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关键词： Autoimmune diseases   Autoimmunity   Cellular immune response   Immunology   T cells  

摘要： Dysregulation of T follicular helper (Tfh) and T follicular regulatory (Tfr) cell homeostasis in germinal centers (GCs) can lead to antibody-mediated autoimmunity. While IL-1(3 modulates the GC response via IL-1R1 and IL-1R2 receptors on follicular T cells in animal models, its role in humans remains unclear. We analyzed Tfh and Tfr phenotypes in human secondary lymphoid organs (tonsils, spleen, and mesenteric lymph nodes) using flow cytometry, single-cell transcriptomics, and in vitro culture, comparing findings with samples from autoimmune patients. We observed organ-specific Tfh/Tfr phenotypes according to activation status and IL-1 receptor expression. An excess of IL-1R1 over IL-1R2 expression promoted a unique activated Tfr subset with Treg and GC-Tfh features. IL-1(3 signaling via IL-1R1 enhanced follicular T cell activation and Tfh-to-Tfr differentiation, while IL-1(3 inhibition upregulated IL-1R1, indicating a tightly regulated process. In autoimmune patients, high IL-1(3 and circulating Tfr levels correlated with increased autoantibody production, linking inflammation, IL-1(3 signaling, and Tfr/Tfh balance. Our findings highlight the critical role of IL-1(3 in follicular T cell activation and suggest that targeting IL-1(3 signaling in Tfh and Tfr cells could be a promising strategy for treating antibody-mediated autoimmune diseases.

关键词： at risk' genotype   ALTR   ALVAL   arthroplasty   metal allergy   pseudotumour  

摘要： Purpose Immune-mediated adverse local tissue reactions (ALTRs) to implanted metallic devices are an increasingly recognised orthopaedic concern. Recent research has identified a critical HLA genotype associated with increased risk of ALTR development around in situ arthroplasty implants. Carriage imparts a > 700% increased relative-risk of high-grade peri-prosthetic lesion development, associated with pain and joint dysfunction and likely contributing to an increased burden of complex revision surgery. Despite being first reported in 2017, the 'at risk' genotype has only subsequently been described in selected metal-on-metal and revision arthroplasty cohorts and no population-level prevalence data has been reported. This novel epidemiologic pilot investigation aimed to explore allele-variant carriage frequencies of the previously-described 'at risk' HLA genotype in an undifferentiated orthopaedic population to inform larger screening investigations. Methods One hundred consecutive patients were prospectively recruited. Targeted HLA class II genotyping was performed using a medium-resolution Luminex-based approach, and secondary screening was performed to identify the presence of four specific alleles previously-associated with immune-mediated reactions to implanted metal devices. Results Our findings, in a non-differentiated orthopaedic cohort, suggest a carrier rate of the previously-defined 'at risk' allele of 38%, with 29% of those sampled carrying the defined 'at risk' genotype. Conclusion Our results show a higher-than-anticipated incidence of the 'at risk' gene and genotype. As genotype-associated ALTRs may contribute to patient dissatisfaction following primary joint replacements, the impact of this result may be greater than had previously been considered. While acknowledging the preliminary nature of these data, they may guide future screening applications of the genotyping analysis and will provide a foundation contribution-to-knowledge for future endeavou

关键词： HLA incompatible transplantation   kidney transplantation   immunoadsorption   positive CDC crossmatch   desensitization   cPRA   highly sensitized patients  

摘要： Background Kidney transplant (KT) candidates with very high calculated panel reactive alloantibody (cPRA >95%) have limited chances to receive an HLA-matched transplant unless they undergo pretransplant *** To assess the efficacy of immunoadsorption (IA) in desensitizing pretransplant KT candidates with high cPRA and positive *** and methods This was a single-center retrospective cohort study involving highly HLA-sensitized patients (cPRA >85%). Forty-nine patients underwent HLA-incompatible (HLAi) KT, of whom 25 (51%) received kidneys from deceased donors. Of these 49 patients, 23 had either a positive complement-dependent cytotoxic cross-match (CDC) and/or a positive flow cytometry cross-match (FCM). The remaining 26 patients had donor-specific anti-HLA (DSAs) detectable only by Luminex (CDC and FCM cross-matches were negative). Only CDC-positive and FCM-positive patients were desensitized. These 49 patients were compared with 160 patients who had cPRA >85% but underwent HLA-compatible (HLAc) KT, i.e., without pretransplant DSAs. Pretransplant desensitization included IA sessions, rituximab, tacrolimus, steroids, and mycophenolate mofetil. Induction therapy consisted of antithymocyte *** and methods This was a single-center retrospective cohort study involving highly HLA-sensitized patients (cPRA >85%). Forty-nine patients underwent HLA-incompatible (HLAi) KT, of whom 25 (51%) received kidneys from deceased donors. Of these 49 patients, 23 had either a positive complement-dependent cytotoxic cross-match (CDC) and/or a positive flow cytometry cross-match (FCM). The remaining 26 patients had donor-specific anti-HLA (DSAs) detectable only by Luminex (CDC and FCM cross-matches were negative). Only CDC-positive and FCM-positive patients were desensitized. These 49 patients were compared with 160 patients who had cPRA >85% but underwent HLA-compatible (HLAc) KT, i.e., without pretransplant DSAs. Pretransplant desens

