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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： 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： 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： 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： bone marrow   CD69   memory T lymphocytes   regulatory T-cells  

摘要： Maintenance of memory T-cells in the bone marrow and systemically depends on the homeostatic cytokines IL-7 and IL-15. An immunological memory may also exist for regulatory T-cells. EOMES+type-1 regulatory (Tr1)-like cells have a rapid in vivo turnover, but whether they are short-lived effector cells or are maintained long-term has not been ***+Tr1-like cells expressing GzmK were enriched among CD69+Ki67-T-cells in the bone marrow of healthy donors, suggesting that they became quiescent and bone marrow-resident. Conversely, CD4+GzmB+ effector T-cells were excluded from the bone marrow-resident fraction. The dichotomy between GzmK+ and GzmB+T-cells was observed both in healthy individuals and in multiple sclerosis patients, and also among CD8+T-cells. Intriguingly, bone marrow-resident CD4+ memory T-cells expressed increased levels of IL-7R alpha, while EOMES+Tr1-like cells were consistently IL-7R alpha lo. However, EOMES+Tr1-like cells expressed the IL-2/15R beta chain, and the latter was induced upon forced expression of EOMES in primary human CD4+ T-cells. Finally, IL-15 rescued EOMES+Tr1-enriched populations from death by neglect but was not required for CD4+ memory T-cell survival. These findings suggest that the bone marrow may provide a survival niche for EOMES+Tr1-like cells. The different IL-7 and IL-15 receptor expression patterns of CD4+ memory T-cells and EOMES+Tr1-like cells suggest furthermore that they compete for different homeostatic niches.