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关键词： IL-17 | immune sex bias | immune sex dimorphism | psoriasis | testosterone | Th17  

摘要： Th17 cells play a crucial role in autoimmune disease pathogenesis. However, the mechanisms behind the sex differences in immune responses, particularly women's higher susceptibility to autoimmune diseases, remain unclear. This study investigated the role of testosterone in modulating the IL-17 response. IL-17 levels and IL-17-expressing cells were compared between males and females, and testosterone's effect on Th17 differentiation was evaluated. In an imiquimod-induced psoriasis mouse model, testosterone supplementation reduced psoriasis severity in female mice, whereas castration of male mice exacerbated psoriasis. Testosterone inhibited both in vitro Th17 differentiation and in vivo IL-17 expression, correlating with reduced psoriasis severity. Molecular studies indicated that testosterone is an inverse agonist of related orphan receptor gamma (RORγt), a key transcription factor for IL-17 expression. These findings offer mechanistic insights into how testosterone limits tissue inflammation in psoriasis and suggest a basis for developing novel testosterone derivatives to target RORγt and suppress Th17-mediated inflammation.

摘要： Abatacept reduces the risk of acute graft versus host disease (GVHD) in matched unrelated donor hematopoietic stem cell transplant (HSCT) for Sickle Cell Disease (SCD). We conducted a retrospective review of patients who underwent matched sibling donor (MSD) HSCT for SCD with and without adding abatacept to standard acute GVHD prophylaxis. Twenty-one patients, median age 7 years (range 2.0-14.8) received MSD HSCT with addition of 4 doses of abatacept to standard calcineurin inhibitor based acute GVHD prophylaxis while six patients, median age 9.8 years (range 1.9-14.4) underwent MSD HSCT with standard prophylaxis. One patient (4.5%) in the abatacept group developed grade II acute skin GVHD, while 3 patients (50%) in standard group developed grade II-III acute skin and gut GVHD (p = 0.022). Grade III-IV GVHD was 0% in abatacept group compared to 33% in standard group (p = 0.043). Disease-free survival was 83% in standard group at a median follow up of 11 years (IQR:9.5-13.25 years), and 100% in the abatacept group at a median follow up of 5 years (IQR:3-8 years). Our data show that addition of abatacept to calcineurin inhibitor based acute GVHD prophylaxis reduces the risk of severe acute GVHD in patients with SCD undergoing MSD HSCT without impacting disease-free survival.

关键词： CRSwNP   IL-33   KIT   mast cell   miR-221-3p  

摘要： BackgroundMast cells (MCs) are involved in type 2 inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP), which depends on interleukin (IL)-33 stimulation. MiR-221 is reported to be an important regulator of MCs, and miR-221-3p can be expressed in CRSwNP. However, the role of miR-221-3p in CRSwNP is *** tissues from control subjects (n = 12) and polyps from patients with CRSwNP (n = 40) were collected. The expression of miR-221-3p and cytokines was detected by real-time quantitative polymerase chain reaction (qPCR). The activation of P65 and ERK was determined by western blotting. The localization of miR-221-3p was detected via in situ hybridization combined with immunofluorescence (IF), and its target was identified via a luciferase reporter system. Human MCs were incubated with IL-33 or stem cell factor. MicroRNA mimics/inhibitor and lentiviral plasmids were used to determine the role of miR-221-3p in *** observed increased expression of miR-221-3p in CRSwNP, and localized its expression in MCs. The expression of miR-221-3p was negatively correlated with that of IL-4, IL-5, and IL-13 in CRSwNP. MiR-221-3p can be induced by IL-33 in MCs and plays a negative regulatory role in cytokine expression and signaling pathways in IL-33-induced MC activation. As the direct target of miR-221-3p, the receptor KIT was negatively correlated with miR-221-3p and decreased in CRSwNP. In MCs, KIT is essential for an effective response to IL-33 stimulation. We here demonstrated that miR-221-3p regulates cytokine expression by targeting KIT in IL-33-activated ***-221-3p inhibits MC-dependent type 2 inflammatory conditions, rendering it a negative regulator of CRSwNP.

