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Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling.

ABSTRACT: Engagement of the CD3/T cell receptor complex in systemic lupus erythematosus (SLE) T cells involves Syk rather than the zeta-associated protein. Because Syk is being considered as a therapeutic target we asked whether Syk is central to the multiple aberrantly modulated molecules in SLE T cells. Using a gene expression array, we demonstrate that forced expression of Syk in normal T cells reproduces most of the aberrantly expressed molecules whereas silencing of Syk in SLE T cells normalizes the expression of most abnormally expressed molecules. Protein along with gene expression modulation for select molecules was confirmed. Specifically, levels of cytokine IL-21, cell surface receptor CD44, and intracellular molecules PP2A and OAS2 increased following Syk overexpression in normal T cells and decreased after Syk silencing in SLE T cells. Our results demonstrate that levels of Syk affect the expression of a number of enzymes, cytokines and receptors that play a key role in the development of disease pathogenesis in SLE and provide support for therapeutic targeting in SLE patients.

SUBMITTER: Grammatikos AP

PROVIDER: S-EPMC3754955 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Sex differences in monocyte activation in systemic lupus erythematosus (SLE).

Project description:IntroductionTLR7/8 and TLR9 signaling pathways have been extensively studied in systemic lupus erythematosus (SLE) as possible mediators of disease. Monocytes are a major source of pro-inflammatory cytokines and are understudied in SLE. In the current project, we investigated sex differences in monocyte activation and its implications in SLE disease pathogenesis.MethodsHuman blood samples from 27 healthy male controls, 32 healthy female controls, and 25 female patients with SLE matched for age and race were studied. Monocyte activation was tested by flow cytometry and ELISA, including subset proportions, CD14, CD80 and CD86 expression, the percentage of IL-6-producing monocytes, plasma levels of sCD14 and IL-6, and urine levels of creatinine.ResultsMonocytes were significantly more activated in women compared to men and in patients with SLE compared to controls in vivo. We observed increased proportions of non-classic monocytes, decreased proportions of classic monocytes, elevated levels of plasma sCD14 as well as reduced surface expression of CD14 on monocytes comparing women to men and lupus patients to controls. Plasma levels of IL-6 were positively related to sCD14 and serum creatinine.ConclusionMonocyte activation and TLR4 responsiveness are altered in women compared to men and in patients with SLE compared to controls. These sex differences may allow persistent systemic inflammation and resultant enhanced SLE susceptibility.

| S-EPMC4259347 | biostudies-literature

Anorexia Nervosa in Juvenile Systemic Lupus Erythematosus (SLE): A Causality Dilemma.

Project description:Juvenile-onset systemic lupus erythematosus (jSLE) is an autoimmune disorder with multifaceted clinical findings in different organ systems. Neuropsychiatric manifestations affect more than half of SLE patients, and there is increasing evidence that anorexia nervosa (AN), a feeding and eating disorder (FED) characterized by significantly reduced energy intake, is among them. Herein, a review of the literature on the potential association between jSLE and AN was performed. Reported clinical cases were identified, and putative pathophysiological mechanisms were sought that could potentially explain the observed relationship between these two pathological entities. Four reports of isolated cases and a case series including seven patients were identified. In this limited patient pool, the diagnosis of AN preceded that of SLE in the majority of cases, whereas in all cases both entities were diagnosed within a time span of two years. Many explanations for the observed relationships have been proposed. AN has been associated with the stress of chronic disease diagnosis; on the other hand, the chronic inflammation associated with AN may contribute to the development/appearance of SLE. Adverse childhood experiences, concentrations of leptin, shared autoantibodies, and genetic traits appear to be important factors in this well-established interplay. In essence, it seems important to increase clinician awareness of the concomitant development of AN and SLE and invite further research on the subject.

| S-EPMC10137086 | biostudies-literature

Belimumab in systemic lupus erythematosus (SLE): evidence-to-date and clinical usefulness.

Project description:Systemic lupus erythematosus (SLE) is a complex autoimmune rheumatic disease with multiple presentations, whose management presents many challenges. Many disease modifying or immunosuppressive drugs have been used with limited success, especially in patients with more severe disease activity. Belimumab is the first drug to be approved specifically for the treatment of SLE in more than 50 years. By blocking the B-cell activating factor, it interferes in B-cell differentiation and survival. Here we consider the results of the clinical trials that led to its approval, as well as the post-hoc analyses, follow-up studies and the current trials.

| S-EPMC5349337 | biostudies-literature

Peli1 negatively regulates noncanonical NF-κB signaling to restrain systemic lupus erythematosus.

Project description:Systemic lupus erythematosus (SLE) is characterized by uncontrolled secretion of autoantibodies by plasma cells. Although the functional importance of plasma cells and autoantibodies in SLE has been well established, the underlying molecular mechanisms of controlling autoantibody production remain poorly understood. Here we show that Peli1 has a B cell-intrinsic function to protect against lupus-like autoimmunity in mice. Peli1 deficiency in B cells induces autoantibody production via noncanonical NF-κB signaling. Mechanically, Peli1 functions as an E3 ligase to associate with NF-κB inducing kinase (NIK) and mediates NIK Lys48 ubiquitination and degradation. Overexpression of Peli1 inhibits noncanonical NF-κB activation and alleviates lupus-like disease. In humans, PELI1 levels negatively correlate with disease severity in SLE patients. Our findings establish Peli1 as a negative regulator of the noncanonical NF-κB pathway in the context of restraining the pathogenesis of lupus-like disease.

| S-EPMC5859150 | biostudies-literature

Categorisation of foot complaints in systemic lupus erythematosus (SLE) from a New Zealand cohort.

