Function In Systemic Lupus Erythematosus Research Articles

Differences in body structure and function between patients with systemic lupus erythematosus and healthy individuals, with particular reference to joint hypermobility

Objectives: To explore differences in body structure and function in systemic lupus erythematosus (SLE) patients and controls, with particular reference to joint hypermobility, and to evaluate the usefulness of the Brighton criteria for diagnosing joint hypermobility syndrome (JHS) in SLE.Method: Female SLE patients were, according to age group, consecutively invited to participate in the study. Controls were healthy females matched for age. All individuals were examined by a physician according to the Brighton criteria, and by an occupational therapist and a physiotherapist to obtain the Beighton scores, overall joint mobility, and manifestations in body structure and function.Results: Sixteen (23%) SLE patients and 19 (27%) controls had a Beighton score ≥ 4 (non-significant, ns), and 39 (55%) individuals in the SLE group and 22 (31%) in the control group satisfied the Brighton criteria for JHS (p < 0.01). Many individuals in both groups exceeded the normative values for joint mobility in joints other than those included in the Beighton score. Stratifying for a Beighton score ≥ 4 vs. < 4, there were no significant differences in body structure or body function constituting JHS either in the SLE patients or in the controls.Conclusions: Although the presence of joint hypermobility in SLE patients was frequent, we could not verify that this caused excess manifestations in addition to the SLE symptoms.

Analysis of the Expression and Function of Immunoglobulin-Like Transcript 4 (ILT4, LILRB2) in Dendritic Cells from Patients with Systemic Lupus Erythematosus.

Dendritic cells (DC) play an important role in the development and maintenance of immune tolerance. Although the inhibitory receptor ILT4/LILRB2 has been related with the tolerogenic phenotype of DC, the possible role of this receptor in the breakdown of DC tolerogenic function in systemic lupus erythematosus (SLE) has not been elucidated. In this study, we analyzed the expression and function of the inhibitory receptor ILT4 in DC from SLE patients. We found that the percentage of ILT4 positive plasmacytoid DC and myeloid DC is significantly diminished in SLE patients. Interestingly, ligation of ILT4 did not affect the maturation or immunogenic capability of DC in healthy controls. In contrast, in SLE patients we observed an inhibitory effect of ILT4 on the immunogenic capability of DC. ILT4 was shown not to have a crucial role in regulating the maturation and function of DC from healthy controls but is partially involved in the maturation process and immunogenic capability of DC from SLE patients, suggesting that other inhibitory receptors, involved in the regulation of DC tolerogenic function, may be impaired in this autoimmune disease.

Impaired phagocytosis of apoptotic cell material in serologically active clinically quiescent patients with systemic lupus erythematosis.

Serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE) account for 8-12% of all patients with SLE, but there is disagreement about whether such patients are indeed clinically stable. Patients with clinically active SLE have decreased macrophage function, although the status of SACQ patients with SLE is unclear. This study compared 18 patients who met the diagnostic criteria for SACQ SLE with 18 healthy volunteers with regard to the capability of macrophages to clear apoptotic bodies by use of a modified serum-free phagocytosis test. Macrophages that naturally differentiated from monocytes were used to engulf apoptotic cells developed from polymorphonuclear neutrophils. The results showed that macrophages from SACQ patients with SLE had less phagocytotic capability than those from healthy controls. The significant reduction of macrophage phagocytotic capability in these patients suggests the potential for disease recurrence. The use of a serum-free method confirmed the presence of intrinsic factors that modulate the decrease of macrophage function in SLE.

Whenmightisn’t right: the impact of muscle weakness on physical function in systemic lupus erythematosus

