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MOG antibody non-P42 epitope is associated with a higher risk of relapse in paediatric MOGAD
Get PDFBACKGROUND: Biomarkers for predicting myelin oligodendrocyte glycoprotein antibody (Ab)-associated disease (MOGAD) clinical course are still missing. Binding capacity to a mutant MOG protein variant (MOG-P42S; non-P42) was shown to correlate with an increased relapse risk in adult patients.The objective of our study was to assess the frequency of binding to the non-P42 MOG variant in a cohort of paediatric MOGAD and to investigate its association with specific clinical profiles and disease course. METHODS: We included children with MOG-Ab seropositive samples collected after their first demyelinating episode from five different centres. We performed live cell-based assays with native full-length MOG (MOG-FL) and mutant MOG-P42S and correlated the results with clinical data. RESULTS: Of the 81 MOG-FL identified patients serum, 40 bound the non-P42 MOG. Non-P42 patients exhibited an earlier median age of onset (p=0.002). Phenotype distribution was different between groups (p=0.001), with non-P42 patients predominantly exhibiting acute disseminated encephalomyelitis phenotype. Notably, the non-P42 group was associated with a higher relapse rate (relative rate: 2.6 (95% CI 1.1 to 6.2), p=0.03), adjusted for clinical phenotype. CONCLUSION: Non-P42 is a promising biomarker for predicting relapse in paediatric MOGAD patients
Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses
No full textMacrophages specialize in phagocytosis, a cellular process that eliminates extracellular matter, including microorganisms, through internalization and degradation. Despite the critical role of phagocytosis during bacterial infection, the fate of phagocytosed microbial cargo and its impact on the host cell are poorly understood. In this study, we show that ingested bacteria constitute an alternative nutrient source that skews immunometabolic host responses. By tracing stable isotope-labelled bacteria, we found that phagolysosomal degradation of bacteria provides carbon atoms and amino acids that are recycled into various metabolic pathways, including glutathione and itaconate biosynthesis, and satisfies the bioenergetic needs of macrophages. Metabolic recycling of microbially derived nutrients is regulated by the nutrient-sensing mechanistic target of rapamycin complex C1 and is intricately tied to microbial viability. Dead bacteria, as opposed to live bacteria, are enriched in cyclic adenosine monophosphate, sustain the cellular adenosine monophosphate pool and subsequently activate adenosine monophosphate protein kinase to inhibit the mechanistic target of rapamycin complex C1. Consequently, killed bacteria strongly fuel metabolic recycling and support macrophage survival but elicit decreased reactive oxygen species production and reduced interleukin-1β secretion compared to viable bacteria. These results provide a new insight into the fate of engulfed microorganisms and highlight a microbial viability-associated metabolite that triggers host metabolic and immune responses. Our findings hold promise for shaping immunometabolic intervention for various immune-related pathologies
Diagnostik und Therapie der ANCA-assoziierten Vaskulitiden: Kurzversion der S3-Leitlinie der Deutschen Gesellschaft für Rheumatologie und Klinische Immunologie e. V. (DGRh) und Deutschen Gesellschaft für Innere Medizin e. V. (DGIM), Deutschen Gesellschaft für Nephrologie e. V. (DGfN), Deutschen Gesellschaft für HNO-Heilkunde und Kopf-Hals-Chirurgie e. V. (DGHNO-KHC), Deutschen Ophthalmologischen Gesellschaft e. V. (DOG), Deutschen Gesellschaft für Neurologie e. V. (DGN), Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V. (DGP), Deutschen Gesellschaft für Pathologie e. V. (DGP), Deutschen Röntgengesellschaft, Gesellschaft für Medizinische Radiologie e. V. (DRG), Bundesverband Deutscher Pathologen, Bundesverband Niere e. V., Deutschen Rheuma-Liga Bundesverband e. V. [Diagnosis and treatment of ANCA-associated vasculitis: short version of the S3 guideline of the German Society for Rheumatology and Clinical Immunology e. V. (DGRh) and German Society for Internal Medicine e. V. (DGIM), German Society for Nephrology e. V. (DGfN), German Society for Otorhinolaryngology and Head and Neck Surgery e. V. (DGHNO-KHC), German Ophthalmological Society e. V. (DOG), German Society for Neurology e. V. (DGN), German Society for Pneumology and Respiratory Medicine e. V. (DGP), German Society for Pathology e. V. (DGP), German Radiological Society, Society for Medical Radiology e. V. (DRG), Federal Association of German Pathologists, Federal Kidney Association e. V., German Rheumatism League Federal Association e. V.]
