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摘要： Osteoarthritis (OA), a prevalent joint disorder, can lead to disability, with no effective treatment available. Interleukin-1 (IL-1) plays a crucial role in the progression of OA, and its receptor antagonist (IL-1Ra), a natural IL-1 inhibitor, represents a promising therapeutic target by obstructing the IL-1 signaling pathway. This study delivered IL-1Ra via adeno-associated virus (AAV), a gene therapy vector enabling long-term protein expression, to treat knee osteoarthritis (KOA) in animal models. scAAV-oIL-1Ra-I1/2 injected directly into the joint in both MMT/ACLT-induced KOA model rat improved abnormal gait (increasing footprint area and pressure), subchondral bone lesions, and significantly reduced cartilage wear and pathological scores. In the MMT-induced KOA rabbit model, weight-bearing asymmetry (indicating pain) improved after 8 weeks of scAAV-oIL-1Ra-I1/2 administration, and X-ray showed decreased K-L scores (severity grade), reduced cartilage loss, and lower pathology scores compared to untreated animals. Additionally, sex-determining region Y-type high mobility group box 9 (SOX9) was co-delivered with IL-1Ra via AAV in ACLT + MMT-induced KOA rats. The combined treatment significantly alleviated subchondral bone lesions, cartilage destruction, synovial inflammation, and pathological scores, demonstrating superior efficacy compared to either treatment administered alone. Co-delivering IL-1Ra and SOX9 inhibited IL-1 mediated inflammatory signaling, maintained cartilage homeostasis, and promoted its repair in KOA models, suggesting potential for clinical use.

关键词： cord blood transplantation   donor selection   HLA   transplantation-related mortality  

摘要： Cord blood transplantation (CBT) is a valuable donor source for patients without human leukocyte antigen (HLA)-matched donors. While CBT has a lower risk of graft-versus-host disease and requires less stringent histocompatibility, it is associated with a higher transplantation-related mortality (TRM) compared to other donor sources. We hypothesized that assessing the immunogenicity of mismatched HLA could reveal non-permissive mismatches contributing to increased TRM. We retrospectively analysed 1498 single-unit CBT cases from 2000 to 2018 across eight Japanese institutions, evaluating the immunogenicity of mismatched HLA using the PIRCHE algorithm to examine binding affinities of HLA-derived epitopes to donor or recipient HLA. Results indicated that Class I epitopes from mismatched recipient HLA-B were significantly associated with poor outcomes due to higher TRM and lower neutrophil engraftment, particularly when presented on matched HLA class I. Notably, epitopes from HLA-B exon 1 showed stronger prognostic significance, with HLA-B alleles carrying M-type leader peptides exhibiting higher affinity for these epitopes. Patients with a matched M-type HLA-B and Class I epitopes derived from mismatched HLA-B exon 1 had worse outcomes. These findings suggest that immunogenicity-informed donor selection could improve CBT outcomes.

关键词： Illumina MiSeq   next generation sequencing (NGS)   novel HLA-allele  

摘要： HLA-A*68:02:27 differs from HLA-A-68:02:01:01 by a single nucleotide variation in Exon 4, codon 206.

关键词： cirrhosis   IL-6   renal impairment   spontaneous bacterial peritonitis   TNF-alpha   VCAM-1  

摘要： Background Multiple mechanisms may contribute to the occurrence of renal impairment (RI) in patients with spontaneous bacterial peritonitis (SBP). One such mechanism is systemic inflammatory response syndrome, which involves the release of pro-inflammatory cytokines (tumour necrosis factor [TNF]-alpha, interleukin [IL]-6 and vascular cell adhesion molecule [VCAM]-1). The goal of this research was to evaluate the role of IL-6, TNF-alpha and VCAM-1 as potential predictors of RI and mortality in cirrhotic patients with *** This study included 90 cirrhotic patients with SBP, divided into two equal groups: group A was patients without RI and group B was patients with RI. Based on mortality outcomes, the patients were further categorized into group 1 (recovery, n=70) and group 2 (death, n=20). TNF-alpha, IL-6 and VCAM-1 serum levels were measured using enzyme-linked immunosorbent *** RI occurred in 50% (45/90) of the study population. Among the 90 patients, 10 (11.1%) had elevated IL-6 levels, 8 (8.9%) had elevated TNF-alpha levels and 6 (6.7%) had elevated VCAM-1 levels. There were no significant variations in cytokine levels between groups A and B. With an area under the curve of 0.5, the three cytokines showed comparable sensitivity and specificity as predictors of *** The use of TNF-alpha, IL-6 and VCAM-1 as predictive markers for RI and mortality in SBP patients is not recommended, as these biomarkers demonstrated limited diagnostic value.

