Insulin Sensitivity Controls Activity of Pathogenic CD4+ T Cells in Rheumatoid Arthritis.

Hyperinsulinemia connects obesity, and a poor lipid profile, with type 2 diabetes (T2D). Here, we investigated consequences of insulin exposure for T cell function in the canonical autoimmunity of rheumatoid arthritis (RA). We observed that insulin levels correlated with the glycolytic index of CD4+ cells but suppressed transcription of insulin receptor substrates, which was inversely related to insulin sensitivity.

Ex Vivo Vascular Imaging and Perfusion Studies of Normal Kidney and Tumor Vasculature.

This work describes a comprehensive study of the vascular tree and perfusion characteristics of normal kidney and renal cell carcinoma. Methods: Nephrectomy specimens were perfused ex-vivo, and the regional blood flow was determined by infusion of radioactive microspheres. The vascular architecture was characterized by micronized barium sulphate infusion.

Metabolic signature and proteasome activity controls synovial migration of CD14 cells in rheumatoid arthritis.

Objective: Activation of Rho-GTPases in macrophages causes inflammation and severe arthritis in mice. In this study, we explore if Rho-GTPases define the joint destination of pathogenic leukocytes, the mechanism by which they perpetuate rheumatoid arthritis (RA), and how JAK inhibition mitigates these effects.

Methods: CD14 cells of 136 RA patients were characterized by RNA sequencing and cytokine measurement to identify biological processes and transcriptional regulators specific for CD14 cells, which were summarized in a metabolic signature (MetSig).

Clinical Significance of Diabetes-Mellitus-Associated Antibodies in Rheumatoid Arthritis.

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).

Survivin promotes a glycolytic switch in CD4 T cells by suppressing the transcription of PFKFB3 in rheumatoid arthritis.

In this study, we explore the role of nuclear survivin in maintaining the effector phenotype of IFNγ-producing T cells acting through the transcriptional control of glucose utilization. High expression of survivin in CD4T 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.

IGF1R signalling is a guardian of self-tolerance restricting autoantibody production.

Objective: 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.

Chronic hyperinsulinemia promotes human hepatocyte senescence.

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.

Rho-GTPase dependent leukocyte interaction generates pro-inflammatory thymic Tregs and causes arthritis.

Conditional mutation of protein geranylgeranyltransferase type I (GGTase-I) in macrophages (GLC) activates Rho-GTPases and causes arthritis in mice. Knocking out Rag1 in GLC mice alleviates arthritis which indicates that lymphocytes are required for arthritis development in those mice. To study GLC dependent changes in the adaptive immunity, we isolated CD4 T cells from GLC mice (CD4GLCs).

MicroRNA and interleukin 6 interplay in the adipose tissue of rheumatoid arthritis patients.

Objectives: MicroRNAs (miRs) are non-translated RNA sequences that elicit negative control over protein expression. The adipose tissue (AT) is considered the major producer of miRs and inflammatory interleukin 6 (IL-6). This study aims to investigate the relationship between production of IL-6 and miRs in AT.

Cohesin-Mediated Chromatin Interactions and Autoimmunity.

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.

Impact of the Uncoupling Protein 1 on Cardiovascular Risk in Patients with Rheumatoid Arthritis.

Adiposity is strongly associated with cardiovascular (CV) morbidity. Uncoupling protein 1 (UCP1) increases energy expenditure in adipocytes and may counteract adiposity. Our objective was to investigate a connection between expression and cardiovascular health in patients with rheumatoid arthritis (RA) in a longitudinal observational study.

Prognostic Significance of BIRC5/Survivin in Breast Cancer: Results from Three Independent Cohorts.

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.

Low Soluble Receptor for Advanced Glycation End Products Precedes and Predicts Cardiometabolic Events in Women With Rheumatoid Arthritis.

Cardiovascular disease (CVD) causes premature mortality in rheumatoid arthritis (RA). Levels of soluble (s)RAGE change with aging, hypertension and hypercholesterolemia. We assessed whether sRAGE was associated with increased risk of CVD in RA patients.

Nicotine Changes the microRNA Profile to Regulate the FOXO Memory Program of CD8 T Cells in Rheumatoid Arthritis.

Smoking suppresses PD-1 expression in patients with rheumatoid arthritis (RA). In this study, we assess if smoking changed the epigenetic control over CD8 T cell memory formation through a microRNA (miR) dependent mechanism. Phenotypes of CD8 T cells from smokers and non-smokers, RA and healthy, were analyzed by flow cytometry.

