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关键词： childhood interstitial lung disease   TNF-α   macrophage   progranulin   fibrotic lung disease   spatial transcriptomics   precision medicine   rare lung disease  

摘要： Background Childhood interstitial and diffuse lung diseases are a collection of rare disorders with significant associated morbidity. Only a small subset of these diseases have precise diagnostic or therapeutic options identified to date. Methods Whole-exome sequencing in a family identified a candidate pathogenic variant predicted to be causing fibrotic lung and liver disease in a child. Digital spatial mRNA profiling of clinical lung biopsies was done to identify aberrant signaling pathways. ELISA confirmed low circulating protein levels in the patient. Findings We identified homozygosity of the ***139Arg loss-of-function progranulin ( GRN ) variant and an alveolar macrophage transcriptomic signature consistent with tumor necrosis factor alpha (TNF-α) pathway activation. This motivated treatment with anti-TNF monoclonal antibodies, resulting in dramatic improvement of the patient’s lung and liver disease. Conclusions These findings demonstrate the clinical utility of convergent multiomics in the evaluation and implementation of precision therapeutics in rare diseases. Funding This work was supported by a grant from the Chan Zuckerberg Initiative Patient-Partnered Collaboration for single-cell analysis of rare inflammatory pediatric disease, the Corkin Family Fund for Research, and in part by cooperative agreement U01TR002623 from the National Center for Advancing Translational Sciences/NIH and the PrecisionLink Project at Boston Children’s Hospital.

关键词： ANCA-associated vasculitis   HLA   GPA   PR3   MPO  

摘要： Objectives ANCA-associated vasculitis (AAV) is a group of systemic autoimmune diseases affecting small blood-vessels. Class-II human leukocyte antigen (HLA) genes are often reported as major genetic determinants. We conducted a systematic review and meta-analysis to evaluate the susceptibility conferred by HLA genes to AAV and five of its clinical subtypes [PR3+AAV, MPO+AAV, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA)]. Methods Relevant articles published March 2024 or previously were retrieved from electronic databases using appropriate keywords. Eligible studies were included according to inclusion/exclusion criteria. Funnel plots, the Newcastle-Ottawa Scale and GRADE tools were used to evaluate the quality of the evidence and the research findings. Statistical analyses were performed using RevMan 5.4.1. The meta-odds ratio and the Z test P-value were considered to check the HLA associations. Results This meta-analysis of associations between HLA alleles and AAV and its subtypes identified 30 significant associations, of which 17 withstood Bonferroni corrections. rs9277554-C from HLA-DPB1 [meta-analysis overall odds ratio (Meta-OR) = 3.92 (3.27-4.69)], rs1049072-A from HLA-DQB1 [Meta-OR = 1.39 (1.27-1.52)] and rs9277341-C from HLA-DPA1 [Meta-OR = 0.41 (0.03-0.57)] were found to be significantly associated (P < 0.00001) with AAV and GPA, respectively. HLA-DRB1*09:01 was found to be significantly associated with (P < 0.00001) (i.e. a predisposing allele for) AAV [Meta-OR = 1.72 (1.46-2.03)], MPO+AAV [Meta-OR = 1.65 (1.41-1.93)] and MPA [Meta-OR = 1.75 (1.41-2.19)]. Significant association (P <= 0.0005) was also observed between HLA-DPB1*01:01 and AAV [Meta-OR = 0.38 (0.24-0.62)] and between HLA-DRB1*11:01 and MPA [Meta-OR = 2.11 (1.39-3.20)]. Sensitivity analysis identified additional significant (P <= 0.001) alleles HLA-DPB1*04:01 and HLA-DPB1*02:01 predisposing patients to AAV and

关键词： adverse effects   dapsone   dapsone hypersensitivity syndrome   HLA   leprosy   multidrug therapy  

摘要： BackgroundThe introduction of the World Health Organization's multidrug therapy (WHO-MDT) has significantly advanced leprosy treatment. Although dapsone is a fundamental component of MDT, it presents risks of adverse drug reactions (ADR), including the potentially fatal dapsone hypersensitivity syndrome (DHS).MethodsConsequently, we conducted a retrospective observational study by reviewing the records of patients registered at the leprosy clinic within the department of dermatology at a tertiary care center from 2010 to 2022. We included all patients who experienced ADR due to dapsone that necessitated its discontinuation, with particular emphasis on those who developed *** 1598 leprosy patients treated with standard WHO-MDT, 45 patients developed ADR requiring cessation of dapsone (2.82% over 12 years). The most common ADR was abnormal liver function tests in 14 patients (0.87%) and anemia in 13 patients (0.81%), including one case each of hemolytic anemia and methemoglobinemia. Neuropsychiatric adverse effects were observed in five patients (0.31%). The incidence of DHS was 0.75% (12 patients), with maculopapular rash being the most frequent cutaneous manifestation. These patients were subsequently treated with MDT without dapsone, along with standard care for the ADR, resulting in no mortality or serious *** dapsone remains a cornerstone in the treatment of leprosy, the potential for clinically significant though infrequent adverse reactions highlights the need for vigilant monitoring and increased awareness among healthcare providers of the diverse manifestations of dapsone-related side effects.