Pascal, the renowned 17th century French philosopher and mathematician, was admittedly concerned less with physical weakness, than with spiritual or moral weakness when he penned this statement of surprise. Nevertheless, the sense of astonishment underlying his words remains apropos to our discussion of physical weakness among individuals with systemic lupus erythematosus (SLE). Reduced physical functioning is common among individuals with SLE and is frequently associated with significantly reduced health-related quality of life [1,2]. Differences in body composition, and in particular differences in muscle strength, represent an important etiology of reduced physical functioning among individuals with SLE. What is truly surprising is that despite the considerable burden of physical disability and muscle weakness in SLE, published data addressing these relationships remain limited. There exists, however, a body of literature examining relationships between body composition, muscle strength and physical disability among other chronic conditions, both rheumatic and nonrheumatic. Among elders and individuals with osteoarthritis (OA), muscle strength and muscle mass (both regional and total body muscle mass) are inversely related to physical disability [3,4]. However, muscle strength is more closely related to the degree of disability than is muscle mass among the elderly [5]. Among individuals with rheumatoid arthritis (RA), similar relationships exist between muscle mass, muscle strength and physical disability [6]; and, similar to in OA, in RA measures related to muscle function are more strongly associated with differences in physical functioning than are measures of muscle mass [7]. Taken together, these observations suggest that muscle strength makes an important contribution to an individual’s physical functioning in various populations. Until recently it was not known whether similar relationships exist among individuals with SLE. Our group recently demonstrated that among women with SLE muscle strength is directly associated with differences in physical functioning even when adjusting for differences in muscle mass; and differences in muscle strength at baseline predict changes in physical functioning 2 years later [8,9]. In this cohort of adult women with SLE, reduced lower extremity muscle strength (measured by knee strength and chair stand time) but not reduced muscle mass was associated with reduced self-reported physical functioning on the SF-36 Physical Functioning subscale and on the Valued Life Activities assessment, when adjusting for covariates such as disease activity, medication use and depression. Reduced knee strength also predicted significant decreases in physical functioning approximately 2 years later, as measured by the Short Physical Performance Battery When might isn’t right: the impact of muscle weakness on physical function in systemic lupus erythematosus

Human Radiation Dosimetry for the N-Methyl-D-Aspartate Receptor Radioligand 11C-CNS5161.

(11)C-CNS5161 (N-(2-chloro-5-methylthiophenyl)-N'-(3-methylthiophenyl)-N'-(11)C-methylguanidine) has been successfully used in PET imaging of N-methyl-d-aspartate (NMDA) receptors. However, no human dosimetry data have been published. We are planning to use this radiotracer for investigating NMDA receptor function in systemic lupus erythematosus, traumatic brain injury, and Parkinson disease. We have therefore undertaken (11)C-CNS5161 PET imaging to measure the whole-body distribution of this radionuclide and to estimate radiation dose to various organs. Dynamic PET studies of the whole body were performed on 5 healthy adults. Regions of interest were drawn over the visualized structures. Resultant time-activity curves were generated and used to determine residence times for dosimetry calculations. S factors were implemented within the OLINDA/EXM software for each structure or organ. For (11)C-CNS5161, organ doses ranged from 0.0002 to 0.0393 mGy/MBq (0.0006-0.1455 rad/mCi). The critical organ for radiation burden was the lungs, with a dose of 0.0393 mGy/MBq (0.1455 rad/mCi). Radiation doses to the reproductive and blood-forming organs were 0.0023, 0.0002, and 0.0020 mGy/MBq (0.0086, 0.0006, and 0.0074 rad/mCi) for the ovaries, testes, and red marrow, respectively. The effective dose equivalent was 0.0106 mSv/MBq (0.0392 rem/mCi). The radiation dosimetry for (11)C-CNS5161 for a standard single injection of 555 MBq (15 mCi) will result in an effective dose equivalent of 5.9 mSv (0.59 rem) and a lung dose of 21.8 mGy (2.18 rad) in young, healthy subjects.

Interferon-α induces altered transitional B cell signaling and function in Systemic Lupus Erythematosus

Previous studies suggest that the B cells of patients with Systemic Lupus Erythematosus (SLE) are hyper-responsive to BCR crosslinking; however, it has been unclear whether this is the result of altered B cell signaling or differences in various B cell subpopulations in SLE patients as compared to healthy controls. Here we have developed a novel Phosflow technique that permits examination of cell signaling in distinct B cell subpopulations stratified based upon developmental stage and cell surface IgM levels, which we use to show that the naïve B cells of SLE patients are hyper-responsive to IgM receptor crosslinking, resulting in increased SYK phosphorylation. We further demonstrate that this hyper-responsiveness is most marked in the transitional B cell subset and that it is associated with altered function, resulting in decreased apoptosis and increased proliferation of these cells. Examination of repeated samples from the same patients revealed that the hyper-responsiveness fluctuated over time, suggesting that it may be mediated by pro-inflammatory factors rather than genetic variations between patients. In support of this concept, incubation of healthy control B cells with IFN-α or SLE plasma induced the hyper-responsive phenotype, which was blocked by anti-IFN-α antibody. Furthermore, no obvious correlation was seen between genetic variants that are proposed to alter BCR signaling and the increased SYK phosphorylation. The findings suggest that pro-inflammatory factors, in particular Type I IFNs, modulate B cell function in SLE in a way that could contribute to the breach of tolerance in this condition.

