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8 recordsLinked to original sources
PubMed1977

Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage.

Glucose-6-phosphate dehydrogenase (G-6-PD) isoenzymes types of granulocytes were determined in eight women with chronic myelocytic leukemia (CML). The patients were heterozygous at the X-linked G-6-PD locus for the common gene, GdB, and a variant, such as GdA, so that both B and A enzyme types were found in skin cells. In contrast to these normal cells, only one G-6-PD type was found in CML granulocytes. The fact that such single-enzyme phenotypes are found in CML granulocytes, but not in nonleukemic granulocytes, provides strong evidence that the disease has a clonal origin. Single-enzyme phenotypes were also found in erythrocytes, platelets and cultured blood macrophages indicating that these cells have a common stem cell which is the site of the abnormality in CML. In the one studied patient, no evidence was found for involvement of cultured marrow fibroblasts. Clonal origin of CML virtually excludes cell recruitment as a sole pathogenetic mechanism. Either the leukemia arises as a consequence of a rare initial event in a single cell, or a series of events occurs in a clone such that it evolves into CML, or both.

Adolescent↗
PubMed1978

Specificity of Fc-receptors on lymphocytes and monocytes for guinea-pig IgG1 and IgG2: phagocytosis of erythrocytes.

The capacity of guinea-pig IgG1 and IgG2 antibodies to induce lymphocyte (K-cell) mediated lysis or monocyte/macrophage mediated phagocytosis of erythrocytes was studied with both human and guinea-pig effector cells. For both species, induction of K-cell mediated lysis was restricted to IgG2 whereas both IgG1 and IgG2 could induce monocyte/macrophage mediated phagocytosis. In competitive inhibition experiments, only complexed IgG2 inhibited lysis mediated by K-cells. The results suggest that the fc-receptors on K-cells only recognize IgG2. In contrast, complexes of both subclasses inhibited phagocytosis by human monocytes, regardless of the subclass of the inducing antibodies. Inhibition of guinea-pig macrophage mediated phagocytosis by IgG2 complexes was also independent of the inducing antibody. Hence, Fc-receptors common for IgG1 and IgG2 seem to be involved in themonocyte/macrophage mediated effector reaction. Free IgG1 was significantly less ingibitory than free IgG2 for human monocytes and hardly at all for guinea-pig macrophages. However, free IgG2, which was cytophilic for these cells, was more aggregated than IgG1. Thus, both molecular structure and state of aggregation determine interaction of IgG with cellular Fc-receptors.

Animals↗
PubMed2025

Sex as a modifier of genetic risk for type 1 diabetes.

Sex differences influence the pathogenesis of type 1 diabetes (T1D), yet most genetic studies have treated sex as a control covariate rather than a dynamic effect modifier. Sex influences immune cell behaviour, including CD4+ and CD8+ T cell activation, regulatory T cell stability, B cell autoantibody production, dendritic cell priming and monocyte/macrophage inflammation. Underlying mechanisms include hormone-responsive enhancers, X-escape gene dosage and sex-biassed chromatin states, intersecting with T1D-associated variants to produce sex-specific immune phenotypes. These insights help explain regional variation in sex ratios of T1D incidence, such as male predominance in high-risk populations and female excess in low-risk populations. Biological sex shapes T1D risk across multiple layers, including polygenic load; environmental exposures such as vitamin D deficiency and enteroviral infection; and sex-specific hormonal, chromosomal and epigenetic influences. An integrative G × E × S (genetic × environmental × sex-specific) liability-threshold framework is thus supported. Clinical and translational implications include developing sex-specific polygenic risk scores, biomarker panels and interventional strategies targeting pathways such as hormone signalling, vitamin D metabolism and the microbiome. Future multi-omic, longitudinal studies are warranted to test genotype-sex interactions, integrate sex as a core effect modifier and enable precision prevention and treatment of T1D in both males and females.

Humans↗
PubMed2026

Impaired Glycolysis Leads to Defective Efferocytosis and Impaired Plaque Resolution in Tet2 Clonal Hematopoiesis.

