Paraneoplastic Anti-3-hydroxy-3-methylglutary-coenzyme A Reductase Antibody-positive Immune-mediated Necrotizing Myopathy in a Patient with Uterine Cancer.
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ABSTRACT:
SUBMITTER: Mizuma A
PROVIDER: S-EPMC5548690 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:ObjectiveAutoantibodies recognizing 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) are found in patients with statin-associated immune-mediated necrotizing myopathy and, less commonly, in statin-unexposed patients with autoimmune myopathy. The main objective of this study was to define the association of anti-HMGCR antibody levels with disease activity.MethodsAnti-HMGCR levels, creatine kinase (CK) levels, and strength were assessed in anti-HMGCR-positive patients. Associations of antibody level with CK level and strength at visit 1 were analyzed in 55 patients, 40 of whom were exposed to statins. In 12 statin-exposed and 5 statin-unexposed patients with serum from 5 serial visits, the evolution of antibody levels, CK levels, and strength was investigated.ResultsAntibody levels were associated with CK levels (P < 0.001), arm strength (P < 0.05), and leg strength (P < 0.05) at visit 1, but these associations were only significant among statin-exposed patients in stratified analyses. With immunosuppressive treatment over 26.2 ± 12.6 months (mean ± SD), antibody levels declined (P < 0.05) and arm abduction strength improved (P < 0.05) in the 17 patients followed up longitudinally. The separate analysis showed that statin-exposed patients developed decreased antibody levels (P < 0.01), decreased CK levels (P < 0.001), improved arm strength (P < 0.05), and improved hip flexion strength (P < 0.05) with treatment. Anti-HMGCR antibody levels did not normalize in any patient.ConclusionIn the entire cohort, initial anti-HMGCR levels correlated with indicators of disease activity; with immunosuppressive treatment, antibody levels declined and arm strength improved. Statin-exposed patients had significant improvements in CK levels and strength whereas statin-unexposed patients did not, suggesting a phenotypic difference between statin-exposed and statin-unexposed anti-HMGCR-positive patients.
| S-EPMC3510338 | biostudies-literature
Project description:In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necrotizing myopathy (IMNM), with autoantibodies that recognize ?200-kd and ?100-kd autoantigens. The purpose of this study was to identify these molecules to help clarify the disease mechanism and facilitate diagnosis.The effect of statin treatment on autoantigen expression was addressed by immunoprecipitation using sera from patients. The identity of the ?100-kd autoantigen was confirmed by immunoprecipitation of in vitro-translated 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) protein. HMGCR expression in muscle was analyzed by immunofluorescence. A cohort of myopathy patients was screened for anti-HMGCR autoantibodies by enzyme-linked immunosorbent assay and genotyped for the rs4149056 C allele, a predictor of self-limited statin myopathy.Statin exposure induced expression of the ?200-kd/?100-kd autoantigens in cultured cells. HMGCR was identified as the ?100-kd autoantigen. Competition experiments demonstrated no distinct autoantibodies recognizing the ?200-kd protein. In muscle biopsy tissues from anti-HMGCR-positive patients, HMGCR expression was up-regulated in cells expressing neural cell adhesion molecule, a marker of muscle regeneration. Anti-HMGCR autoantibodies were found in 45 of 750 patients presenting to the Johns Hopkins Myositis Center (6%). Among patients ages 50 years and older, 92.3% had taken statins. The prevalence of the rs4149056 C allele was not increased in patients with anti-HMGCR.Statins up-regulate the expression of HMGCR, the major target of autoantibodies in statin-associated IMNM. Regenerating muscle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. These studies demonstrate a mechanistic link between an environmental trigger and the development of sustained autoimmunity. Detection of anti-HMGCR autoantibodies may facilitate diagnosis and direct therapy.