AB1080 Comparison of Physical Function in SLE and RA Using Mdhaq

BackgroundThe rheumatic diseases have significant impact on patients' physical function. Patient reported outcome (PRO) tools provide insight into physical function, and are the most significant clinical predictor of work disability...

AB0043 Regulatory Function of Natural Killer Cells in Systemic Lupus Erythematosus (SLE)

BackgroundNatural killer (NK) cells are large granular lymphocytes that belong to the innate immunity. The activation or inhibition of NK cells is regulated by several membrane receptors, commonly designated as...

AB0023 In Vivo Effects of Epratuzumab, A Monoclonal Antibody Targeting Human CD22, on B Cell Function in Human CD22 Knock-In (HUKI) Mice

BackgroundEpratuzumab is a humanized monoclonal antibody that targets the B cell-specific protein CD22 and is currently in Phase 3 clinical trials in patients (pts) with systemic lupus erythematosus (SLE). Epratuzumab...

P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.

Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients

Patients with the autoimmune rheumatic disease systemic lupus erythematosus (SLE) have multiple defects in lymphocyte signaling and function that contribute to disease pathogenesis. Such defects could be attributed to alterations in metabolic processes, including abnormal control of lipid biosynthesis pathways. Here, we reveal that CD4+ T cells from SLE patients displayed an altered profile of lipid raft-associated glycosphingolipids (GSLs) compared with that of healthy controls. In particular, lactosylceramide, globotriaosylceramide (Gb3), and monosialotetrahexosylganglioside (GM1) levels were markedly increased. Elevated GSLs in SLE patients were associated with increased expression of liver X receptor β (LXRβ), a nuclear receptor that controls cellular lipid metabolism and trafficking and influences acquired immune responses. Stimulation of CD4+ T cells isolated from healthy donors with synthetic and endogenous LXR agonists promoted GSL expression, which was blocked by an LXR antagonist. Increased GSL expression in CD4+ T cells was associated with intracellular accumulation and accelerated trafficking of GSL, reminiscent of cells from patients with glycolipid storage diseases. Inhibition of GSL biosynthesis in vitro with a clinically approved inhibitor (N-butyldeoxynojirimycin) normalized GSL metabolism, corrected CD4+ T cell signaling and functional defects, and decreased anti-dsDNA antibody production by autologous B cells in SLE patients. Our data demonstrate that lipid metabolism defects contribute to SLE pathogenesis and suggest that targeting GSL biosynthesis restores T cell function in SLE.

Impact of genetic variants on B-cell development and function in systemic lupus erythematosus

Impact of genetic variants on B-cell development and function in systemic lupus erythematosus

MicroRNA-let-7a promotes E2F-mediated cell proliferation and NFκB activation in vitro

Epigenetic factors, including altered microRNA (miRNA) expression, may contribute to aberrant immune cell function in systemic lupus erythematosus (SLE). MiRNA-let-7a (let-7a) has been shown to directly alter cell cycle progression and proinflammatory cytokine production. Due to the crucial role of let-7a in cell division and inflammation, we investigated let-7a-mediated proliferation and NFκB translocation in J774A.1 macrophages and MES 13 mesangial cells in vitro. In immune-stimulated cells transfected with let-7a, cell proliferation was significantly increased over time. There was a significant increase in the number of immune-stimulated cells in S and G2 phases. Immune-stimulated cells overexpressing let-7a had increased nuclear translocation of NFκB. Bioinformatical analysis revealed that the E2F family, critical regulators of the G1-S transition, has potential binding sites for let-7a in their mRNA transcripts. Let-7a overexpression significantly increased the expression of the cell cycle activator E2F2 and increased retinoblastoma protein (Rb) phosphorylation in immune-stimulated cells. The cell cycle inhibitor E2F5 was significantly decreased in let-7a-transfected cells that were immune-stimulated. Bioinformatical analysis revealed E2F2 and NFκB are transcription factors predicted to regulate the let-7a promoter. We analyzed transcriptional regulation of let-7a by real-time RT-PCR using chromatin immunoprecipitation with E2F2 and NFκB antibodies. There was an increase in E2F2 and NFκB binding in DNA enriched for the let-7a promoter in immune-stimulated cells. Silencing E2F2 or NFκB significantly decreased let-7a expression and IL-6 production in immune-stimulated cells. Taken together, our results suggest that overexpression of let-7a may contribute to hyperplasia and the proinflammatory response in SLE.