No full textVasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) is a rare disease with a potentially severe course. Affected patients should be diagnosed as quickly as possible and given suitable treatment according to the current study situation. Considerable progress has been made in the treatment of this disease in recent years, so that a largely evidence-based therapy with immunosuppressants and biologics is now possible. The guideline on the diagnosis and treatment of ANCA-associated vasculitis was raised from S1 level (2017) to S3 level. This guideline is the first German guideline on the diagnosis and treatment of ANCA-associated vasculitis at S3 level
Self-limited, sodium-dependent osmotic diuresis causes polyuria after living donor kidney transplantation
Get PDFBACKGROUND AND HYPOTHESIS: Polyuria, defined as urine output exceeding 3 l per day, is common following living donor kidney transplantation, yet its frequency and mechanisms are unclear. This study investigates the pathophysiology and potential recipient- or donor-specific factors influencing post-transplantation polyuria. METHODS: We retrospectively evaluated 35 consecutive living donor kidney transplantations performed at the University Medical Center Marburg between 2018 and 2024. Clinical and laboratory characteristics of recipients and donors as well as the daily routine blood tests and 24-hour urine collections of the first 10 days post-transplantation were analyzed. RESULTS: Polyuria occurred in 69.7% of recipients on the first day post-transplantation, independent of residual diuresis, ischemia time, or donor pre-transplantation urine volume. Urine output decreased to normal within 10 days, with no differences in serum creatinine or urinary kidney injury markers between polyuric and non-polyuric patients. Mechanistically, polyuria was driven by sodium-dependent osmotic diuresis, with sodium excretion being the sole decisive driver of early post-transplantation urine volume. CONCLUSIONS: Polyuria after living donor kidney transplantation occurred in nearly 70% of cases without affecting short-term graft function and is explained by sodium-dependent osmotic diuresis. No donor- or recipient-specific predictors could be identified. Careful volume management is crucial in managing this condition
Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration
Get PDFThe colon epithelium frequently incurs damage through toxic influences. Repair is rapid, mediated by cellular plasticity and acquisition of the highly proliferative regenerative state. However, the mechanisms that promote the regenerative state are not well understood. Here, we reveal that upon injury and subsequent inflammatory response, IFN-γ drives widespread epithelial remodeling. IFN-γ promotes rapid apoptotic extrusion of fully differentiated surface colonocytes, while simultaneously causing differentiation of crypt-base stem and progenitor cells towards a colonocyte-like lineage. However, unlike homeostatic colonocytes, these IFN-γ-induced colonocytes neither respond to nor produce BMP-2 but retain regenerative capacity. The reduction of BMP-2-producing epithelial surface cells causes a remodeling of the surrounding mesenchymal niche, inducing high expression of HGF, which promotes proliferation of the IFN-γ-induced colonocytes. This mechanism of lineage replacement and subsequent remodeling of the mesenchymal niche enables tissue-wide adaptation to injury and efficient repair
Clonal lineage tracing of innate immune cells in human cancer
Get PDFInnate immune cells constitute the majority of the tumor microenvironment (TME), where they mediate both natural anti-tumor immunity and immunotherapy responses. While single-cell T- and B-cell receptor sequencing has provided fundamental insights into the clonal dynamics of human adaptive immunity, the lack of appropriate tools has precluded similar analysis of innate immune cells. Here, we describe a method that leverages somatic mitochondrial DNA (mtDNA) mutations to reconstruct clonal lineage relationships between single cells across cell types in native human tissues. We jointly sequenced single-cell transposase-accessible chromatin and mtDNA to profile n=124,958 cells from matched tumor, non-involved lung tissue (NILT), and peripheral blood of