| 1. |
- Chandrasekaran, Venkatagaran, et al.
(author)
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Cohesin-Mediated Chromatin Interactions and Autoimmunity
- 2022
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Journal article (peer-reviewed)abstract
- Proper physiological functioning of any cell type requires ordered chromatin organization. In this context, cohesin complex performs important functions preventing premature separation of sister chromatids after DNA replication. In partnership with CCCTC-binding factor, it ensures insulator activity to organize enhancers and promoters within regulatory chromatin. Homozygous mutations and dysfunction of individual cohesin proteins are embryonically lethal in humans and mice, which limits in vivo research work to embryonic stem cells and progenitors. Conditional alleles of cohesin complex proteins have been generated to investigate their functional roles in greater detail at later developmental stages. Thus, genome regulation enabled by action of cohesin proteins is potentially crucial in lineage cell development, including immune homeostasis. In this review, we provide current knowledge on the role of cohesin complex in leukocyte maturation and adaptive immunity. Conditional knockout and shRNA-mediated inhibition of individual cohesin proteins in mice demonstrated their importance in haematopoiesis, adipogenesis and inflammation. Notably, these effects occur rather through changes in transcriptional gene regulation than through expected cell cycle defects. This positions cohesin at the crossroad of immune pathways including NF-kB, IL-6, and IFN gamma signaling. Cohesin proteins emerged as vital regulators at early developmental stages of thymocytes and B cells and after antigen challenge. Human genome-wide association studies are remarkably concordant with these findings and present associations between cohesin and rheumatoid arthritis, multiple sclerosis and HLA-B27 related chronic inflammatory conditions. Furthermore, bioinformatic prediction based on protein-protein interactions reveal a tight connection between the cohesin complex and immune relevant processes supporting the notion that cohesin will unearth new clues in regulation of autoimmunity.
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| 2. |
- Erlandsson, Malin, 1972, et al.
(author)
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Survivin promotes a glycolytic switch in CD4+ T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.
- 2022
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In: iScience. - : Elsevier BV. - 2589-0042. ; 25:12
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Journal article (peer-reviewed)abstract
- In this study, we explore the role of nuclear survivin in maintaining the effector phenotype of IFNγ-producing Tcells acting through the transcriptional control of glucose utilization. High expression of survivin in CD4+T cells was associated with IFNγ-dependent phenotype and anaerobic glycolysis. Transcriptome of CD4+ cells and sequencing of survivin-bound chromatin showed that nuclear survivin had a genome-wide and motif-specific binding to regulatory regions of the genes controlling cell metabolism. Survivin coprecipitates with transcription factors IRF1 and SMAD3, which repressed the transcription of the metabolic check-point enzyme phosphofructokinase 2 gene PFKFB3 and promoted anaerobic glycolysis. Combining transcriptome analyses of CD4+ cells and functional studies in glucose metabolism, we demonstrated that the inhibition of survivin reverted PFKFB3 production, inhibited glucose uptake, and reduces interferon effects in CD4+ cells. These results present a survivin-dependent mechanism in coordinating the metabolic adaptation of CD4+T cells and propose an attractive strategy to counteract IFNγ-dependent inflammation in autoimmunity.
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| 3. |
- Jensen, Maja, 1978, et al.
(author)
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Survivin prevents the polycomb repressor complex 2 from methylating histone 3 lysine 27
- 2023
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In: Iscience. ; 26:7
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Journal article (peer-reviewed)abstract
- This study investigates the role of survivin in epigenetic control of gene transcription through interaction with the polycomb repressive complex 2 (PRC2). PRC2 is responsible for silencing gene expression by trimethylating lysine 27 on histone 3. We observed differential expression of PRC2 subunits in CD4(+) T cells with varying levels of survivin expression, and ChIP-seq results indicated that survivin colocalizes with PRC2 along DNA. Inhibition of survivin resulted in a significant increase in H3K27 trimethylation, implying that survivin prevents PRC2 from functioning. Peptide microarray showed that survivin interacts with peptides from PRC2 subunits, and machine learning revealed that amino acid composition contains relevant information for predicting survivin interaction. NMR and BLI experiments supported the interaction of survivin with PRC2 subunit EZH2. Finally, protein-protein docking revealed that the survivin-EZH2 interaction interface overlaps with catalytic residues of EZH2, potentially inhibiting its H3K27 methylation activity. These findings suggest that survivin inhibits PRC2 function.
