The interplay of inflammation and cardiovascular disease in systemic lupus erythematosus

Patients with systemic lupus erythematosus have up to a 50-fold increased risk of developing atherosclerotic cardiovascular disease. Recent advances in the etiology of vascular damage in this disease stress the interplay of lupus-specific inflammatory factors with traditional cardiac risk factors, leading to increased endothelial damage. This review analyzes the putative role that immune dysregulation and lupus-specific factors may play in the pathogenesis of premature vascular damage in this disease. The potential role of various cytokines, in particular type I interferons, in the development of accelerated atherosclerosis is examined. Potential therapeutic targets are discussed

Suboptimal cardiovascular risk factor identification and management in patients with rheumatoid arthritis: a cohort analysis

Abstract Introduction Accelerated cardiovascular (CV) disease significantly contributes to increased mortality in rheumatoid arthritis (RA) patients, with a risk comparable to the one observed in patients with type 2 diabetes mellitus (DM). Part of this enhanced risk in RA is attributed to traditional cardiovascular risk factors (CRFs). The aims of this study were to determine how often traditional CRFs are identified and managed by (a) rheumatologists, compared with primary care physicians (PCPs) in RA patients; and (b) PCPs among patients with RA, DM, and the general population (GP). Methods A retrospective cohort study compared age/gender/ethnicity-matched patients from three groups: RA, DM, and GP (without RA or DM); n = 251 patients per group. Electronic patient records were reviewed during a continuous 12-month period between June 2007 and April 2011 to assess whether CRFs were identified and managed. Results In RA patients, PCPs managed obesity, BP, and lipids significantly more often than did rheumatologists. PCPs managed obesity, BP, and lipids significantly more often in diabetic patients than in the other two groups, and more often in the GP than in RA patients. In patients with elevated BMI, PCPs managed weight in 68% of the DM group, 46% of the GP, and 31% of the RA group (P < 0.0001 for all groups; P = 0.006 between RA and GP groups). Conclusions Rheumatologists identify and manage CRFs less frequently than PCPs. PCPs manage CRFs less frequently in RA patients, compared to the GP and DM. Given the increased CV risk associated with RA, physicians need to more aggressively manage CRFs in these patients.http://deepblue.lib.umich.edu/bitstream/2027.42/112715/1/13075_2012_Article_3854.pd

Myeloid dendritic cells display downregulation of C-type lectin receptors and aberrant lectin uptake in systemic lupus erythematosus

Abstract Introduction There is a growing body of evidence implicating aberrant dendritic cell function as a crucial component in the immunopathogenesis of systemic lupus erythematosus. The purpose of the present study was to characterize the phagocytic capacity and expression of receptors involved in pathogen recognition and self-nonself discrimination on myeloid dendritic cells from patients with lupus. Methods Unstimulated or stimulated monocyte-derived dendritic cells were obtained from lupus patients and healthy control individuals, and expression of C-type lectin receptors (mannose receptor and dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin), complement-receptor 3 and Fcγ receptors was determined by flow cytometry. Dextran uptake by lupus and control dendritic cells was also assessed by flow cytometry. Serum IFNγ was quantified by ELISA, and uptake of microbial products was measured using fluorescently labeled zymosan. Results When compared with dendritic cells from healthy control individuals, unstimulated and stimulated lupus dendritic cells displayed significantly decreased dextran uptake and mannose receptor and dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin expression. Decreased expression of the mannose receptor was associated with high serum IFNγ levels, but not with maturation status or medications. Diminished dextran uptake and mannose receptor expression correlated with lupus disease activity. There were no differences between control and lupus dendritic cells in the expression of other pattern recognition receptors or in the capacity to uptake zymosan particles Conclusions Lupus dendritic cells have diminished endocytic capacity, which correlates with decreased mannose receptor expression. While this phenomenon appears primarily intrinsic to dendritic cells, modulation by serum factors such as IFNγ could play a role. These abnormalities may be relevant to the aberrant immune homeostasis and the increased susceptibility to infections described in lupus.http://deepblue.lib.umich.edu/bitstream/2027.42/112498/1/13075_2008_Article_2366.pd