The Percentage of FoxP3+Helios+ Treg Cells Correlates Positively With Disease Activity in Systemic Lupus Erythematosus

To assess the use of Helios in combination with FoxP3 as a superior method for identifying non-cytokine-producing human Treg cells in patients with systemic lupus erythematosus (SLE) and to determine if FoxP3+Helios+ Treg cells are maintained at normal levels in patients with clinically active disease. Peripheral blood mononuclear cells (PBMCs) were purified from the blood of healthy volunteer donors and from 52 consecutive patients with SLE of varying clinical activity (Systemic Lupus Erythematosus Disease Activity Index scores of 0, 2-4, and ≥ 5). PBMCs (either fresh or after 4 hours of stimulation for cytokine production) were then analyzed by flow cytometry for the expression of cell surface markers (CD4, CD25, CD127, and CD45RA) and transcription factors (FoxP3 and Helios), as well as for the production of cytokines (interleukin-2 and interferon-γ). FoxP3+Helios+ Treg cells were found to be non-cytokine producing in both SLE patients and healthy controls. Patients with clinically active SLE had higher percentages of FoxP3+Helios+ Treg cells than did patients with inactive SLE or healthy controls. When corrected for the total CD4 cell count, the absolute numbers of FoxP3+Helios+ Treg cells in patients with moderately-to-highly active SLE were normal. Previous reports of a deficiency in Treg cell number or function in SLE are limited by their use of CD25, either alone or in combination with other markers, to identify human Treg cells. Helios in combination with FoxP3 is a superior method for detecting all non-cytokine-producing Treg cells, irrespective of CD25 or CD45RA expression. Using this method, we showed that FoxP3+Helios+ Treg cell numbers are not reduced in patients with clinically active SLE.

Gene-function studies in systemic lupus erythematosus

The aetiology of systemic lupus erythematosus (SLE) is complex and is known to involve both genetic and environmental factors. In a small number of patients, single-gene defects can lead to the development of SLE. Such genes include those encoding early components of the complement cascade and the 3'-5' DNA exonuclease TREX1. In addition, genome-wide association studies have identified single-nucleotide polymorphisms that confer some susceptibility to SLE. In this Review, we discuss selected examples of genes whose products have distinctly altered function in SLE and contribute to the pathogenic process. Specifically, we focus on the genes encoding integrin αM (ITGAM), IgG Fc receptors, sialic acid O-acetyl esterase (SIAE), the catalytic subunit of protein phosphatase PP2A (PPP2CA) and signalling lymphocytic activation molecule (SLAM) family members. Moreover, we highlight the changes in epigenetic signatures that occur in SLE. Such epigenetic modifications, which are abundantly present and might alter gene expression in the presence or absence of susceptibility variants, should be carefully considered when deconstructing the contribution of individual genes to the complex pathogenesis of SLE.

AB0014 Implication of VEGFR2 in systemic lupus erythematosus: A combined genetic and structural biological approach

BackgroundThe vascular endothelial growth factor receptor 2 (VEGFR2) gene polymorphisms have already been correlated with vascular diseases such as Coronary Heart Disease (CHD). In view of the premature atherosclerosis observed...

AB0649 Morphofunctional penile alterations with severe sperm abnormalities in antiphospholipid syndrome associated with systemic lupus erythematosus

BackgroundWe identified severe sperm abnormalities associated with intravenous cyclophosphamide (IVCYC) use and reduced penile dimensions with no deleterious effect in erectile function in systemic lupus erythematosus (SLE) patients.1 In contrast,...

FRI0277 Arterial stiffness in systemic lupus erythematosus (SLE) patients: a controlled study

BackgroundArterial stiffness reflects changes in mechanical properties of vascular wall that occurs early with onset of vascular disease and may be a reliable surrogate marker for cardiovascular disease (CVD) in...