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| 4. |
- Larasati Anindya, Atsarina, et al.
(author)
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Bayesian progress curve analysis of MicroScale thermophoresis data
- 2022
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In: Digital Discovery. - : Royal Society of Chemistry (RSC). - 2635-098X. ; 1:3, s. 325-332
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Journal article (peer-reviewed)abstract
- MicroScale Thermophoresis (MST) follows the movement of fluorescent-labelled biomolecules with different sizes along a temperature gradient. The presence of a “contrary trend” pattern, that is, the trend of fluorescence change reversing at higher titrant concentrations, is a well-known problem with uncertain cause. Conventionally, binding curves and kinetic parameters are derived from MST datasets using regression analysis on isolated time windows, while the rest of the data are ignored, and the “contrary trend” fluorescent levels are also usually removed as outliers. This biased approach can be avoided with a more continuous analysis of the entire kinetic process. The Bayesian model of MST progress curves allows the inference of parameters and modelling of the whole experiment. The removal of unusual data points is unnecessary once the anomalous kinetic process is identified. This alternative data analysis approach was applied to our MST datasets from survivin–hSgol2 interactions, and the results show that the binding curves remained sigmoid when all data were included. We were also able to infer the value and uncertainty of the dissociation constant (KD) by ascribing the anomalous data points to a new, linear kinetic component. This approach demonstrates good posterior predictions from the MST process in both short and longer experiments as well as the feasibility of KD inference from short experiments.
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| 5. |
- Oparina, Nina, et al.
(author)
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Prognostic Significance of BIRC5/Survivin in Breast Cancer: Results from Three Independent Cohorts.
- 2021
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In: Cancers. - : MDPI AG. - 2072-6694. ; 13:9
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Journal article (peer-reviewed)abstract
- Breast cancer (BC) histological and molecular classifications significantly improved the treatment strategy and prognosis. Inhibitor of apoptosis BIRC5/survivin is often overexpressed in cancers, however, indications of its importance in BC are inconsistent. We integrate BIRC5 protein and mRNA measures with clinical associates and long-term outcome in three independent cohorts Protein levels of BIRC5 were measured in primary lysates of 845 patients of the West Swedish BC cohort (VGR-BC) and linked to 5- and 27-years survival. The results were externally validated in transcriptomic data from METABRIC and SCAN-B cohorts. Survival analysis showed that high levels of BIRC5 were consistently associated with a poor probability of 5-year overall survival. High BIRC5 in VGR-BC contributed negatively to the disease-specific survival at 5 and 27 years. Subsets with different status by ER (estrogen receptor) expression and presence of nodal metastasis supported independent association of high BIRC5 with poor prognosis in all cohorts. In METABRIC and SCAN-B cohorts, high levels of BIRC5 mRNA were associated with the basal-like and luminal B molecular BC subtypes and with increasing histologic grade. BIRC5 is a sensitive survival marker that acts independent of ER and nodal status, and its levels need to be considered when making treatment decisions.
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| 6. |
- Baboota, Ritesh, et al.