BACKGROUND: Clonal hematopoiesis (CH) arising from mutations in hematopoietic genes has been identified as an important risk factor for atherosclerotic cardiovascular disease. Despite the established role of some CH mutations in promoting atherosclerosis progression, their role in clinically relevant LDL (low-density lipoprotein) lowering-induced plaque remodeling or regression has not been extensively studied. METHODS: To assess the effects of TET2 (tet methylcytosine dioxygenase 2) CH on plaque resolution, we prepared control or chimeric Tet2+/- CH mice with conditional deletion of Tet2 in hematopoietic stem cells during LDL lowering-induced plaque remodeling. After establishing atherosclerosis by Western diet feeding for 12 weeks in Ldlr-/- mice, Tet2 was deleted by tamoxifen injection, and hypercholesterolemia was either normalized to simulate clinical lipid management, or mice were continued on the Western diet. RESULTS: Unlike control mice, Tet2+/- CH mice failed to significantly reduce necrotic core area or increase fibrous cap thickness and showed impaired macrophage efferocytosis during LDL lowering. Single-cell RNA sequencing and gene set enrichment analysis of aortic cell populations revealed that Tet2 deficient monocyte/macrophage populations were defective in glycolysis, phagocytosis, and actin polymerization. Tet2-deficient bone marrow-derived macrophages and Tet2+/- induced pluripotent stem cell-derived human macrophages showed defective ability to sustain continuing rounds of efferocytosis. Bone marrow-derived macrophages displayed reduced apoptotic cell binding and internalization and impaired activity of Wiskott-Aldrich syndrome protein and SCAR (suppressor of cyclic AMP receptor) homolog complex mediated actin polymerization. We linked these defects to reduced anaerobic glycolysis and lactate levels and rescued them by lactate supplementation or by treatment with the HIF-1α (hypoxia-inducible factor 1α) activator molidustat. Molidustat treatment reversed the defects in necrotic core and fibrous cap formation during LDL lowering-induced plaque remodeling in Tet2+/- CH mice. Reduced plasma lactate levels were also shown in TET2 clonal hematopoiesis of indeterminate potential carriers in the UK Biobank. CONCLUSIONS: Our data identify impaired efferocytosis and glycolysis-lactate-actin polymerization pathways in advanced atherosclerosis as potential therapeutic targets to induce proresolving restructuring of the plaque immune cells and to promote beneficial atherosclerosis remodeling in subjects with TET2 CH.

LDL lowering↗
PubMed2026

Integrated Pan-Cancer, Single-Cell, and Spatial Transcriptomic Analyses Identify ZDHHC12 as a Biomarker Associated with Macrophage Infiltration and the Immune Landscape in Glioma.

BACKGROUND: The tumor immune microenvironment (TME) critically influences cancer progression and therapeutic response. However, the pan-cancer expression landscape, prognostic relevance, and spatial distribution of ZDHHC12 remain incompletely characterized. This study investigated the prognostic value of ZDHHC12 and its associations with immune microenvironmental features and drug sensitivity. METHODS: Data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets were used to evaluate ZDHHC12 expression and prognosis across cancer types. Immune infiltration analyses, single-cell RNA sequencing, and spatial transcriptomics were integrated to characterize the associations of ZDHHC12 with the cancer immunity cycle and the spatial architecture of glioma. Drug sensitivity and immunotherapy-related metrics were assessed using pharmacogenomic databases and computational prediction models. RESULTS: ZDHHC12 was aberrantly expressed across multiple tumors and was associated with patient prognosis. Its expression was broadly correlated with immune cell recruitment- and activation-related signatures. In glioma, single-cell and spatial transcriptomic analyses showed enrichment of ZDHHC12 in monocyte/macrophage populations and spatial co-localization with BAK1, CD68, and CD163. ZDHHC12 expression was also associated with predicted drug sensitivity and immunotherapy-related metrics. CONCLUSION: ZDHHC12 may serve as a candidate pan-cancer prognostic biomarker. In glioma, its expression is associated with macrophage-enriched and immunosuppressive microenvironmental features. Functional studies are required to establish causality and determine its therapeutic relevance.

GBM↗
PubMedDate not supplied

The effect of Corynebacterium parvum on the proliferation of monocyte precursors in the bone marrow of mice.

The anti-tumour activity of C. parvum is thought to be mediated via the monocyte/macrophage system (Scott, 1974). These cells originate from rapidly dividing precursors in the bone marrow and it might be at this level that C. parvum exerts its action. To test this hypothesis bone marrow T0 Swiss mice has been cultured according to the method of Bradley and Metcalf (1966), which gives an index of the number of proliferating macrophage precursor cells at the time of sacrifice. Experiments were set up at various times following a single i.p. injection of 700 microgram of an anti-tumour strain of C. parvum (CN 6134-Wellcome Research Laboratories). Controls received 700 microgram of either C. diphtheriae CN 2000 or C. parvum CN 5888, a strain with no anti-tumour activity. Macrophage colony counts in those mice receiving "active" C. parvum were significantly higher than those in controls at intervals from 2 h to 3 weeks post-treatment. This time course parallels certain immunological properties of C. parvum and suggests a possible mode of action.

Animals↗
PubMed2025

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

Setdb2↗