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关键词： CD247   FOXP3   Gene   Methylation   HLA haplotypes  

摘要： Background: Celiac disease is an autoimmune disorder that affects the small intestine in people with gluten intolerance. HLA-DQ2 and DQ8 have been associated with Celiac Disease. CD247 is a subunit of the T cell receptor complex and Forkhead box P3 (FOXP3) is a transcription factor involved in the regulation of the immune response. Expression levels of these two markers in various diseases, including autoimmune disorders, are controversial. In this context, we aimed to shed light on the etiopathogenesis of Celiac disease by determining the methylation profile of CD247 and FOXP3 genes, and to calculate the frequency of HLA-DQ haplotypes in this disease. Methods: Methylated and unmethylated copy numbers of the CD247 and FOXP3 genes in samples were calculated using the methylation-specific qPCR method. The records regarding HLA-DQ2 and DQ8 genotypes previously detected from our patients by Real Time PCR and tissue transglutaminase IgA (TTG-IgA) by ELISA, were analyzed. Results: CD247 methylation rate in our patients was significantly lower than in controls. According to the Marsh classification, the methylation level in Marsh type 2-3 patients was statistically lower than in type 1. On the contrary, FOXP3 had a significantly higher methylation rate in the patient group compared to healthy controls, and this gene was also found to be more methylated in Marsh type 2-3 patients than in Marsh type 1. In the patient group, HLA-DQ2 positivity was 82.5% and HLA-DQ8 positivity was 37.5%. Conclusion: The data suggest that CD247 expression is upregulated, whereas FOXP3 expression is downregulated in Celiac disease. Among HLA haplotypes, HLA-DQ2 heterodimer came to the forefront with its frequency in terms of celiac predisposition.

关键词： Platelet component   Transfusion-associated graft-versus-host dis-   ease   HLA   haplotype  

摘要： Clinical application of pathogen-reduction technology (PRT) is often restricted to platelet and non-cellular components, representing a minor fraction of the overall blood supply. The greatest benefit for patient safety may eventually derive from PRT in red cells, which is still unavailable for routine use. PRT is more effective to inactivate leukocytes than current irradiation, particularly pertinent for Japan with the only universal irradiation of cellular blood components. Elsewhere, only vulnerable patient cohorts are receiving irradiated cellular components. Blood components treated with approved PRT systems are exempt from irradiation if the patient requires irradiated components. Transfusion medicine has a strategic opportunity to develop and eventually utilize PRT for all cellular components, other than hematopoietic progenitor cell products. PRT would then enable leukocyte inactivation for 100 % of the blood supply, beneficial for transfusion safety in all patients.

关键词： 17 HLA-related loci   allele frequency   haplotype frequency   linkage disequilibrium  

摘要： Although the allele and haplotype frequencies of 11 HLA loci (HLA-A, B, C, DRB1, DRB3/4/5, DQA1, DQB1, DPA1 and DPB1) have been reported in different populations, rare studies have simultaneously assessed the allele distributions of non-classical HLA class I genes (HLA-E/F/G/H) and MICA/MICB together with the 11 classical HLA loci, or further analysed the haplotype frequencies covering the 17 loci. The present study aims to investigate the allele diversity and haplotype frequencies of 17 HLA-related loci including HLA genes and MICA/MICB simultaneously using a hybrid capture (HC)-based NGS method. A total of 358 HLA alleles including 177 class I and 137 class II alleles, as well as 29 MICA and 15 MICB alleles were identified in this project. The most frequent alleles at each locus were A*11:01 (29.10%), B*40:01 (14.46%), C*01:02 (19.90%), DRB1*09:01 (15.61%), DQB1*03:01 (18.48%), DPB1*05:01 (40.13%), DQA1*01:02 (22.58%), DPA1*02:02 (55.27%), DRB3*02:02 (65.95%), DRB4*01:03 (95.20%), DRB5*01:01 (75.97%), E*01:03 (62.63%), F*01:01 (97.07%), G*01:01 (70.74%), H*01:01 (35.87%), MICA*010:01 (19.90%) and MICB*005:02 (57.53%), respectively. The haplotype frequencies for different combinations of HLA loci were estimated and linkage disequilibrium (LD) between alleles for all pairs of neighbouring loci were calculated. The most frequent haplotype covering 17 loci was F*01:01-G*01:01-H*01:01-A*02:07-E*01:03-C*01:02-B*46:01-MICA*010:01-MICB*005:02-DRB4*01:03-DRB1*09:01-DQA1*03:02-DQB1*03:03-DPA1*02:02-DPB1*05:01 with a frequency of 3.18%. This is the first study on allelic polymorphism, haplotype inference and LD covering 17 HLA-related loci simultaneously in the Shenzhen Chinese population. These results will extend our knowledge of the allelic diversity of the HLA complex and provide population genetics data for transplantation and HLA-associated disease studies.