Project description:Foot complaints have been shown to be common in systemic lupus erythematosus (SLE) and heterogeneous in nature. We aimed to categorize self-reported foot complaints in people with SLE and foot symptoms.A self-administered validated questionnaire was posted to 406 people with SLE attending adult rheumatology clinics across three health boards in Auckland, New Zealand. In addition to foot pain, vascular complaints, dermatological lesions and neurological symptoms were included in the analysis. Pairwise correlations among the variables were undertaken followed by factor analysis to identify and categorise associations between reported foot complaints.From the questionnaires returned, 93 full datasets were analysed. Participants' were predominantly female (n = 87, 93.7%), with mean (SD) age of 50.4 (14.3) years and a mean (SD) disease duration of 13.1 (11) years. Three categories of foot complaint were determined: 'foot pain', 'skin disorders' and 'vascular insufficiency'. These three groups provided the best fit (0.91) to describe the wide range of foot complaints reported by those with SLE. Factor analysis for foot pain demonstrated a high positive loading for the inter-correlation of foot pain in past month (0.83), foot pain today (0.71), intermittent claudication (0.71), numbness (0.62), loss of balance (0.81), swelling (0.59), foot joint pain (0.77), arch pain (0.68) and tendon pain (0.77). Skin disorders demonstrated a very high positive loading for 3 factors skin rash (0.82), blistering skin rash (0.95) and foot ulceration (0.88). In vascular insufficiency a high positive loading for cold feet (0.83), chilblains (0.76) and Raynaud's phenomenon (0.70).This work suggests people with SLE report three independent categories of foot complaints; foot pain, skin disorders or vascular insufficiency.

| S-EPMC5530459 | biostudies-other

Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE).

Project description:Systemic lupus erythematosus (SLE) is a complex autoimmune disorder with multiple susceptibility genes. We have previously reported suggestive linkage to the chromosomal region 14q21-q23 in Finnish SLE families.Genetic fine mapping of this region in the same family material, together with a large collection of parent affected trios from UK and two independent case-control cohorts from Finland and Sweden, indicated that a novel uncharacterized gene, MAMDC1 (MAM domain containing glycosylphosphatidylinositol anchor 2, also known as MDGA2, MIM 611128), represents a putative susceptibility gene for SLE. In a combined analysis of the whole dataset, significant evidence of association was detected for the MAMDC1 intronic single nucleotide polymorphisms (SNP) rs961616 (P -value = 0.001, Odds Ratio (OR) = 1.292, 95% CI 1.103-1.513) and rs2297926 (P -value = 0.003, OR = 1.349, 95% CI 1.109-1.640). By Northern blot, real-time PCR (qRT-PCR) and immunohistochemical (IHC) analyses, we show that MAMDC1 is expressed in several tissues and cell types, and that the corresponding mRNA is up-regulated by the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) in THP-1 monocytes. Based on its homology to known proteins with similar structure, MAMDC1 appears to be a novel member of the adhesion molecules of the immunoglobulin superfamily (IgCAM), which is involved in cell adhesion, migration, and recruitment to inflammatory sites. Remarkably, some IgCAMs have been shown to interact with ITGAM, the product of another SLE susceptibility gene recently discovered in two independent genome wide association (GWA) scans.Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE.

| S-EPMC2785483 | biostudies-literature

Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.

Project description:Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.

| S-EPMC5150694 | biostudies-literature

miRNAs expression in kidney tissues of systemic lupus erythematosus (SLE) individuals

Project description:MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states, including inflammatory autoimmune diseases. By using high-throughput microRNA profiling analysis, we identified a series of miRNAs dysregulated in local inflammatory lesions of human patients with autoimmune diseases such as SLE. We isolated the renal biopsy samples from eight SLE patients as well as tumor adjacent kidney tissues from four kidney cancer patients as controls for comparison. Total RNA was extracted for the TaqManM-BM-. Low Density Assay v3.0

2012-12-19 | E-GEOD-37426 | biostudies-arrayexpress

Gene expression in RNP autoantibody+ systemic lupus erythematosus (SLE) patient blood

Project description:The goal of this study was to characterize gene expression profiles in RNP autoantibody+ SLE versus healthy blood donors with a focus on select cytokines that may be important in B cell activation and differentiation, including BAFF, IL-21, and IL-33. We utilized Affymetrix microarrays to characterize the global program of gene expression in the SLE patients, and to identify differentially expressed genes in patients compared to healthy controls. We examined a cohort of 79 consecutive patients classified as anti-ribonuclear protein (anti-RNP)+ systemic lupus erythematosus (SLE). All patients provided RNA samples obtained after providing informed consent. There were 73 female and 6 male subjects. Disease duration ranged from 0 to 453 months with a median of 37.5 months. SLE Disease Activity Index (SLEDAI) ranged from 0 to 31 with a median of 6. mRNA from the blood of a SLE cohort (79 patients with some repeat visits for a total of 99 arrays) and 30 healthy volunteers (one array per volunteer) were analyzed.

2015-01-01 | E-GEOD-61635 | biostudies-arrayexpress

Systemic lupus erythematosus

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-06-03 | E-GEOD-46923 | biostudies-arrayexpress