关键词： Autoimmunity   Bullous pemphigoid   IL-5   Mouse model   T cell line  

摘要： Bullous pemphigoid is an autoimmune subepidermal blistering disease caused by anti-type XVII collagen (COL17) antibodies. Bullous pemphigoid has some immunological features such as eosinophilic infiltration and the deposition of IgE autoantibodies in the skin;however, the mechanism behind such features remains largely unclear. We focused on the autoantigen-specific CD4+ T cells, which are considered to regulate immune response. We established COL17-specific CD4+ T cell lines in vitro. Wild-type mice were immunized with synthesized peptides that include a pathogenic epitope of COL17, and lymphocytes were subjected to a limiting dilution assay. We established 5 T cell lines and examined the pathogenicity by transferring them with COL17-primed B cells into Rag-2-/-/COL17-humanized mice that express human COL17 but not mouse COL17 in the skin. Notably, 3 lines induced bullous pemphigoid-like skin changes associated with subepidermal separation and eosinophilic infiltration histologically and the production of anti-COL17 antibodies. The other 2 lines did not induce such phenotypes. RNA-sequencing analysis revealed that T helper 2 cytokines, particularly IL-5, were highly expressed in the pathogenic T-cell lines. Anti-IL-5 antibody administration significantly reduced the skin changes and attenuated the production of autoantibodies. Thus, the production of IL-5 is critical for COL17-specific CD4+ T cells to induce bullous pemphigoid phenotypes in vivo.

关键词： Celiac disease   Gluten-free diet   Osteoclastogenesis   Bone metabolism   Osteoporosis  

摘要： The etiology of bone loss in celiac disease (CeD) remains a clinical challenge, with uncertainties present such as the extent of involvement of malabsorption and inflammation-induced osteoresorption processes in development of osteopenia/osteoporosis (OPN/OP), or reasons for failure to achieve healthy bone mass (BMD) even after long-term gluten-free diet (GFD) treatment. This observational prospective study explores the in vitro osteoclastogenic potential of peripheral blood precursors originating from adult active (newly diagnosed and untreated) celiac disease patients (aCeD) and describes the longitudinal changes in osteoclastogenesis after long-term adherence to GFD. To find connections between in vitro observations and in vivo bone metabolism changes, serum levels of 25(OH)D3, PTH, bCTX, PINP, CRP, IL-6, RANKL and OPG were measured before and after GFD and levels of these markers were correlated with the rate of osteoclastogenesis in vitro . OPG and IL-6 showed associations with BMD and/or presence of OPN/OP. Patients after GFD (CeD-GFD) exhibited improved BMD and increased serum 25(OH)D3 levels, alongside reduced bCTX and PINP levels. Compared to healthy donors, aCeD osteoclast genesis in vitro was higher and, surprisingly, remained elevated even in CeD-GFD patients. Negative correlation was found between osteoclastogenesis rate and serum OPG in aCeD, while osteoclastogenesis rate positively correlated with PTH in CeD-GFD. These results highlight OPG as marker for risk of OPN/OP in CeD and suggest that improvement of BMD after GFD is a result of uncoupling between bone metabolism and osteoresorptive action of osteoclasts after GFD. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： confirmatory allele   HLA-DQB1   NGS   novel allele  

摘要： Novel HLA-DQB1*06:03:54, HLA-DQB1*06:526 alleles and confirmatory HLA-DQB1*06:494 allele were detected during the HLA typing process.

