Neutrophils isolated from systemic lupus erythematosus patients exhibit a distinct functional phenotype.

Neutrophil dysregulation, particularly of a low-density subset, is associated with systemic lupus erythematosus (SLE); however, the exact role of normal-density neutrophils in SLE remains unknown. This study compares activation and functional phenotypes of neutrophils from SLE patients and healthy controls to determine potential contributions to SLE pathogenesis. Surface activation markers and release of neutrophil extracellular traps (NETs), granule proteins, and cytokines/chemokines were measured in resting and stimulated neutrophils from SLE patients (n=19) and healthy controls (n=10).

Epstein Barr Virus and Autoimmune Responses in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease. Infections or infectious reactivation are potential triggers for initiation of autoimmunity and for SLE flares. Epstein-Barr virus (EBV) is gamma herpes virus that has been associated with several autoimmune diseases such as SLE, multiple sclerosis, Sjogren's syndrome, and systemic sclerosis.

Epstein Barr virus nuclear antigen 1 (EBNA-1) peptides recognized by adult multiple sclerosis patient sera induce neurologic symptoms in a murine model.

Multiple sclerosis (MS) is an autoimmune demyelinating disease with progressive neurodegeneration and complex etiology likely involving genetic and environmental factors. MS has been associated with Epstein Barr virus (EBV) infection, with patients often showing enhanced responses to EBV antigens. To determine whether abnormal EBV nuclear antigen-1 (EBNA-1) humoral immunity can serve as an initiator of autoimmune responses in MS, we investigated the fine specificities of the humoral immune response against EBNA-1 in MS patients using solid phase epitope mapping.

Study of Frontal Alpha Asymmetry in Mild Depression: A Potential Biomarker or Not?

Background: Depression, despite being the most common of mental illness lacks any quantifiable and absolute biomarker. Frontal alpha asymmetry (FAA) is proposed as biomarker of depression both in resting and activated state. Yet, the location of extraction of alpha, clinical utility as well as validity of FAA is uncertain.

Epstein Barr Virus Interleukin 10 Suppresses Anti-inflammatory Phenotype in Human Monocytes.

Epstein Barr virus (EBV) is a gamma herpes virus associated with certain malignancies and autoimmune diseases. EBV maintains latency in B cells with occasional reactivation, in part by overcoming the host immune response with viral homologs of several human proteins. EBV interleukin 10 (vIL-10), a lytic phase protein, is a homolog of human IL-10 (hIL-10).

Frontal Theta Asymmetry as a Biomarker of Depression.

Introduction: Electroencephalography (EEG) has been used extensively to study affective disorders. Quantitative spectral analysis of an EEG scan has been used to assess the biological basis of emotional disorders such as depression as well as to investigate biomarkers of affective disorders. Inter-hemispheric asymmetries in both baseline and stimulus-evoked frequencies (alpha, beta, theta, and delta) are potential biomarkers of depression.

Biomarkers in connective tissue diseases.

Autoimmune connective tissue diseases are clinically variable, making biomarkers desirable for assessing future disease risk, supporting early and accurate diagnosis, monitoring disease activity and progression, selecting therapeutics, and assessing treatment response. Because of their correlations with specific clinical characteristics and often with disease progression, autoantibodies and other soluble mediators are considered potential biomarkers. Additional biomarkers might reflect downstream pathologic processes or appear because of ongoing inflammation and damage.

Urinary high-mobility group box-1 associates specifically with lupus nephritis class V.

Introduction: High-mobility group box 1 protein (HMGB-1) has been implicated in the pathogenesis of lupus nephritis (LN). There is increased HMGB-1 expression in the kidneys and increased levels are observed in serum and urine of patients with LN. This study was performed to determine whether the increased urinary HMGB-1 was specific for active lupus or secondary to renal damage.

Immune-Mediated Nephropathy and Systemic Autoimmunity in Mice Does Not Require Receptor Interacting Protein Kinase 3 (RIPK3).

Immune mediated nephropathy is one of the most serious manifestations of lupus and is characterized by severe inflammation and necrosis that, if untreated, eventually leads to renal failure. Although lupus has a higher incidence in women, both sexes can develop lupus glomerulonephritis; nephritis in men develops earlier and is more severe than in women. It is therefore important to understand the cellular and molecular mechanisms mediating nephritis in each sex.

SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.

Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex, however, the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca(2+)- and ROS-induced PTP opening using RNAi-based screening.

17β estradiol regulates adhesion molecule expression in mesangial cells during glomerulonephritis.

We showed previously that 17β estradiol (E2) led to improved survival in nephrotoxic serum induced nephritis (NTN) in male mice. In this study we determined whether E2 regulates vascular cell adhesion molecule (VCAM)-1, an adhesion molecule that is upregulated in kidney during autoimmune nephritis, in mesangial cells (MC). We show that E2 inhibited VCAM-1 up-regulation in kidneys in vivo during NTN, and in MCs upon TNFα stimulation.

Ca2+ signals regulate mitochondrial metabolism by stimulating CREB-mediated expression of the mitochondrial Ca2+ uniporter gene MCU.

Cytosolic Ca2+ signals, generated through the coordinated translocation of Ca2+ across the plasma membrane (PM) and endoplasmic reticulum (ER) membrane, mediate diverse cellular responses. Mitochondrial Ca2+ is important for mitochondrial function, and when cytosolic Ca2+ concentration becomes too high, mitochondria function as cellular Ca2+ sinks. By measuring mitochondrial Ca2+ currents, we found that mitochondrial Ca2+ uptake was reduced in chicken DT40 B lymphocytes lacking either the ER-localized inositol trisphosphate receptor (IP3R), which releases Ca2+ from the ER, or Orai1 or STIM1, components of the PM-localized Ca2+ -permeable channel complex that mediates store-operated calcium entry (SOCE) in response to depletion of ER Ca2+ stores.