Low serum IGF1 is associated with hypertension and predicts early cardiovascular events in women with rheumatoid arthritis.

Objectives: Since low insulin-like growth factor (IGF) 1 is often linked to inflammation, we analyze whether serum levels of IGF1 are associated with cardiovascular disease (CVD) in rheumatoid arthritis (RA) in a longitudinal observational study.

Methods: A CVD risk was estimated (eCVR) in 184 female RA patients (mean age 52 years) and in 132 female patients after ischemic stroke (mean age 56 years) with no rheumatic disease, using the Framingham algorithm. The median level of IGF1 divided the cohorts in IGF1 and IGF1 groups.

Inflammation in the hippocampus affects IGF1 receptor signaling and contributes to neurological sequelae in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory joint disease with a neurological component including depression, cognitive deficits, and pain, which substantially affect patients' quality of daily life. Insulin-like growth factor 1 receptor (IGF1R) signaling is one of the factors in RA pathogenesis as well as a known regulator of adult neurogenesis. The purpose of this study was to investigate the association between IGF1R signaling and the neurological symptoms in RA.

Smoking Is Associated With Low Levels of Soluble PD-L1 in Rheumatoid Arthritis.

Background: Smoking is a risk factor for developing rheumatoid arthritis (RA), but the mechanism remains uncertain. We previously demonstrated that smoking lowers the T cell activation threshold by limiting programmed death protein 1 (PD-1) expression.

Aim: To investigate how smoking influence the levels of soluble PD-1 ligand (sPD-L1).

Survivin Measurement improves Clinical Prediction of Transition From Arthralgia to RA-Biomarkers to Improve Clinical Sensitivity of Transition From Arthralgia to RA.

Arthralgia often predates development of rheumatoid arthritis (RA). A set of joint symptoms commonly found in patients during their transition from arthralgia to RA, has been recently proposed. To combine clinical and serological markers and to improve recognition of imminent rheumatoid arthritis (RA) among patients with arthralgia.

Inhibition of CCL3 abrogated precursor cell fusion and bone erosions in human osteoclast cultures and murine collagen-induced arthritis.

Objective: Macrophage inflammatory protein 1-alpha (CCL3) is a chemokine that regulates macrophage trafficking to the inflamed joint. The agonistic effect of CCL3 on osteolytic lesions in patients with multiple myeloma is recognized; however, its role in skeletal damage during inflammatory arthritis has not been established. The aim of the study was to explore the role of osteoclast-associated CCL3 upon bone resorption, and to test its pharmacological blockade for protecting against bone pathology during inflammatory arthritis.

Effects of implant-delivered insulin on bone formation in osteoporotic rats.

Osteoporosis is a major cause of age-related fractures. Healing complications in osteoporotic patients are often associated with increased mortality and morbidity. Stimulation of the implant-adjacent bone could be beneficial in terms of the surgical outcome.

Survivin improves the early recognition of rheumatoid arthritis among patients with arthralgia: A population-based study within two university cities of Sweden.

Objectives: The aim of this study was to validate the use of survivin for preclinical recognition of rheumatoid arthritis (RA) among patients with unexplained arthralgia.

Methods: Serum levels of survivin and the arthritis-specific autoantibodies RF and ACPA were measured in total of 5046 patients with musculoskeletal complains during 12 consecutive months in Gothenburg and in Umeå. Among them, 303 arthralgia patients were identified and prospectively followed.

High Expression of STAT3 in Subcutaneous Adipose Tissue Associates with Cardiovascular Risk in Women with Rheumatoid Arthritis.

Despite the predominance of female patients and uncommon obesity, rheumatoid arthritis (RA) is tightly connected to increased cardiovascular morbidity. The aim of this study was to investigate transcriptional activity in the subcutaneous white adipose tissue (WAT) with respect to this disproportionate cardiovascular risk (CVR) in RA. CVR was estimated in 182 female patients, using the modified Systematic Coronary Risk Evaluation scale, and identified 93 patients with increased CVR.

IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis.

Background: Signalling through insulin-like growth factor 1 receptor (IGF-1R) is essential for cell survival, but may turn pathogenic in uncontrolled tissue growth in tumours. In rheumatoid arthritis (RA), the IGF-1R signalling is activated and supports expansion of the inflamed synovia.

Aim: In the present study, we assess if disruption of IGF-1R signalling resolves arthritis.