RepoMed (Medizinische Hochschule Hannover)
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Comparative analysis of albumin quotient and total CSF protein in immune-mediated neuropathies: a multicenter study on diagnostic implications
No full textIntroduction Blood-cerebrospinal fluid (CSF) barrier dysfunction is pivotal for diagnosing immune-mediated neuropathies, especially in spinal nerve root inflammation. Typically, either total CSF protein or the CSF to serum albumin ratio (QAlb) is measured. Total CSF protein measurements have limitations, notably its fixed reference value regardless of age, in contrast to the age-dependent reference for QAlb. Our goal was to evaluate both markers in patients with immune-mediated neuropathies. Methods In our multicenter research, we collected retrospective CSF data from patients suffering from immune-mediated neuropathies across four German research centers. These parameters were analyzed in relation to their clinical characteristics. Results Out of 419 samples, 36 (8.6%) displayed a notable variation between total CSF protein and QAlb values. A detailed analysis revealed that patients displaying elevated QAlb but normal total CSF protein levels were significantly younger at disease onset (p = 0.01), at the time of diagnosis (p = 0.005), and when undergoing lumbar puncture (p = 0.001) compared to patients with elevated CSF protein and normal QAlb levels. These effects were especially evident for the subgroup of samples derived by female patients. Discussion Our work confirms the crucial role of QAlb in diagnosing immune-mediated neuropathies and particularly its efficacy as a marker for evaluating the blood-CSF barrier in patients with an earlier disease onset. Considering the significance of the albumin quotient, its assessment is especially advisable in younger patients of female sex to avoid missing a potential barrier dysfunction that might be falsely negative when using total protein
Role of Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in inflammation and pathogen-associated interactions
No full textLectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is known as a major receptor for oxidized low-density lipoproteins (oxLDL) and plays a significant role in the genesis of atherosclerosis. Recent research has shown its involvement in cancer, ischemic stroke, and diabetes. LOX-1 is a C-type lectin receptor and involved in the activation of immune cells and inflammatory processes. It may further interact with pathogens, suggesting a role in infections or the host's response. This review compiles the current knowledge of potential implications of LOX-1 in inflammatory processes and in host-pathogen interactions with a particular emphasis on its regulatory role in immune responses. Also discussed are genomic and structural variations found in LOX-1 homologues across different species as well as potential involvements of LOX-1 in inflammatory processes from the angle of different cell types and organ-specific interactions. The results presented reveal both similar and different structures in human and murine LOX-1 and provide clues as to the possible origins of different modes of interaction. These descriptions raise concerns about the suitability, particularly of mouse models, that are often used in the analysis of its functionality in humans. Further research should also aim to better understand the mostly unknown binding and interaction mechanisms between LOX-1 and different pathogens. This pursuit will not only enhance our understanding of LOX-1 involvement in inflammatory processes, but also identify potential targets for immunomodulatory approaches
Influence of titin variants on myocardial function in a 3D disease model of Peripartum Cardiomyopathy using human induced pluripotent stem cells
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Exploiting the immune modulatory properties of stem cell derived macrophages in therapeutic and pharmaceutical applications
No full textTranscription factor Tfap2a orchestrates a gene regulatory network mediating renal collecting duct cell differentiation and tubular architecture
No full textThese are primary data used for creating the figures of Leiz J, et al. 2024 (manuscript under revision). Transcription factor Tfap2a orchestrates a gene regulatory network mediating renal collecting duct cell differentiation and tubular architecture. Background: Mutations of the transcription factor TFAP2A are associated with congenital anomalies of the kidney and urinary tract in humans. Tfap2a knockout in mouse collecting ducts causes tubular epithelial abnormalities, but the detailed molecular functions of Tfap2a in the kidney tubules are unknown. Methods: We investigated gene regulatory networks regulated by Tfap2a in mouse kidney collecting ducts through a combination of gene knockout and transcriptomics approaches. Conditional Tfap2a knockout (KO) mice (Hoxb7-Cre; Tfap2aflox/flox) underwent detailed histomorphological and physiological examinations. Single-nucleus and bulk RNA-sequencing data, and in situ hybridizations of adult Tfap2a KO mouse kidneys were integrated with in silico Tfap2a motif mapping in existing ATAC-seq datasets. Results: Tfap2a expression and its motif activity were high in normal mouse collecting duct principal cells according to integrated transcriptomics, chromatin occupancy analyses, and in situ hybridization. Histomorphological analyses of collecting duct-specific Tfap2a KO mice indicated a progressive postnatal tubular dilation of outer medullary collecting ducts. Integrative analyses combining existing ATAC-seq datasets with newly generated single-nucleus RNA-sequencing data from the kidneys of 3-month-old Tfap2a KO mice and littermate controls identified deregulated expression of genes involved in cell adhesion and WNT signaling pathways, including Alcam (a cell adhesion molecule) and Wnt9b (a non-canonical WNT). These findings were orthogonally validated by in situ hybridization. Conclusions: Tfap2a controls tubular diameter and epithelial differentiation in mouse collecting ducts by controlling a regulatory network that includes Wnt9b and Alcam
Human CFTR deficient iPSC-macrophages reveal impaired functional and transcriptomic response upon Pseudomonas aeruginosa infection
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Histamine and Th2 cytokines independently and synergistically upregulate MMP12 expression in human M2 macrophages
No full textBeyond Th2 cells and various immune cells, M2 macrophages have been identified in lesional skin of atopic dermatitis (AD) indicating their involvement in the disease's underlying mechanisms. MMP12, a matrix-degrading enzyme, which is predominantly produced by macrophages, is increased in skin lesions of AD patients. In this study we investigated the expression of MMP12 mRNA in lesional AD skin at single cell level through RNA sequencing (scRNA-seq) and the expression of MMP12 in M2 macrophages from healthy individuals and AD patients in response to Th2 cytokines and histamine using quantitative PCR and ELISA. Additionally, we analyzed macrophages from dupilumab-treated AD patients using the same methods to assess the influence of Th2 cytokines on MMP12 expression ex-vivo. ScRNA-seq identified macrophages as the primary producers of MMP12 in lesional AD skin. In-vitro, both MMP12 mRNA and protein expression were significantly increased in monocytes during differentiation to M2 macrophages in the presence of histamine, of Th2 cytokines or of Th2 cytokines in combination with histamine. In M2 macrophages obtained from dupilumab-treated AD patients, the upregulation of MMP12 expression by IL-4 and IL-13 was attenuated. Our findings unveil a novel mechanism whereby Th2 cytokines and histamine regulate MMP12 expression, potentially impacting skin barrier homeostasis in AD