(author)
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Chronic hyperinsulinemia promotes human hepatocyte senescence
- 2022
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In: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 64
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Journal article (peer-reviewed)abstract
- Objective: Cellular senescence, an irreversible proliferative cell arrest, is caused by excessive intracellular or extracellular stress/damage. Increased senescent cells have been identified in multiple tissues in different metabolic and other aging-related diseases. Recently, several human and mouse studies emphasized the involvement of senescence in development and progression of NAFLD. Hyperinsulinemia, seen in obesity, metabolic syndrome, and other conditions of insulin resistance, has been linked to senescence in adipocytes and neurons. Here, we investigate the possible direct role of chronic hyperinsulinemia in the development of senescence in human hepatocytes. Methods: Using fluorescence microscopy, immunoblotting, and gene expression, we tested senescence markers in human hepatocytes subjected to chronic hyperinsulinemia in vitro and validated the data in vivo by using liver-specific insulin receptor knockout (LIRKO) mice. The consequences of hyperinsulinemia were also studied in senescent hepatocytes following doxorubicin as a model of stress-induced senescence. Furthermore, the effects of senolytic agents in insulin- and doxorubicin-treated cells were analyzed. Results: Results showed that exposing the hepatocytes to prolonged hyperinsulinemia promotes the onset of senescence by increasing the expression of p53 and p21. It also further enhanced the senescent phenotype in already senescent hepatocytes. Addition of insulin signaling pathway inhibitors prevented the increase in cell senescence, supporting the direct contribution of insulin. Furthermore, LIRKO mice, in which insulin signaling in the liver is abolished due to deletion of the insulin receptor gene, showed no differences in senescence compared to their wild-type counterparts despite having marked hyperinsulinemia indicating these are receptor-mediated effects. In contrast, the persistent hyperinsulinemia in LIRKO mice enhanced senescence in white adipose tissue. In vitro, senolytic agents dasatinib and quercetin reduced the prosenescent effects of hyperinsulinemia in hepatocytes. Conclusion: Our findings demonstrate a direct link between chronic hyperinsulinemia and hepatocyte senescence. This effect can be blocked by reducing the levels of insulin receptors or administration of senolytic drugs, such as dasatinib and quercetin.
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| 7. |
- Castellví, I., et al.
(author)
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Safety and effectiveness of abatacept in systemic sclerosis: The EUSTAR experience
- 2020
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In: Seminars in Arthritis and Rheumatism. - : Elsevier BV. - 0049-0172. ; 50:6, s. 1489-1493
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Journal article (peer-reviewed)abstract
- Objective: To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc). Methods: Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests. Results: Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p<0.03 and p<0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p<0.05) and on morning stiffness at 6 and 12 months (p<0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p<0.05). No changes in lung or gastrointestinal involvement were found. Conclusions: ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care. © 2020 Elsevier Inc.
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| 8. |
- Erlandsson, Malin, 1972, et al.
(author)
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Clinical Significance of Diabetes-Mellitus-Associated Antibodies in Rheumatoid Arthritis
- 2022
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In: Cells. - : MDPI AG. - 2073-4409. ; 11:22
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Journal article (peer-reviewed)abstract
- Rheumatoid arthritis (RA) is a canonical autoimmune disease that shares numerous risk factors with diabetes mellitus (DM). The production of autoantibodies is a characteristic feature in both diseases. To determine the frequency and specificity of DM-related antibodies (DMab) in RA patients and to study whether DMab associates with new DM cases in RA patients, we measured DMab defined as IgG against glutamic acid decarboxylase (GADA), tyrosine phosphatase (IA2-ab), and zinc transporter (ZnT8-ab) in a cohort of 290 RA patients (215 women and 75 men, median disease duration 11 years). Of those, 21 had a DM diagnosis at baseline. The development of new DM cases and mortality were traced in a 10-year prospective follow-up. Predictive analyses for DM and mortality were carried out by the Mantel-Cox regression. We found that 27 of the patients (9.3%) had DMab, equally often men and women. The presence of DMab was more frequent in patients with DM (p = 0.027. OR 4.01, 95%CI [1.20; 11.97]), suggesting their specificity for the disease. Men had more prevalent incidental DM at the baseline (12% vs. 5%, p = 0.030) and among the new DM cases (p = 0.012. HR 6.08, 95%CI [1.57; 25]). New DM developed equally frequently in DMab-positive and DMab-negative patients. DM, but not DMab, significantly increased the estimated mortality rate in RA patients (p = 0.021, OR 4.38 [1.2; 13.52]). Taken together, we conclude that DMab are associated with DM in RA patients, but they are not solely enough to predict disease development or mortality in those patients.
