Unraveling IFN-I response dynamics and TNF crosstalk in the pathophysiology of systemic lupus erythematosus.

Introduction: The innate immune system serves the crucial first line of defense against a wide variety of potential threats, during which the production of pro-inflammatory cytokines IFN-I and TNFα are key. This astonishing power to fight invaders, however, comes at the cost of risking IFN-I-related pathologies, such as observed during autoimmune diseases, during which IFN-I and TNFα response dynamics are dysregulated. Therefore, these response dynamics must be tightly regulated, and precisely matched with the potential threat.

The immunologic etiology of psychiatric manifestations in systemic lupus erythematosus: A narrative review on the role of the blood brain barrier, antibodies, cytokines and chemokines.

Introduction: The aim of this narrative review is to provide an overview of the literature on the possible immunologic pathophysiology of psychiatric manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods: A systematic search on PubMed was conducted. English studies with full text availability that investigated the correlation between blood-brain barrier (BBB) dysfunction, intrathecal synthesis of antibodies, antibodies, cytokines, chemokines, metalloproteinases, complement and psychiatric NPSLE manifestations in adults were included.

Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology.

The introduction of biologic DMARDs into rheumatology has resulted in a substantial reduction of the burden of many rheumatic diseases. In the slipstream of the success achieved with these biologic DMARDs, some conventional immunosuppressive drugs have also found use in new indications. Notably, mycophenolate mofetil, azathioprine and tacrolimus have made their way from solid organ transplantation drugs to become useful assets in rheumatology practice.

Quantification of Double Stranded DNA Breaks and Telomere Length as Proxies for Corneal Damage and Replicative Stress in Human Keratoconus Corneas.

Purpose: The pathogenesis of keratoconus (KC) is multifactorial, and associated with oxidative stress and subsequent DNA damage. We investigate differences in DNA damage and replicative stress in patients with KC, and in healthy and diseased controls.

Methods: We obtained 64 corneal buttons from 27 patients with KC after corneal transplant surgery, 21 with a decompensated graft (DG), and 16 healthy controls (HC).

B-cells and schizophrenia: A promising link or a finding lost in translation?

Recent genetic studies have suggested a potential role for B-cells in the pathogenesis of schizophrenia. Greater insight in the functioning of B-cells in patients with schizophrenia is therefore of importance. In this narrative review we aim to give an overview of the current literature on B-cells and schizophrenia.

mTOR inhibition by metformin impacts monosodium urate crystal-induced inflammation and cell death in gout: a prelude to a new add-on therapy?

Objective: Gout is the most common inflammatory arthritis worldwide, and patients experience a heavy burden of cardiovascular and metabolic diseases. The inflammation is caused by the deposition of monosodium urate (MSU) crystals in tissues, especially in the joints, triggering immune cells to mount an inflammatory reaction. Recently, it was shown that MSU crystals can induce mechanistic target of rapamycin (mTOR) signalling in monocytes encountering these crystals in vitro.

Telomere quantification in frontal and temporal brain tissue of patients with schizophrenia.

Recent imaging studies have suggested that accelerated aging occurs in schizophrenia. However, the exact cause of these findings is still unclear. In this study we measured telomere length, a marker for cell senescence, in gray and white matter brain tissue from the medial frontal gyrus (MFG) and superior temporal gyrus (STG) of 9 patients with schizophrenia and 11 controls.

Metformin, A New Era for an Old Drug in the Treatment of Immune Mediated Disease?

Background: Metformin, a widely prescribed blood glucose normalizing antidiabetic drug, is now beginning to receive increasing attention due to its anti-inflammatory properties.

Objective: To provide a critical and comprehensive review of the available literature describing the effects of metformin on the immune system and on auto-inflammatory diseases.

Results: Based on the available scientific literature, metformin suppresses immune responses mainly through its direct effect on the cellular functions of various immune cell types by induction of AMPK and subsequent inhibition of mTORC1, and by inhibition of mitochondrial ROS production.

Association of MicroRNA-618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis.

Objective: Plasmacytoid dendritic cells (PDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to PDC dysregulation and a persistent type I IFN signature are largely unexplored, especially in patients with systemic sclerosis (SSc), a disease in which PDCs infiltrate fibrotic skin lesions and produce higher levels of IFNα than those in healthy controls. This study was undertaken to investigate potential microRNA (miRNA)-mediated epigenetic mechanisms underlying PDC dysregulation and type I IFN production in SSc.

Aberrant leukocyte telomere length in Birdshot Uveitis.

Purpose: Birdshot Uveitis (BU) is an archetypical chronic inflammatory eye disease, with poor visual prognosis, that provides an excellent model for studying chronic inflammation. BU typically affects patients in the fifth decade of life. This suggests that it may represent an age-related chronic inflammatory disease, which has been linked to increased erosion of telomere length of leukocytes.