关键词： airway inflammation   mitochondria   mitochondrial function   succinate dehydrogenase   TNF alpha  

摘要： Tumor necrosis factor-alpha (TNF alpha) is a pro-inflammatory cytokine, which mediates acute inflammatory effects in response to allergens, pollutants, and respiratory infections. Previously, we reported that TNF alpha increased maximum O-2 consumption rate (OCR) and mitochondrial volume density (MVD) in human airway smooth muscle (hASM) cells. However, TNF alpha decreased maximum OCR when normalized to mitochondrial volume. In addition, TNF alpha altered mitochondrial distribution and motility within hASM cells. Although high-resolution respirometry is valuable for assessing mitochondrial function, it overlooks mitochondrial structural and functional heterogeneity within cells. Therefore, a direct measurement of cellular mitochondrial function provides valuable information. Previously, we developed a confocal-based quantitative histochemical technique to determine the maximum velocity of the succinate dehydrogenase (SDH) reaction (SDHmax) in single cells and observed that cellular SDHmax corresponds with MVD. Therefore, we hypothesized that TNF alpha decreases SDHmax per mitochondrion in hASM cells. The hASM cells were treated with TNF alpha (20 ng/mL, 6 h, and 24 h) or untreated (time-matched control). Using three-dimensional (3-D) confocal imaging of labeled mitochondria and a concentric shell method for analysis, we quantified MVD, mitochondrial complexity index (MCI) and SDHmax relative to the nuclear membrane. Within each shell, SDHmax and MVD peaked in the perinuclear compartments and decreased toward the distal compartments of the cell. When normalized to mitochondrial volume, SDHmax decreased in the perinuclear compartments compared with distal compartments. TNF alpha caused a significant shift in mitochondrial morphometry and function compared to control. In conclusion, mitochondria within individual cells exhibit distinct morphological and functional heterogeneity, which is disrupted during acute inflammation. NEW & NOTEWORTHY Mitochondria show context-sp

关键词： interleukin 13   club cell   mucin   brain-derived neurotrophic factor   airway mechanics  

摘要： Introduction Brain-derived neurotrophic factor (BDNF) is a neural plasticity molecule that is increasingly recognized for its role in airway pathophysiology, including diseases like asthma. Although many cells in the airway can produce BDNF, our understanding of epithelial-derived BDNF and its role in airway health and disease remains *** In the current study, we studied male and female mice with conditional loss of Bdnf in airway club cells and challenged them intranasally with saline (vehicle control) or interleukin 13 (IL-13) for 4 days. We measured pulmonary mechanics and the abundance and secretion characteristics of the major secreted mucin glycoproteins, mucin 5B (Muc5b) and mucin 5ac (Muc5ac).Results Female mice with conditional loss of club cell Bdnf showed increased Muc5b protein in the airway epithelia under basal and IL-13-stimulated conditions compared to female mice with intact Bdnf. In contrast, conditional loss of club cell Bdnf in male mice augmented whole-lung Muc5ac mRNA levels under basal and IL-13-stimulated conditions. IL-13-treated female mice with conditional loss of club cell Bdnf showed decreased airway elastance in response to increasing concentrations of nebulized methacholine, suggesting that loss of club cell Bdnf had a protective effect. No statistically significant differences were observed in pulmonary mechanics between male mice with or without conditional loss of epithelial cell Bdnf, although treatment effects of IL-13 were noted. Mechanistic and complementary studies performed in NCI-H322 cells, a human cell line with "club cell-like" characteristics, failed to demonstrate a relationship among BDNF, IL-13 signaling, and Muc5ac at the mRNA *** These data highlight sex-dependent differences and club cell-specific effects of Bdnf in regulating airway physiology under inflammatory conditions in mice, suggesting that further studies are needed to understand potential translational implications.