early-stage non-small cell lung cancer (NSCLC) patients, as well as n=93,757 cells from matched tumor and peripheral blood of ovarian cancer patients. Single-cell concomitant profiling of lineage and cell states of thousands of immune cells resolved clonality across cell types, tissue sites, and malignancies. Clonal tracing of innate immune cells demonstrates that TME-resident myeloid subsets, including macrophages and type 3 dendritic cells (DC3), are clonally linked to both circulating and tissue-infiltrating monocytes. Further, we identify distinct DC-biased and macrophage-biased myeloid clones, enriched in the tumor and NILT, respectively, and find that their circulating monocyte precursors exhibit distinct epigenetic profiles, suggesting that myeloid differentiation fate may be predetermined before TME infiltration. These results delineate the clonal pathways of intratumoral myeloid cell recruitment and differentiation in human cancer and suggest that remodeling of the tumor myeloid compartment may be peripherally programmed
Charting the path in rodent functional neuroimaging
Get PDFDriven by a period of accelerated progress and recent technical breakthroughs, whole- brain functional neuroimaging in rodents offers exciting new possibilities for addressing basic questions about brain function and its alterations. In response to lessons learned from the human neuroimaging community, leading scientists and researchers in the field convened to address existing barriers and outline ambitious goals for the future. This article captures these discussions, highlighting a shared vision to advance rodent functional neuroimaging into an era of increased impact
How vascularization is reciprocally coupled to chondrogenesis and osteogenesis in bone healing: lessons from the growth plate
Get PDFDespite considerable progress, the underlying mechanisms that enable scar-free regeneration in bone after injury are still not well understood. Here, we compared the spatiotemporal distribution of SOX9-positive chondrocytes, SPARC-positive hypertrophic chondrocytes and osteoblasts, versus Osterix-positive osteoblasts, i.e. key cell types in cartilage and bone formation, in the fracture gap of a mouse osteotomy model with the orderly sequence of events observed in the growth plate. We show that external mechanical stability determines the spatial distribution of osteoblastic and chondrogenic cell populations at day 7, thus defining the site of chondrogenesis initiation. At day 14, only rigid, but not semi-rigid fixation promoted the formation of avascular regions within previously vascularized areas. We thus propose a model how mechanical stabilization promotes bone healing: Blood vessel growth into the hematoma is followed by localized vascular degradation as chondrogenesis progresses, ultimately leading to vascular regrowth via endochondral ossification initiated at the tips of the distal bones. Deepening our understanding of these processes and how they ultimately relate to scar-free bone regeneration is of significant medical relevance as they can provide instructions how to promote fracture healing
Advanced peptide nanoparticles enable robust and efficient delivery of gene editors across cell types
Get PDFEfficient delivery of the CRISPR/Cas9 system and its larger derivatives, base editors, and prime editors remain a major challenge, particularly in tissue-specific stem cells and induced pluripotent stem cells (iPSCs). This study optimized a novel family of cell-penetrating peptides, hPep, to deliver gene-editing ribonucleoproteins. The hPep-based nanoparticles enable highly efficient and biocompatible delivery of Cre recombinase, Cas9, base-, and prime editors. Using base editors, robust and nearly complete genome editing was achieved in the human cells: HEK293T (96%), iPSCs (74%), and muscle stem cells (80%). This strategy opens promising avenues for ex vivo and, potentially, in vivo applications. Incorporating silica particles enhanced the system’s versatility, facilitating cargo-agnostic delivery. Notably, the nanoparticles can be synthesized quickly on a benchtop and stored as lyophilized powder without compromising functionality. This represents an important advancement in the feasibility and scalability of gene-editing delivery technologies