关键词： B cells   IgE   IL-17RB   IL-25   type 2 inflammation  

摘要： BackgroundAlarmin cytokine IL-25 promotes type 2 inflammatory responses in disorders such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) and known targets include ILC2 and Th2 cells. However, other cellular targets for IL-25 remain poorly *** investigate induction and expression of IL-25 receptor (IL-17RB) by B cells and evaluate responsiveness of IL-17RB-expressing B cells to IL-25 in ***-17RB expression, regulation and function on B cells were evaluated in peripheral blood-derived B cells by flow cytometry and RT-PCR, including in response to IgE-inducing stimuli (anti-CD40 mAb and IL-4). Single-cell RNA sequencing was used to compare IL-17RB+ and IL-17RB-activated peripheral blood-derived B cells. To evaluate B cell IL-17RB expression within type 2 inflamed tissue, B cells were compared from nasal polyps, control turbinate tissue and matched peripheral *** of B cells with anti-CD40 and IL-4 increased IL-17RB expression at both protein and mRNA level, which was further upregulated by IL-25. B cells induced to express IL-17RB responded to IL-25 with enhanced antibody production. Single-cell RNA-sequencing showed that IL17RB+ activated B cells expressed higher levels of IGHE, CCL17 and CCL22 compared to IL17RB- B cells. B cells from nasal polyp tissue expressed higher levels of surface IL-17RB compared with control tissue, correlating with patient-reported CRSwNP severity (SNOT-22).ConclusionPeripheral blood B cells activated under IgE-inducing conditions express surface IL-17RB, and tissue IL-17RB+ B cells are increased in type 2 inflammation. IL-17RB+ cells have a distinct transcriptional profile and respond to IL-25 with enhanced antibody production, highlighting the IL-25/IL-17RB pathway as a potential therapeutic target for CRSwNP and other type 2 inflammatory disorders.

关键词： HLA mismatch   anti‐HLA antibodies   cardiovascular evaluation   coronary artery disease   host versus graft antibodies   lung transplantation   revascularization   transplant candidate selection  

摘要： AIMS:Coronary artery disease (CAD) is a frequent comorbidity in lung transplant (LuTx) candidates. The impact of allogenic organ transplantation and the corresponding alterations in immune response on the progression of CAD remains poorly understood. In this study, we sought to analyze the effect of donor-recipient overall human leukocyte antigen (HLA) and HLA-DQ mismatch on cardiovascular outcomes following LuTx. METHODS AND RESULTS:This retrospective analysis of adult patients receiving lung transplantation at the LMU University Hospital between 2012 and 2018 included 310 patients, the majority of whom (67.4%) had undergone double lung transplantation. There were no significant differences in the incidence of the primary composite endpoint between patients with high/low HLA mismatches (22 [7.9%] vs. 4 [12.9%]; p = 0.311). Numerically higher rates of the primary endpoint, myocardial infarction, and cardiovascular death in the low HLA mismatch group can partially be explained by differences in baseline rates of CAD and coronary sclerosis. Notably, neither HLA-DQ mismatch nor the occurrence of rejection episodes or cytomegalovirus (CMV) infection was associated with the occurrence of cardiovascular events following transplantation. CONCLUSION:In this study cohort, high HLA mismatch and HLA-DQ mismatch were not associated with increased adverse cardiovascular events. Furthermore, neither transplant rejection nor CMV infection increased the risk for cardiovascular events. The high cardiovascular event rates following LuTx necessitate meticulous cardiovascular follow-up, irrespective of immunological matching.