关键词： cognitive impairment   disturbed astrocyte   IL-33   neuropathic pain   oxidative stress  

摘要： Cognitive impairment is one of the most common comorbidities in individuals suffering from neuropathic pain. However, the mechanisms underlying pain-associated cognitive dysfunction remain unclear. Studies show that IL-33 is essential for synaptic plasticity, which is necessary for learning and memory formation. Here, we used a spared nerve injury (SNI) model in mice to induce cognitive dysfunction associated with neuropathic pain. Behavioral changes following surgery were assessed using Von Frey test, open field test, and novel object recognition test. Immunofluorescence, chemical genetics, and stereotaxic injections were used to investigate the potential mechanisms. Mitochondrial morphology and oxidative stress levels were evaluated using transmission electron microscopy and by measuring the superoxide dismutase (SOD) activity and reactive oxygen species (ROS) production. The data suggest that animals after SNI with comorbid memory dysfunction exhibited a decline in IL-33 levels in the dorsal hippocampal CA3 region, accompanied by disturbed astrocytes. The expression of IL-33-positive astrocytes was reduced, and the number of dendritic spines was decreased. In addition, SOD activity was decreased, ROS production increased, accompanied with impaired mitochondrial morphology in synapses. Exogenous IL-33 administration or enhancing endogenous IL-33 release via chemogenetic activation of astrocytes alleviated cognitive impairment. These effects were mediated by improvement in mitochondrial morphology, reduction in oxidative stress levels, and increase in the number of dendritic spines. Findings indicated that IL-33 derived from astrocytes in the dorsal CA3 contributes to synaptic plasticity and oxidative stress in SNI mice. Accordingly, IL-33 may serve as a potential therapeutic target for pain-associated cognitive impairment. NEW & NOTEWORTHY IL-33 is important for synaptic plasticity and oxidative stress in spared nerve injury mice. Chemogenetic activation of target

关键词： Copyrights  

摘要： Regulatory T cell (Treg cell) therapy has been transformed through the use of chimeric antigen receptors (CARs). We previously found that human Treg cells minimally produce IL-10 and have a limited capacity to control innate immunity compared to type 1 regulatory T cells (Tr1 cells). To create "hybrid" CAR Treg cells with Tr1 cell-like properties, we examined whether the PDCD1 locus could be exploited to endow Treg cells with CAR-regulated IL-10 expression. CRISPR-mediated PD1 deletion increased CAR Treg cell activation, and knock-in of IL10 under control of the PD1 promoter resulted in CAR-induced IL-10 secretion. IL10 knock-in improved CAR Treg cell function, as determined by increased suppression of dendritic cells and alloantigen- and islet autoantigen-specific T cells. In vivo, IL10 knock-in CAR Treg cells were stable, safe, and suppressed dendritic cells and xenogeneic graft-versus-host disease. CRISPR-mediated engineering to simultaneously remove an inhibitory signal and enhance a suppressive mechanism is a previously unexplored approach to improve CAR Treg cell potency.

关键词： multiple sclerosis   HLA-DRB1   HLA-DQB1   genetic susceptibility   Moroccan population  

摘要： Introduction: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) that leads to inflammation and demyelination, manifesting in either a relapsing-remitting or progressive form. As a multifactorial disease, MS involves both genetic and environmental factors, with a known significant contribution from human leukocyte antigen (HLA) genes, mainly represented by the HLA-DRB1 and HLA-DQB1 loci, which have been linked to either susceptibility or protection, but variably across populations and ethnic groups. We aimed to study the distribution and polymorphism of HLA-DRB1 and HLA-DQB1 alleles in a population with MS from the southern Moroccan region, in comparison with healthy controls. Materials and Methods: A cross-sectional study was conducted over a period of 2 years (2022-2024) in a MS cohort including 40 patients and 100 healthy controls. DRB1 and DQB1 HLA genotyping was performed using a high-resolution reverse sequence-specific oligonucleotide (SSO) method, based on the Luminex system (xMAP technology, One lambda (R)). Data were analyzed using SPSS 26;differences in allele frequencies were evaluated by the Chi-square test and Fisher's exact test. OR (95% CI) was calculated, and FDR corrections were applied for multiple testing. Results: Among the various HLA-DRB1 and DQB1 alleles studied, including those considered as predisposing to MS, the DQB1*02:01 and DRB1*15:01 alleles were more prevalent in MS patients, with 40% and 8.8% vs. 16% and 4.08% in controls respectively, although these differences were not statistically significant (p = 0.06 and p = 0.12). Likewise, the DRB1*15:01-DQB1*06:02 association was significantly more prevalent in the MS group (9%, p = 0.004). In contrast, the DRB1*07:01 allele, linked to protection against MS in many populations, was significantly predominant in controls (17%, p = 0.004). Similarly, the DRB1*07:01-DQB*02:01 combination was rather more frequent in controls (12%, p = 0.01). Confront