关键词： NKG2D   CAR T   IL-15   pancreatic carcinoma   JAK/STAT5  

摘要： The application of CAR T therapy has significantly improved the efficacy of hematological tumors. However, there are still some challenges in the treatment of solid tumors, mainly because the complex immune microenvironment affects the proliferation of T cells, making T cells unable to function well. IL-15 has been reported to be a cytokine that can activate T cells and promote the proliferation and survival of T cells, especially CD8+ T cells. The complex formed by the high-affinity binding of IL-15 and IL-15R alpha can bind to IL-2/IL-15R beta/gamma heterodimer on the surface of T cells, thereby activating downstream signaling pathways in T cells. In this study, we explored the activity of NKG2D-CAR T expressing IL-15/IL-15R alpha complex (IL15C) on pancreatic cancer. The results of in vitro experiments showed that CAR T cells expressing IL15C had a stronger killing effect on tumor cells and showed a dose-dependent effect. In addition, the proliferation and anti-apoptosis levels of CAR T cells were enhanced after the co-expression of IL15C. IL15C regulates the function of T cells by activating the JAK/STAT5 signaling pathway of T cells. In vivo experiments showed that IL15C-NKG2D-CAR T cells could better inhibit tumor growth than the control group. This study provides a new idea for improving the efficacy of CAR T cells in the treatment of pancreatic cancer.

关键词： 血小板   病理性瘢痕   细胞因子   炎症   血管生成  

摘要： 病理性瘢痕是皮肤创伤愈合过程中的一种异常现象，目前病理性瘢痕的发病机制尚不明确，影响病理性瘢痕形成的因素主要包括创伤后炎症反应、血管形成、组织重塑及纤维化等过程。研究表明血小板在病理性瘢痕形成过程中发挥着重要作用。血小板是止血凝血的重要介质，活化的血小板通过脱颗粒释放细胞因子如转化生长因子-β（transforming growth factor-β，TGF-β）、血小板衍生生长因子（platelet derived growth factor，PDGF），表达膜表面蛋白如CD40配体（CD40L）、Toll样受体（Toll-like receptor， TLR）以及释放血小板微粒(platelet microparticles， PMPs)影响伤口愈合的多个阶段，其通过激活不同的信号通路，共同调控病理性瘢痕的发生与发展。近年来，研究发现抗血小板药物在缓解人体多脏器纤维化中具有积极意义，本文通过总结血小板在病理性瘢痕发病机制中的作用及研究进展，以期为病理性瘢痕的防治提供新思路。

关键词： autoimmunity   antigen presentation   B cells  

摘要： T cell tolerance to self can prevent self-reactive B cells from mounting effective autoimmune responses by limiting their available help. However, tolerance may be compromised during infection if small amounts of soluble cross-reactive pathogen antigens containing functional T cell epitopes are released for capture by activated B cells. Here, we assess this scenario and show that na & iuml;ve B cells engaged and activated by membrane-bound antigens lacking T helper epitopes are impaired in their ability to capture and present additional soluble antigens containing T helper epitopes. This limits their ability to acquire help from cognate CD4+ T cells required for effective antibody responses. Failure to capture and present soluble antigen is due to IgM and IgD downregulation when engaged with membrane-bound antigen. Interestingly, IgG+ B cells are not similarly constrained and effectively capture soluble antigens. Our findings suggest control of na & iuml;ve B cell tolerance partially depends on efficient receptor downregulation upon antigen engagement.

关键词： cetacean   conservation   harbour porpoise   Major Histocompatibility Complex   reference genome   whole-genome resequencing  

摘要： The Major Histocompatibility Complex (MHC) is a central element in the vertebrate immune system. While MHC genes are a common target of conservation genomic studies, it has been challenging to reliably amplify locus-specific alleles, which is especially problematic when studying endangered lineages, like some harbour porpoise (Phocoena phocoena) populations and subspecies. Here, we manually annotated all MHC II genes in the harbour porpoise genome and genotyped every exon 2 in 47 individuals (94 individuals for DRB1 and DQB genes) spanning six geographical regions, including the endangered Black Sea porpoise subspecies (Phocoena phocoena relicta) and the critically endangered Baltic proper population of the North Atlantic subspecies (P. p. phocoena). We performed gene-wise analyses of diversity and selection and put the results into perspective with 22 available harbour porpoise genomes. Furthermore, we characterised all MHC II genes in 19 available long-read genomes of cetaceans and terrestrial outgroups to study the MHC II evolution across the cetacean diversification. From the 10 MHC II loci annotated in the harbour porpoise genome, two (DRB1 and DQB) exhibited inflated allelic diversity and signatures of positive selection. Interestingly, DRB genes followed different evolutionary trajectories in mysticetes and odontocetes. Our results have significant conservation implications since we identified reduced MHC II diversity in the endangered Black Sea subspecies and provide a case study for reliable MHC II genotyping in other species. Further, our study demonstrates the need for long-read genomes to understand the genomic architecture of MHC and to accurately assess its diversity and evolution.