关键词： Cytomegalovirus   UL54 mutation   Letermovir   Hematopoietic stem cell transplant   Inborn error of immunity  

摘要： Cytomegalovirus (CMV) infection remains one of the most common and challenging post-transplant infections. Children with inborn errors of immunity (IEI) and T-cell dysfunction are at high risk for CMV infection, which can be complicated by refractory and/or resistant cases. This case describes a Nepalese girl with MHC class II deficiency, who presented at 3 months of age with CMV and Pneumocystis jirovecii pneumonia. Hematopoietic stem cell transplantation (HSCT) was planned as a curative treatment for IEI. Initial antiviral therapy with ganciclovir, followed by foscarnet, achieved undetectable CMV viral loads. However, the viral load rebounded during foscarnet therapy. HSCT was performed at 7 months of age using peripheral blood stem cells from her CMV-seropositive father, despite the recipient's high CMV viral load. Empiric combination therapy with cidofovir (an unapproved drug in Japan), foscarnet, leflunomide, and artesunate was initiated. CMV genetic testing revealed UL54 mutations conferring high-level resistance to foscarnet and moderate-level resistance to ganciclovir. The regimen was adjusted to letermovir, ganciclovir, leflunomide, and artesunate, which successfully suppressed the viral load following engraftment. At three months post-HSCT, combination therapy was discontinued after sustained undetectable CMV viral loads. Although CMV infection was controlled, the patient died from idiopathic pulmonary hemorrhage at five months post-HSCT. This case highlights the potential efficacy of a letermovir-inclusive therapy regimen in managing drug-resistant CMV with UL54 mutations in a pediatric HSCT recipient.

关键词： Asthma   benralizumab   IL-5   mepolizumab   mast cells   mast cell progenitors  

摘要： Background: Therapies targeting IL-5 or its receptor (IL-5Ra) are currently used to treat patients with severe eosinophilic asthma. Objective: We sought to investigate the impact of anti-IL-5 and anti-IL-5Ra biological therapies on mast cells (MCs) and their progenitors. Methods: Surface IL-5Ra expression was investigated on MCs and their progenitors in mouse lungs and bone marrow and in human lungs and blood. Isolated human MC progenitors cultured in the presence or absence of IL-5 were analyzed in vitro. Circulating MC progenitors were quantified in patients with severe asthma before and after anti-IL-5 (mepolizumab) or anti-IL-5Ra (benralizumab) therapy. Gene expression analysis of MC progenitors was performed before and after anti-IL-5Ra therapy. Results: Approximately 50% of the human primary lung MCs and 30% of the human MC progenitors from individuals with allergic asthma expressed IL-5Ra. In patients with mild to moderate allergic asthma and mice with acute allergic airway inflammation, the fraction of IL-5Ra1 MC progenitors was elevated. In addition, IL-5 promoted the proliferation and/or survival of isolated human MC progenitors. Furthermore, patients with severe asthma from 2 independent cohorts demonstrated a reduction in blood MC progenitors after anti-IL-5 or anti-IL-5Ra treatment. This was associated with improved asthma control as well as a decline in both blood eosinophils and TH2 cells. Finally, the blood MC progenitors remaining after anti-IL-5Ra (benralizumab) treatment exhibited a downregulated expression of genes involved in growth and proliferation. Conclusions: This study introduces the possibility that the clinical effects of targeting IL-5/IL-5Ra in severe asthma may also involve reduction of MC populations. (J Allergy Clin Immunol 2025;155:1310-20.)

关键词： HLA-C*15:292   HLA-C*15:02:01   next-generation sequencing  

摘要： HLA-C*15:292 differs from HLA-C*15:02:01 by a G>A substitution in exon 2.

摘要： Anti-interleukin 17 use has been associated with a higher risk of candidiasis, as this cytokine is involved in maintaining mucosal barriers and orchestrating immune responses to fungal pathogens. We performed a real-life retrospective multicentre study aiming to assess the risk of candidiasis in patients undergoing treatment with bimekizumab at labelled dosage for psoriasis, for at least 16 weeks.