关键词： Autoimmune   HLA   IgLON5   Progressive supranuclear palsy   Peptide modelling   Tau  

摘要： Objectives: Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen (HLA) locus on chromosome 6 is a polymorphic region with complex linkage patterns that has been implicated in several autoimmune and neurological disorders. The HLA locus has not been systematically examined in PSP. It is unclear whether tau and HLA can interact to induce an autoimmune disease mechanism. Methods: We evaluated an autopsy confirmed PSP cohort (n = 44) and compared allele/haplotype frequencies to those of the reference group of a local deceased Canadian donor pool. We performed HLA-Tau peptide binding prediction and modelling of HLA Class II - Tau Peptide interactions. Findings: Odds ratio was 2.94(95% CI 1.01 to 8.55;p = 0.047) for DQB1*06:01 allele, and 2.59(95% CI 1.39 to 4.83;p = 0.0025) for the narcolepsy-associated haplotype (DRB1*15:01-DQB1*06:02). One patient with 4-repeat tau PSP-type pathology was a carrier of the IgLON5-associated haplotype (DRB1*10:01-DQB1*05:01). HLA-Tau peptide binding prediction and modelling of HLA Class II - Tau Peptide interactions revealed strong-binding tau peptides but not the PSP-protofilament fold for alleles DQA1*01:02-DQB1*06:02 and DQA1*01:03-DQB1*06:01. Conclusion: Our study suggests that epitopes within the tau peptide may bind to HLA alleles that are found in a subset of PSP patients supporting the notion of an autoimmune pathophysiological component. These findings have implications for subtyping and stratifying patients for therapies, including those targeting immune modulation.

关键词： Pharmacogenetic testing   Pharmacogenetics   Pharmacogenomic   Implementation   DPYD   TPMT   HLA  

摘要： Purpose Although already a lot of research has been done on pharmacogenetic tests to inform the choice and/or dosing of medicines, the implementation and clinical uptake remain limited. This study assessed the implementation of pharmacogenetic (PGx) testing on a national scale by analyzing access to and volumes of reimbursed PGx. Methods The use of pharmacogenetic tests was examined via a cross-sectional online survey among the Belgian laboratories, collecting data on PGx targets, testing volumes and technologies used. The focus was on reimbursed tests. Additional data were sourced from the national reimbursement database to describe uptake of testing per medication. Results The uptake of PGx testing in Belgium varied by medication, with significant implementation for fluoropyrimidines, abacavir, and thiopurines. DPYD gene testing was the most frequently performed PGx test, due to endorsed (inter)national guidelines. Reimbursement rules shape access to PGx, with the majority of PGx tests performed in dedicated centers for human genetics (CHG). Access to HLA laboratories for HLA targets was not optimal and some laboratories without a CHG also included constitutional PGx targets in somatic oncology panels. Conclusion This nationwide study demonstrates that in a country where the prescribers have access to a relatively extensive list of reimbursable PGx tests, the implementation of PGx testing is shaped by the presence of endorsed evidence-based clinical practice guidelines, as well as organizational and logistical factors.

关键词： cetirizine   IL-33   inflammation   mast cell   preterm birth  

摘要： Problem: In order to gain a deeper understanding of the mechanisms underlying LPS-mediated preterm birth, it is crucial to investigate the relationship between preterm birth and mast cells (MCs). Moreover, the role of antihistamines in inflammatory processes during pregnancy remains incompletely understood. Method of Study: CD-1 female mice were administered intrauterine lipopolysaccharide (LPS) via midline laparotomy to establish an inflammation-induced preterm birth model. The experimental groups (n = 6 per group) were formed as Nonpregnant and pregnant control, Sham, PBS, LPS, Cetirizine (CET) control, and two CET treatment groups (CET 10 mg/kg-low dose, and CET 20 mg/kg-high dose with LPS administration). Tissue samples were analyzed using immunohistochemistry and Western blot techniques. Results: Our findings suggest that MCs play a significant role in preterm birth, with LPS administration inducing MC dysfunction in the reproductive tract during pregnancy. Additionally, high doses of CET may support inflammatory responses. A particularly notable result was the reduction in interleukin-33 (IL-33) expression in the cervix during LPS-induced preterm birth. This suggests that IL-33 may serve as a potential biomarker for preterm birth in the cervix. Conclusions: The effects of CET during LPS-mediated preterm birth appear to be dose-dependent, warranting further exploration of their role in this context.