A Novel Epitope from CD22 Regulates Th1 and Th17 Cell Function in Systemic Lupus Erythematosus

The published antibodies (Abs) against CD22 on B cells including Epratuzumab could inhibit B cell activation mainly through binding to C2-set Ig domain of CD22, but they are rarely reported to modulate the pathogenic CD4+ T cell function in systemic lupus erythematosus (SLE). Recently, it was proved that the extracellular amino-terminal V-set Ig domain of CD22 might mediate the interaction of B and T cells, but for now the exact effect of this domain on CD4+ T cell biology have not been identified. Thus, in this study, we screened out a peptide termed B2285 from this V-set Ig domain, developed the novel specific anti-B2285 Abs in rabbits, and investigated their effects in MRL/lpr mice with spontaneous SLE. The results showed that anti-B2285 Abs could ameliorate the disease severity obviously in spontaneous SLE mice with the decreased differentiations of Th1 and Th17 cells and no changes of Th2 and Treg cells. In co-cultured B cells and CD4+ T cells, this specific anti-CD22 Abs was observed to inhibit the anti-dsDNA Abs production, CD4+ T cells proliferation, the protein levels of T-bet and RORγt, and the mRNA levels of TNF-α, IFN-γ, IL-6 and IL-17 in CD4+ T cells. Moreover, the expression of CD45RO on CD4+ T cells could be also apparently diminished by this novel Abs. The data suggested that anti-B2285 Abs could slow SLE progression significantly by regulating Th1 and Th17 cells function via B-T cell interaction and the cytokine network regulation. The treatment against V-set Ig domain of CD22 would be a valuable therapeutic method for SLE and other autoimmune diseases.

100 SYSTEMIC LUPUS ERYTHEMATOSUS IS ASSOCIATED WITH IMPAIRED MYOCARDIAL STRAIN AND VASCULAR FUNCTION, INCREMENTAL TO THAT CAUSED BY TRADITIONAL RISK FACTORS: A CARDIOVASCULAR MAGNETIC RESONANCE STUDY

<h3>Introduction</h3> Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder that commonly affects the heart. The impact of SLE on the heart is a 7–9 times greater incidence of cardiovascular disease(CVD) in SLE patients compared to healthy controls. Moreover, female patients with SLE between 35 and 44 years old have an incidence of myocardial infarction over 50 times greater than that observed in the Framingham cohort. The exact cause of this excess CVD burden in SLE is poorly understood, but is thought to be multi-factorial. Cardiovascular magnetic resonance (CMR) has the capacity of simultaneously assessing non-invasively cardiac function, altered vascular distensibility, myocardial strain and fibrosis. <h3>Objective</h3> The purpose of this study was to assess cardiac and vascular function and myocardial strain in patients with SLE and to determine their relation to the presence of cardiovascular risk factors (CVRFs) and SLE disease duration. <h3>Methods</h3> 11 SLE patients with no CVRFs (11 female, mean age 37±7), 19 SLE patients with CVRFs (18 female, mean age 47±11), 39 normal controls (39 female, mean age 45±12), and 11 controls with CVRFs (11 female, mean age 52±9), underwent CMR at 1.5 T. All patients with previously known CVD were excluded. CVRFs, disease activity index and duration of disease were recorded for each subject. Biventricular volumes and function, LGE, myocardial strain and vascular function were assessed by CMR. Aortic distensibility and pulse wave velocity (PWV) were measured in the ascending aorta, proximal descending aorta and distal descending aorta. <h3>Results</h3> There were no differences in left ventricular (LV) volumes and LV ejection fraction between the four groups (table&nbsp;1). SLE patients with CVRFs showed the greatest reduction in mid short axis circumferential systolic strain, peak diastolic strain rate, and vascular indices. SLE patients without CVRFs showed a similar degree of vascular dysfunction and deformational abnormality as controls with CVRFs. Aortic distensibility (Rs=−0.59, p&lt;0.001) and total pulse wave velocity (Rs=0.29, p=0.01) correlated with SLE disease duration (table&nbsp;2). <h3>Conclusions</h3> Evidence of impaired circumferential systolic strain and vascular function in SLE is demonstrated on CMR assessment, which is independent and incremental to that due to traditional CVRFs.