The role of aldosterone blockade in murine lupus nephritis

Abstract Background The purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB × NZW) F1 murine lupus model. Methods Female NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria, renal function, and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points. Targeted microarray analysis was performed on renal tissue, with subsequent real-time PCR analysis of several differentially expressed genes. Results Treatment with spironolactone was well tolerated by the mice throughout the course of their disease progression, with no significant differences in azotemia or serum potassium levels between vehicle-treated and spironolactone-treated animals. By 36 weeks of age, fewer spironolactone-treated mice developed nephrotic range proteinuria as compared with the control mice (control 70.8%, 25 mg/kg spironolactone 51.3%, and 50 mg/kg spironolactone 48.6%). Compared with control mice, mice treated with 25 mg/kg spironolactone had significantly lower serum anti-single-stranded DNA levels (2,042 μg/ml versus 1,036 μg/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 μg/ml versus 614 μg/ml; P = 0.05). Spironolactone-treated mice exhibited decreased histopathologic evidence of inflammation and tissue damage, as compared with control mice. Additionally, spironolactone treatment resulted in decreased expression in the kidney of several inflammatory and proapoptotic genes, including those encoding interferon-γ, B lymphocyte stimulator (BlyS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), tumor necrosis factor related weak inducer of apoptosis (TWEAK), and Fas ligand. Conclusion Aldosterone receptor blockade is safe and well tolerated in progressive murine lupus nephritis, and it results in decreased levels of clinical proteinuria, lower serum levels of autoantibodies, and decreased kidney damage. It appears to modulate inflammatory changes during the progression of glomerulonephritis and may also have a previously undescribed role in attenuating apoptosishttp://deepblue.lib.umich.edu/bitstream/2027.42/112839/1/13075_2007_Article_2203.pd

High‐Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152788/1/art41059_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152788/2/art41059.pd

Dysfunction of endothelial progenitor cells is associated with the type I IFN pathway in patients with polymyositis and dermatomyositis

Objective. Alterations in phenotype and function of endothelial progenitor cells (EPCs) have been associated with poor vascular outcomes and impaired vascular repair in various conditions. Our hypothesis was that patients with PM and DM have dysregulation of EPCs driven by type I IFN and IL-18 similar to other autoimmune diseases. Methods. Quantification of circulating EPCs was performed by flow cytometry in patients with PM/DM and matched healthy controls. The ability of EPCs to differentiate into mature endothelial cells was investigated by light and fluorescence microscopy quantification in the presence or absence of PM/DM or control serum, neutralizing antibodies to type I IFN receptor or IL-18. Serum type I IFN activity was quantified by induction of type I IFN-inducible genes in HeLa cells. Circulating IL-18 concentrations were assessed by ELISA. Results. Circulating EPCs were significantly lower in PM/DM patients compared with controls. PM/DM EPCs displayed a decreased capacity to differentiate into mature endothelial cells and PM/DM serum significantly inhibited differentiation of control EPCs. This effect was reversed in the majority of samples with neutralizing antibodies to IL-18 or to type I IFN receptor or by a combination of these antibodies. Patients with associated impairments in EPC function had higher type I IFN serum activity. Conclusion. PM/DM is associated with dysregulation of EPC phenotype and function that may be attributed, at least in part, to aberrant IL-18 and type I IFN pathways. The implication of these vasculopathic findings for disease prognosis and complications remains to be determined

The Peroxisome Proliferator Activated Receptor‐γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139088/1/jah3374.pd

Type I Interferons Are Associated with Subclinical Markers of Cardiovascular Disease in a Cohort of Systemic Lupus Erythematosus Patients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94405/1/Somers_2012_Type_I_Interferons_subclinical_markers.pdf165

Brief Report: Endothelial Progenitor Cell Phenotype and Function Are Impaired in Childhood‐Onset Systemic Lupus Erythematosus

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112288/1/art39149.pd

Real-time deformability cytometry reveals sequential contraction and expansion during neutrophil priming.

It has become increasingly apparent that the biomechanical properties of neutrophils impact on their trafficking through the circulation and in particularly through the pulmonary capillary bed. The retention of polarized or shape-changed neutrophils in the lungs was recently proposed to contribute to acute respiratory distress syndrome pathogenesis. Accordingly, this study tested the hypothesis that neutrophil priming is coupled to morpho-rheological (MORE) changes capable of altering cell function. We employ real-time deformability cytometry (RT-DC), a recently developed, rapid, and sensitive way to assess the distribution of size, shape, and deformability of thousands of cells within seconds. During RT-DC analysis, neutrophils can be easily identified within anticoagulated "whole blood" due to their unique granularity and size, thus avoiding the need for further isolation techniques, which affect biomechanical cell properties. Hence, RT-DC is uniquely suited to describe the kinetics of MORE cell changes. We reveal that, following activation or priming, neutrophils undergo a short period of cell shrinking and stiffening, followed by a phase of cell expansion and softening. In some contexts, neutrophils ultimately recover their un-primed mechanical phenotype. The mechanism(s) underlying changes in human neutrophil size are shown to be Na+ /H+ antiport-dependent and are predicted to have profound implications for neutrophil movement through the vascular system in health and disease