgDM9CP-8 was the highest in haemocytes. Recombinant CgDM9CP-8 was able to bind various PAMPs (MAN, PGN and LPS) and microbes (Vibrio splendidus, Staphylococcus aureus, Bacillus subtilis, Pichia pastoris, and Yarrowia lipolytica). CgDM9CP-8 protein was distributed in haemocytes and cell-free haemolymph. After lipopolysaccharide (LPS) or V. splendidus stimulation, the mRNA expressions of CgDM9CP-8 in haemocytes were significantly up-regulated at 3 and 6 h, respectively. rCgDM9CP-8 exhibited binding activity to V. splendidus and E. coli, inhibiting their growth in vitro. CgDM9CP-8 was able to bind CgMASPL-1 both in vivo and in vitro to lead to complement CgC3 cleavage. In addition, in CgDM9CP-8-RNAi oysters, the mRNA expressions of interleukin 17s (CgIL17s) in haemocytes decreased significantly after V. splendidus stimulation. These results suggested that CgDM9CP-8 functioned as a pattern recognition and antibacterial molecule to regulate the mRNA expressions of CgIL17s through the activation of CgC3 in C. gigas.

摘要： Periodontitis is associated with aspiration pneumonia. However, the relationship between periodontitis and aspiration pneumonia remains unclear. This study investigated the virulence factor of Porphyromonas gingivalis, which exacerbates aspiration pneumonia, and the role of IL-35, an inhibitory heterodimeric cytokine of Epstein-Barr virus-induced gene 3 (EBI3) and p35, in aspiration pneumonia using Ebi3 knockout (KO) mice. Aspiration pneumonia was induced by the intratracheal injection of Streptococcus pneumoniae and P. gingivalis culture supernatant (mixed infection). Leupeptin was used to inhibit gingipain, a virulence factor of P. gingivalis. Four days after infection, lung tissues were collected for analyses. The percentage of interstitium in the group with mixed infection and leupeptin treatment was significantly reduced compared with the nonleupeptin administration group. Additionally, the percentage of interstitium in the field of Ebi3 KO mice was significantly increased compared with wild-type (WT) mice in mixed infection. IL-35 production in WT mice with mixed infection was significantly increased compared with the control group. IL-17 production in Ebi3 KO mice was significantly increased compared with WT mice with mixed infection. These findings suggest that gingipain exacerbates aspiration pneumonia and that IL-35 may contribute to suppressing the exacerbation of aspiration pneumonia. (Am J Pathol 2025, 195: 652-662;https://***/10.1016/ ***.2024.11.009)

关键词： alcoholic cirrhosis   alcohol-related liver disease   ALD   cirrhosis   liver disease   steatotic liver disease  

摘要： Background: There are no FDA-approved therapies for alcohol-associated liver disease (ALD). Preclinical studies indicate that blocking IL-23/IL-17 signalling may reverse liver injury. Guselkumab, an IL-23-specific antibody approved for psoriasis, may be beneficial for ALD. Aims: We aimed to assess the safety and tolerability of guselkumab in patients with ALD. Methods: This phase-1 dose-escalation study included patients with >= 2 DSM-5 criteria for alcohol use disorder, significant steatosis (MRI-PDFF >= 8%) and MRE < 3.63 kPa (to exclude advanced disease). Guselkumab was given subcutaneously on Days 1 and 29 in 30, 70 or 100 mg dose cohorts. Primary endpoints were adverse events (AEs) and dose-limiting toxicity. Results: We enrolled 13 patients (three 30 mg, three 70 mg, and seven 100 mg). Eleven completed the study and two early discontinued in the 100 mg group. Of them, 77% were men, and the median age was 53 [IQR 49-61] years. The median MRI-PDFF and MRE were 18.4% [IQR 8.4%-34.0%] and 2.5 [2.2-2.6] kPa, respectively. The most frequent AEs were hyperuricemia (13%, mild only) and elevated lipase (11%, mild and moderate). There were no serious adverse events or significant variations in liver enzymes. There was a suppression of peripheral interleukin (IL)-17, IL-23, IL-1b and TNF-alpha in the 70 and 100 mg groups, and a significant decrease in alcohol consumption over time (AUDIT-C: 6 [3-7] vs. 5 [1-6], p = 0.023). Conclusions: Guselkumab is safe in doses up to 100 mg and may reduce inflammation markers in ALD. These findings support further phase 2 studies to evaluate the efficacy of guselkumab in ALD, particularly in patients with severe phenotypes.

关键词： AAV2   HAdV   HLA   adeno-associated virus 2   adenovirus   autoantibodies   paediatric hepatitis  

摘要： An outbreak of severe acute hepatitis of unknown aetiology in children (HUAC) was reported by the United Kingdom (UK) in spring 2022. Within days, a corresponding increase was identified in Ireland. A multi-agency incident management team (IMT), led by the Health Protection Surveillance Centre (HPSC), established a national case definition, trawling questionnaire, testing protocol and communications plan. Between 1 October 2021 and 12 May 2023, 44 probable and three possible cases of HUAC were identified in Ireland with a median age of 3 years. Adeno-associated virus 2 (AAV2), detected in 18 of 31 probable cases, and SARS-CoV-2 antibodies in 22 of 37 of probable cases were the most common infectious agents, followed by human herpes virus 7 (18/33) and adenovirus (20/44). Immunological findings included the human leukocyte antigen (HLA) class II allele in 17 of 32 cases. Autoantibodies were found in 15 of 40 patients. Our findings corroborate those of the UK, which suggested a link between HUAC and AAV2 and another virus, in children predisposed due to presence of a particular HLA class II type. Close collaboration with the UK, the European Centre for Disease Prevention and Control (ECDC) and World Health Organization (WHO) was invaluable in the investigation.