Expression of ERAP2 and LST1 is increased before start of therapy in rheumatoid arthritis patients with good clinical response to glucocorticoids.

Objectives: Glucocorticoids (GC) remain a cornerstone of rheumatoid arthritis (RA) therapy, although a third of patients do not respond adequately. In order to find potential predictors for clinical response, the gene expression profile of CD4+T-cells as important players in the pathogenesis of RA was analysed before pulse therapy with 1000 mg methylprednisolone.

Methods: Patients were treated with 3x1000 mg methylprednisolone in 5 days; hereafter response was determined by the European League Against Rheumatism (EULAR) response criteria.

Gout Is a Chronic Inflammatory Disease in Which High Levels of Interleukin-8 (CXCL8), Myeloid-Related Protein 8/Myeloid-Related Protein 14 Complex, and an Altered Proteome Are Associated With Diabetes Mellitus and Cardiovascular Disease.

Objective: The frequent association of gout with metabolic syndrome and cardiovascular disease (CVD) suggests that it has a systemic component. Our objective was to study whether circulating proinflammatory cytokines are associated with comorbidities in gout patients.

Methods: We studied 330 gout patients from 3 independent cohorts and compared them with 144 healthy individuals and 276 disease controls.

Inflamm-ageing and Senescence in Gout: The Tale of an Old King's Disease.

Gout is the most common auto-inflammatory arthritis that leads to severe comorbidities such as cardiovascular diseases, renal impairment and metabolic disorders at an early age. We hypothesize that chronic as well as frequent flares of intermittent inflammation, caused by uric acid contribute to an early onset of cardiovascular-, renal- and metabolic diseases. Persistent exposure of the cells to such inflammatory events elaborates DNA damage, excessive cell turnover inconsistent with age and telomere shortening which is representative for accelerated senescence.

The role of genetics and epigenetics in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a complex autoimmune disease of unclear aetiology. A multitude of genetic studies, ranging from candidate-gene studies to genome-wide association studies, have identified a large number of genetic susceptibility factors for SSc and its clinical phenotypes, but the contribution of these factors to disease susceptibility is only modest. However, in an endeavour to explore how the environment might affect genetic susceptibility, epigenetic research into SSc is rapidly expanding.

Longitudinal changes of telomere length and epigenetic age related to traumatic stress and post-traumatic stress disorder.

Several studies have reported an association between traumatic stress and telomere length suggesting that traumatic stress has an impact on ageing at the cellular level. A newly derived tool provides an additional means to investigate cellular ageing by estimating epigenetic age based on DNA methylation profiles. We therefore hypothesise that in a longitudinal study of traumatic stress both indicators of cellular ageing will show increased ageing.

Overlapping gene expression profiles indicative of antigen processing and the interferon pathway characterize inflammatory fibrotic skin diseases.

Inflammatory fibrotic disorders have been of high interest both for dermatologists and rheumatologists. Although the phenotypic end stage of this group of diseases is ultimately the same, namely fibrosis, patients present with different clinical features and are often treated with distinct therapeutic modalities. This review addresses whether there is evidence for different underlying molecular pathways in the various inflammatory fibrotic diseases such as localized scleroderma, pediatric lichen sclerosus, adult lichen sclerosus, eosinophilic fasciitis and systemic sclerosis.

Accelerated telomere shortening in rheumatic diseases: cause or consequence?

Accelerated aging of the immune system (immune aging), represented by telomere shortening, has been implicated in a variety of rheumatic diseases. Studies addressing telomere shortening in rheumatic diseases so far yielded controversial results. The current review aims to provide an overview on the role of immune aging in a plethora of immune-mediated conditions including systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis.

New insight on the Xq28 association with systemic sclerosis.

Objective: To evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).

Methods: We analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays.

Genetics of systemic sclerosis: an update.

Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, immune cell activation, and fibrosis of the skin and internal organs. Over the past few years, a role for genetics in the susceptibility for SSc has been established. This review aims to provide an update on the progress made in the past year or so within the field of SSc genetics research.

Polymorphisms in the interleukin 4, interleukin 13, and corresponding receptor genes are not associated with systemic sclerosis and do not influence gene expression.

Objective: Polymorphisms in the genes encoding interleukin 4 (IL4), interleukin 13 (IL13), and their corresponding receptors have been associated with multiple immune-mediated diseases. Our aim was to validate these previous observations in patients with systemic sclerosis (SSc) and scrutinize the effect of the polymorphisms on gene expression in various populations of peripheral blood leukocytes.

Methods: We genotyped a cohort of 2488 patients with SSc and 2246 healthy controls from The Netherlands, Spain, United Kingdom, Italy, Germany, and France.

Deciphering the genetic background of systemic sclerosis.

Systemic sclerosis (SSc) is a severe autoimmune connective tissue disease. Over the years, evidence for a genetic background of SSc susceptibility has clearly accumulated. This article aims to provide an extensive overview of genetics in SSc research.