| S-EPMC3335400 | biostudies-literature
Project description:Background: The therapeutic regimen of immune-mediated necrotizing myopathy (IMNM), a category of immune-related myopathies featuring progressive proximal muscle weakness and extremely high level of serum creatine kinase, remains a formidable barrier for clinicians. The proposed study intended to investigate new diagnostic biomarkers based on high-throughput sequencing data of IMNM and generate novel IMNM management strategies by bioinformatics technology. Methods: Eighteen IMNM patients were synthesized in a local sequencing cohort (high-throughput sequencing data) with Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis to pinpoint robust IMNM-related differentially expressed genes (DEGs). The definitive feature genes were categorized by employing the protein-protein interaction (PPI) network, Least Absolute Shrinkage Selection Operator (LASSO), and support vector machine recursive feature elimination (SVM-RFE), and their sample discriminatory utility was appraised by obtaining the area under the curve (AUC) of the receiver operating curve (ROC) curve. The expression difference of key genes was verified by quantitative real-time polymerase chain reaction (qRT-PCR). Enrichment analysis of predefined gene sets disclosed the hidden functions of diagnostic DEGs. The 28 immune cell abundance patterns in the IMNM cohort were measured using single-sample gene set enrichment analysis (ssGSEA). Results: We recognized 193 genes that were aberrantly upregulated in the IMNM population and were firmly affiliated with immune-inflammatory responses, regulation of skeletal and cardiac muscle contraction and lipidprotein metabolism. LTK, MYBPH, and MYL4 were authenticated as diagnostic markers for IMNM (all AUC = 1.00), and functional enrichment analysis highlighted that these genes were notably integrated with immune-inflammatory response, autophagy-lysosome pathway and myofiber differentiation and regeneration. Ultimately, ssGSEA revealed a pronounced immune cell infiltrative microenvironment in the IMNM population. The results revealed the most significant relationship among CD4 T cells, CD8 T cells, macrophages, natural killer cells, T helper cells, Th17 cells and dendritic cells. Conclusion: LTK, MYBPH, and MYL4 might be served as diagnostic molecules for IMNM and possibly yield innovative insights into the mechanisms of progression and therapeutic options for IMNM in the future.
2024-09-30 | GSE213055 | GEO
Project description: Not available
| S-EPMC4999323 | biostudies-literature
Project description:The regulation of 3-hydroxy-3-methylglutaryl-CoA reductase was studied in mouse uterine epithelium. The enzyme was rapidly inactivated during incubation with ATP/Mg2+ in vitro, and could be re-activated by incubation with partially purified rat liver phosphoprotein phosphatase. Enzyme activity was rapidly inhibited by mevalonate injection in vivo to approx. 30% of control. The percentage of total enzyme active in vivo was measured by inclusion of NaF in the isolation buffers. The percentage of enzyme active in vivo 18 h after stimulation by oestrogens remained at approx. 25% after inhibition of activity by mevalonate injection, cholesterol feeding or progesterone pretreatment. However, 9 h after oestrogen stimulation, cholesterol feeding inhibited enzyme activity to 57% of control, 94% of which was in the active form. We conclude that, although all components for a reversible phosphorylative regulation of 3-hydroxy-3-methylglutaryl-CoA reductase activity are present in uterine epithelial cells, a role in the rapid changes in epithelial enzyme activity has not been demonstrated.
| S-EPMC1147553 | biostudies-other
Project description:The characteristics of 3-hydroxy-3-methylglutaryl-CoA reductase from mouse uterine epithelial cells were studied. Preliminary experiments showed that enzyme activity was stimulated approx. 10-fold 18h after administration of 100ng of oestradiol-17 beta. This activity was associated with all particulate fractions of the uterine luminal cell. The Km for D-3-hydroxy-3-methylglutaryl-CoA was 5.54 +/- 1.12 microM. The detailed time-course of oestrogen stimulation showed two peaks of activity, 9 and 15h after hormone treatment. The DNA content of the epithelial cells doubled between 6 and 12h after hormone treatment, whereas the protein content increased linearly over the 18h period. The peak of enzyme activity at 9h is associated with early S phase of the epithelial cells; the peak at 15h may be associated with a second S phase or with mitosis. Pretreatment with progesterone for 3 days before injection of oestradiol-17 beta (a treatment which inhibits uterine epithelial DNA synthesis) reduced the oestrogenic stimulation of enzyme activity by 63%; progesterone treatment alone did not stimulate enzyme activity. These data suggest that uterine epithelial 3-hydroxy-3-methylglutaryl-CoA reductase may play an important role in the cell cycle in this tissue.
| S-EPMC1153414 | biostudies-other
Project description:In this study, we take advantage of the ability of HMG-CoA reductase (HMGR) from Pseudomonas mevalonii to remain active while in its crystallized form to study the changing interactions between the ligands and protein as the first reaction intermediate is created. HMG-CoA reductase catalyzes one of the few double oxidation-reduction reactions in intermediary metabolism that take place in a single active site. Our laboratory has undertaken an exploration of this reaction space using structures of HMG-CoA reductase complexed with various substrate, nucleotide, product, and inhibitor combinations. With a focus in this publication on the first hydride transfer, our structures follow this reduction reaction as the enzyme converts the HMG-CoA thioester from a flat sp(2)-like geometry to a pyramidal thiohemiacetal configuration consistent with a transition to an sp(3) orbital. This change in the geometry propagates through the coenzyme A (CoA) ligand whose first amide bond is rotated 180° where it anchors a web of hydrogen bonds that weave together the nucleotide, the reaction intermediate, the enzyme, and the catalytic residues. This creates a stable intermediate structure prepared for nucleotide exchange and the second reduction reaction within the HMG-CoA reductase active site. Identification of this reaction intermediate provides a template for the development of an inhibitor that would act as an antibiotic effective against the HMG-CoA reductase of methicillin-resistant Staphylococcus aureus.