关键词： Porcine epidemic diarrhea virus   Protein kinase R like endoplasmic reticulum   kinase   Eukaryotic initiation factor 2 alpha   Cellular translation   Nuclear factor kappa B   Interferon  

摘要： Porcine epidemic diarrhea virus (PEDV) is one of the most important porcine pathogens for which no preventive and antiviral treatment measures are available. A pervious study revealed that the unfolded protein response (UPR) induced by endoplasmic reticulum (ER) stress can be utilized to inhibit PEDV replication. Here, we demonstrated that the UPR suppresses the replication of multiple genotypes of PEDV in both Vero and swine testis (ST) cells, primarily through activation of the PERK-eIF2 alpha branch among the three UPR pathways. The PERK-eIF2 alpha pathway inducers CCT020312 and salubrinal efficiently inhibited the replication of multiple genotypes of PEDV in both Vero and ST cells, whereas the inhibitor AMG PERK 44 promoted PEDV replication. Furthermore, we found that PERK-eIF2 alpha arm-mediated inhibition of PEDV replication is caused by phosphorylated eIF2 alpha-induced attenuation of global protein translation. Additionally, phosphorylated eIF2 alpha promotes NF kappa B signaling activation and facilitates to the production of IFN-I, eliciting innate immunity to suppress viral replication. These data show that PERK-eIF2 alpha pathway dampens the replication of multiple genotypes of PEDV, suggesting that this target may be exploited to develop as a broad-spectrum anti-PEDV drugs.

关键词： HLA‐DQA1*03:01:19   HLA‐genotyping   Illumina   next generation sequencing   novel allele  

摘要： The HLA-DQA1*03:01:19 allele differs from HLA-DQA1*03:01:01:01 by a single nucleotide substitution in exon 3.

关键词： Ankylosing spondylitis   Anti-TNF therapy resistance   Helicobacter pylori   Idot   nflammation  

摘要： BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory disease that poses challenges in treatment due to resistance to anti-tumour necrosis factor (anti-TNF) therapies. This study investigates whether Helicobacter (H. pylori) infection contributes to reduced anti-TNF treatment response in AS *** cross-sectional study was conducted on 159 patients with AS. H. pylori infection was assessed using serological assays (ELISA for Iga and Igg), histopathological examination of gastric biopsies, and stool antigen testing. Disease activity and functional impairment were evaluated using ESR, CRP, BASFI, and ASDAS-CRP *** with anti-TNF therapy resistance exhibited significantly higher H. pylori Iga seropositivity (p = 0.01) and histopathological positivity (p = 0.03). Additionally, they had longer anti-TNF treatment duration and higher inflammatory markers, including ESR, CRP, BASFI, and ASDAS-CRP scores, indicating a more significant inflammatory burden and functional *** findings suggest chronic H. pylori infection may contribute to anti-TNF therapy resistance in AS by promoting systemic inflammation and gut barrier dysfunction. These results underscore the importance of early, aggressive treatment strategies and suggest that H. pylori eradication may potentially enhance the efficacy of anti-TNF drugs. Future interventional studies are required to validate these findings and explore H. pylori screening as a therapeutic approach in AS *** points center dot Resistance to anti-TNF therapy in AS presents a significant challenge, with the underlying mechanisms not yet fully *** dot This study identifies Helicobacter pylori (H. pylori) infection as a potential contributor to anti-TNF drug resistance in ankylosing spondylitis (AS), with Iga seropositivity and histopathological positivity being markedly higher in resistant *** dot Chronic H. pylori infection may promote systemic inflam

关键词： Human leukocyte antigen (HLA)   Genetic polymorphisms   Magnetic resonance imaging (MRI)   Brain imaging   Multiple sclerosis (MS)  

摘要： This systematic review and meta-analysis synthesizes current evidence on associations between genetic polymorphisms of human leukocyte antigen (HLA) class I and II molecules, which play key roles in antigen presentation and immune response regulation, and brain imaging phenotypes across various neurological and psychiatric conditions. The strongest associations were observed in multiple sclerosis (MS), where HLADRB1*15:01 was linked to increased lesion volume and disease progression. Meta-analyses revealed significant pooled effect sizes for both T1 and T2 lesion volumes. Emerging evidence also suggests that variants in HLA class I and II genes contribute to brain structural changes associated with age-related cognitive decline, schizophrenia, and Gulf War illness. Our findings revealed stronger patterns of association between HLA class II polymorphisms with brain imaging implications as compared to class I in neurodegenerative conditions. Considering HLA class II roles in exogenous protein/peptide presentation, this highlights the potential importance of neuroimmune-environmental interactions as contributing factors to disease pathogenesis and progression. Population-based studies from the UK Biobank highlight the potential influence of HLA class I and II genetic polymorphisms on brain structure beyond disease-specific contexts, suggesting broader implications for neurodevelopment and neurodegeneration. Despite these emerging insights, the limited availability of studies using imaging modalities beyond structural MRI, along with inconsistent findings within specific diseases and across conditions, underscores the need for further investigation into the mechanistic contributions of specific genetic variants on impacting brain structural and functional outcomes. Future research should include larger, more diverse study cohorts and employ advanced genotyping technologies to provide a more comprehensive investigations of HLA's role on brain health across the lifespan.