The role of necrotic cell death in the pathogenesis of immune mediated nephropathies.

Necrosis, an inflammatory form of cell death, has been considered to be an accidental death and/or cell death due to injury. However, the literature in the last decade has established that necrosis is a regulated form of cell death, and that inhibition of specific molecular pathways leading to necrosis can block it and reduce inflammation. Since necrotic lesions are observed in several immune mediated human pathologies, in this review we will discuss the impact that this form of programmed cellular demise has in the pathology of immune mediated nephropathies.

Differential regulation of cell death programs in males and females by Poly (ADP-Ribose) Polymerase-1 and 17β estradiol.

Cell death can be divided into the anti-inflammatory process of apoptosis and the pro-inflammatory process of necrosis. Necrosis, as apoptosis, is a regulated form of cell death, and Poly-(ADP-Ribose) Polymerase-1 (PARP-1) and Receptor-Interacting Protein (RIP) 1/3 are major mediators. We previously showed that absence or inhibition of PARP-1 protects mice from nephritis, however only the male mice.

Myeloid dendritic cells from B6.NZM Sle1/Sle2/Sle3 lupus-prone mice express an IFN signature that precedes disease onset.

Patients with systemic lupus erythematosus show an overexpression of type I IFN-responsive genes that is referred to as "IFN signature." We found that B6.NZMSle1/Sle2/Sle3 (Sle1,2,3) lupus-prone mice also express an IFN signature compared with non-autoimmune C57BL/6 mice.

Caspase-activated DNase is required for maintenance of tolerance to lupus nuclear autoantigens.

Objective: Caspase-activated DNase (CAD) is an endonuclease that is activated by active caspase 3 during apoptosis and is responsible for degradation of chromatin into nucleosomal units. These nucleosomal units are then included in apoptotic bodies. The presence of apoptotic bodies is considered important for the generation of autoantigen in autoimmune diseases, such as systemic lupus erythematosus (SLE), that are characterized by the presence of antinuclear antibodies.

Requirement of FADD, NEMO, and BAX/BAK for aberrant mitochondrial function in tumor necrosis factor alpha-induced necrosis.

Necroptosis represents a form of alternative programmed cell death that is dependent on the kinase RIP1. RIP1-dependent necroptotic death manifests as increased reactive oxygen species (ROS) production in mitochondria and is accompanied by loss of ATP biogenesis and eventual dissipation of mitochondrial membrane potential. Here, we show that tumor necrosis factor alpha (TNF-α)-induced necroptosis requires the adaptor proteins FADD and NEMO.

Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation.

Necrotic lesions and necrotic cell death characterize severe autoimmune nephritides, and contribute to local inflammation and to progression of the disease. Poly(ADP-ribose) polymerase-1 (PARP-1), a DNA repair enzyme, is involved in the induction of necrosis and is a key player in the acute and chronic inflammation. Therefore, we hypothesized that PARP-1 controls the severity of nephritis by mediating the induction of necrosis in the kidney.

Counterregulation of clathrin-mediated endocytosis by the actin and microtubular cytoskeleton in human neutrophils.

We have recently reported that disruption of the actin cytoskeleton enhanced N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated granule exocytosis in human neutrophils but decreased plasma membrane expression of complement receptor 1 (CR1), a marker of secretory vesicles. The present study was initiated to determine if reduced CR1 expression was due to fMLP-stimulated endocytosis, to determine the mechanism of this endocytosis, and to examine its impact on neutrophil functional responses. Stimulation of neutrophils with fMLP or ionomycin in the presence of latrunculin A resulted in the uptake of Alexa fluor 488-labeled albumin and transferrin and reduced plasma membrane expression of CR1.

Comparison of proteins expressed on secretory vesicle membranes and plasma membranes of human neutrophils.

Secretory vesicles are neutrophil intracellular storage granules formed by endocytosis. Understanding the functional consequences of secretory vesicle exocytosis requires knowledge of their membrane proteins. The current study was designed to use proteomic technologies to develop a more complete catalog of secretory vesicle membrane proteins and to compare the proteomes of secretory vesicle and plasma membranes.

Heat shock protein 27 regulates neutrophil chemotaxis and exocytosis through two independent mechanisms.

The targets of the p38 MAPK pathway responsible for regulation of neutrophil chemotaxis and exocytosis are unknown. One target of this pathway is the actin-binding protein, heat shock protein 27 (Hsp27). Therefore, we tested the hypothesis that Hsp27 mediates p38 MAPK-dependent chemotaxis and exocytosis in human neutrophils through regulation of actin reorganization.

The actin cytoskeleton regulates exocytosis of all neutrophil granule subsets.

A comprehensive analysis of the role of the actin cytoskeleton in exocytosis of the four different neutrophil granule subsets had not been performed previously. Immunoblot analysis showed that, compared with plasma membrane, there was less actin associated with secretory vesicles (SV, 75%), gelatinase granules (GG, 40%), specific granules (SG, 10%), and azurophil granules (AG, 5%). Exocytosis of SV, SG, and AG was measured as increased plasma membrane expression of CD35, CD66b, and CD63, respectively, with flow cytometry, and GG exocytosis was measured as gelatinase release with an ELISA.

Calcium channel blockers and the CVS reflex responses during lower body suction.

Nine normal men (mean age 27.6 yr) were exposed to continuous lower-body suction pressure (LBSP) of -20 to -50 mmHg (for 5 min at each level) on four different occasions after having consumed a single oral therapeutic dose of either diltiazem, nifedipine, verapamil, or a placebo, randomly, in a single blind manner. The suction was applied at 12.