| S-EPMC4007485 | biostudies-literature
Project description:ObjectiveWe examined a cohort of Australian patients with statin exposure who developed a necrotizing autoimmune myopathy (NAM) associated with a novel autoantibody against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and describe the clinical and therapeutic challenges of managing these patients and an optimal therapeutic strategy.MethodsClinical, laboratory, EMG, and histopathologic results and response to immunomodulation are reported in 6 Australian patients with previous statin exposure and antibodies targeting HMGCR.ResultsAll patients presented with painless proximal weakness following statin therapy, which persisted after statin cessation. Serum creatine kinase (CK) levels ranged from 2,700 to 16,200 IU/L. EMG was consistent with a myopathic picture. Muscle biopsies revealed a pauci-immune necrotizing myopathy. Detailed graphical representation of the clinical course of these patients showed a close association with rising CK and an increase in clinical weakness signifying relapses, particularly upon weaning or ceasing steroids. All 6 patients were responsive to initial steroid therapy, with 5 relapsing upon attempts to wean steroids. Both CK and clinical strength improved with the reinstitution of immunotherapy, in particular steroids and IV immunoglobulin (IVIg). All patients required treatment with varying multiagent immunosuppressive regimens to achieve clinical remission, including prednisone (n = 6), IVIg (n = 5), plasmapheresis (n = 2), and additional therapy including methotrexate (n = 6), cyclophosphamide (n = 2), rituximab (n = 2), azathioprine (n = 1), and cyclosporine (n = 1).ConclusionsRecognition of HMGCR antibody-associated NAM is important because these patients are responsive to immunosuppression, and early multiagent therapy and a slow and cautious approach to withdrawing steroids may improve outcomes.
| S-EPMC4386794 | biostudies-literature
Project description:ObjectivesEvidence-based treatment protocols are currently lacking for immune-mediated necrotizing myopathy (IMNM). In this multicentre retrospective study, we examined baseline clinical characteristics and treatment variables that may predict short-term outcomes of patients with IMNM.MethodsMuscle biopsies from the John Hunter Hospital and the Royal Adelaide Hospital obtained between 2012 and 2019 were reviewed at a single laboratory at South Australia Pathology. All biopsies with histological features of IMNM were identified. Demographics of study subjects, clinical information and myositis-specific antibody status were recorded along with muscle strength, serum creatine kinase (CK) and treatment regimens at baseline and 3 and 6 months. Primary outcome measures were muscle strength and serum CK at 3 and 6 months. Mixed-effects regression models in a Bayesian framework were performed using the R statistical package.ResultsFemale sex, older age, initial prednisone dose and i.v. methylprednisolone were associated with greater improvement in serum CK. In patients with moderate-severe disease at baseline, early IVIG was associated with greater improvement in hip flexor strength at 6 months.ConclusionEarly IVIG was associated with clinical improvement in the short-term follow-up in IMNM. Female sex, older age, initial oral prednisone dose and initial use of i.v. methylprednisolone were associated with better biochemical improvement.
| S-EPMC9434226 | biostudies-literature
Project description:Objective: The intestine occupies the critical interface between cholesterol absorption and excretion. Despite this, surprisingly little is known about the role of de novo cholesterol synthesis in this organ, and its relationship to whole body cholesterol homeostasis. In addition to cholesterol, the mevalonate pathway is responsible for the synthesis of numerous non-sterol isoprenoids. Here we investigate the physiological importance of the mevalonate pathway within the intestine, through genetic deletion of the rate-limiting enzyme. Approach and Results: Mice lacking 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) in intestinal villus and crypt epithelial cells were generated using a Villin-Cre transgene. In contrast to intestine-specific Srebp-2 and Scap knockouts, mice with intestinal-specific loss of Hmgcr are viable through adulthood and fertile. Hmgcr was efficiently deleted based on mRNA levels, as well as quantitative analysis of Hmgcr alleles by droplet digital PCR. Lipidomics revealed substantial reductions in the abundance of numerous non-sterol isoprenoids and sterol intermediates within the epithelial layer, while cholesterol levels were preserved. Although the intestinal knockout mice are born smaller, there is no net defect in feed efficiency or triglyceride absorption due to compensatory changes in bile acid composition and intestinal growth. At the cellular level, loss of Hmgcr is compensated for quickly after weaning through a dramatic expansion of the stem cell compartment within the crypts. Conclusions: Genetic loss of Hmgcr in the intestine is compatible with life, through mechanisms involving compensatory changes in bile acid composition, increased absorptive surface area, and expansion of the resident stem cell compartment.
2021-01-12 | GSE164589 | GEO