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| 9. |
- Erlandsson, Malin, 1972, et al.
(author)
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IGF1R signalling is a guardian of self-tolerance restricting autoantibody production.
- 2022
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In: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Journal article (peer-reviewed)abstract
- Insulin-like growth factor 1 receptor (IGF1R) acts at the crossroad between immunity and cancer, being an attractive therapeutic target in these areas. IGF1R is broadly expressed by antigen-presenting cells (APC). Using mice immunised with the methylated albumin from bovine serum (BSA-immunised mice) and human CD14+ APCs, we investigated the role that IGF1R plays during adaptive immune responses.The mBSA-immunised mice were treated with synthetic inhibitor NT157 or short hairpin RNA to inhibit IGF1R signalling, and spleens were analysed by immunohistology and flow cytometry. The levels of autoantibody and cytokine production were measured by microarray or conventional ELISA. The transcriptional profile of CD14+ cells from blood of 55 patients with rheumatoid arthritis (RA) was analysed with RNA-sequencing.Inhibition of IGF1R resulted in perifollicular infiltration of functionally compromised S256-phosphorylated FoxO1+ APCs, and an increased frequency of IgM+CD21+ B cells, which enlarged the marginal zone (MZ). Enlargement of MHCII+CD11b+ APCs ensured favourable conditions for their communication with IgM+ B cells in the MZ. The reduced expression of ICOSL and CXCR5 by APCs after IGF1R inhibition led to impaired T cell control, which resulted in autoreactivity of extra-follicular B cells and autoantibody production. In the clinical setting, the low expression of IGF1R on CD14+ APCs was associated with an involuted FOXO pathway, non-inflammatory cell metabolism and a high IL10 production characteristic for tolerogenic macrophages. Furthermore, autoantibody positivity was associated with low IGF1R signalling in CD14+ APCs.In experimental model and in patient material, this study demonstrates that IGF1R plays an important role in preventing autoimmunity. The study raises awareness of that immune tolerance may be broken during therapeutic IGF1R targeting.
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| 10. |
- Ferrannini, E., et al.
(author)
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Mannose is an insulin-regulated metabolite reflecting whole-body insulin sensitivity in man
- 2020
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In: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495. ; 102
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Journal article (peer-reviewed)abstract
- Mannose is a glucose-associated serum metabolite mainly released by the liver. Recent studies have shown several unexpected pleiotropic effects of mannose including increased regulatory T cells (Tregs), prevention of auto-immune disease and ability to reduce growth of human cancer cells. We have previously shown in large cohorts that elevated serum mannose levels are associated with future development of type 2 diabetes (T2D) and cardiovascular disease. However, potential direct effects of mannose on insulin sensitivity in vivo or in vitro are unknown. We here show that administration of mannose (0.1 g/kg BW twice daily) for one week in man did not elicit negative effects on meal-modified glucose tolerance, markers of inflammation or insulin levels. Tregs number and insulin signaling in human liver cells were unchanged. These data suggest that mannose is a marker, and not a mediator, of insulin resistance. To verify this, we examined serum mannose levels during long-term euglycemic hyperinsulinemic clamps in non-diabetic and T2D individuals. Mannose was reduced by insulin infusion in proportion to whole-body insulin sensitivity. Thus, mannose is a biomarker of insulin resistance which may be useful for the early identification of diabetic individuals with insulin resistance and increased risk of its complications. © 2019 Elsevier Inc.
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