关键词： Aicardi–Goutières syndrome   cGAS   type I IFN response   mitochondria   THP-1  

摘要： In humans, mutations in sterile alpha motif and histidineaspartate domain-containing protein 1 (SAMHD1) lead to the development of a type I interferonopathy known as Aicardi-Gouti & egrave;res syndrome (AGS). AGS can present with a variety of severe phenotypes in patients, and a hallmark of this disease is chronic activation of type I interferon (IFN) signaling. However, the mechanism through which type I IFN signaling is activated in the absence of functional SAMHD1 is not known. Here, we investigated the molecular pathways that lead to type I IFN signaling activation in the absence of SAMHD1. Our investigations revealed that chronic activation of type I IFN signaling in SAMHD1-knockout (KO) monocytes is cyclic GMP-AMP synthase (cGAS)-dependent. Analysis of other nucleic acid sensors showed that type I IFN signaling in SAMHD1-KO cells is not dependent on melanoma differentiation-associated protein 5 (MDA5) or retinoic acid-inducible gene I (RIG-I). In agreement with our observation that type I IFN signaling is dependent on cGAS, two inhibitors of the cGAS-stimulator of IFN genes pathway, G140 and H151, effectively prevented type I IFN activation in SAMHD1-KO monocytes. We also found that type I IFN signaling in SAMHD1-KO monocytes is dependent on type I IFN receptor expression. Further exploration revealed mitochondrial malfunction in SAMHD1-KO monocytes that is likely to leak mitochondrial components into the cytoplasm. Overall, our work suggests that genetic knock out of SAMHD1 leads to mitochondrial disfunction, resulting in the presence of mitochondrial DNA in the cytoplasm, which triggers cGAS and the type I IFN response.

关键词： KIR receptors   genetic phenomena   genetic variation   inbreeding   maternal–foetal histocompatibility   molecular epidemiology   pregnancy   pregnancy‐induced hypertension   pre‐eclampsia  

摘要： In pregnancy, semi-allogenic foetal trophoblasts express a specific HLA profile mediating maternal leukocyte contact, crucial for placentation. Paradoxically, maternal immunomodulation requires foetal antigen recognition, especially involving certain HLA molecules. Pre-eclampsia, a severe hypertensive complication, has been linked to antigenic similarity. Previously, we showed no selection for HLA (in)compatibility in uncomplicated naturally conceived pregnancies. However, pre-eclamptic pregnancies were associated with increased total maternal-foetal HLA and HLA-C matching. These associations suggest a role for HLA mismatches in immune regulation leading to an uncomplicated pregnancy. To better understand HLA homozygosity in human reproduction, we aimed to determine if there is a preferential selection for HLA compatibility in a genetically isolated population, and its relation to hypertensive complications. A nested case-control study, comprising 125 uncomplicated pregnancies and 50 with hypertensive complications (29 with pregnancy-induced hypertension, 21 with pre-eclampsia) was conducted in a genetically isolated Dutch population (F 1.3-3.1). Maternal and foetal HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and maternal killer-cell immunoglobulin-like receptor (KIR) genotyping were performed. Maternal-foetal HLA (mis)match counts were compared to expected values from randomisation of paternal HLA haplotypes over maternal haplotypes of the foetuses. Mismatched CD4 T cell epitopes presented by maternal HLA class II were predicted using the PIRCHE-II algorithm. In uncomplicated pregnancies, no difference was found between observed and expected maternal-foetal HLA (mis)matches. However, pregnancies with hypertensive complications showed significantly higher observed HLA-DQB1 mismatches, reflected in PIRCHE-II scores. No significant differences were found in KIR/HLA-C frequencies. Interpretation is limited by the small sample size and the grouping of distinct hypertensive disor