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At least 811 records · Page 45Linked to original sources
PubMed2005

HIV-associated immune complex glomerulonephritis with "lupus-like" features: a clinicopathologic study of 14 cases.

BACKGROUND: While the most common glomerular lesion associated with human immunodeficiency virus (HIV) infection is collapsing focal segmental glomerulosclerosis (FSGS) [HIV-associated nephropathy (HIVAN)], immune complex-mediated forms of glomerulonephritis have been increasingly reported. One form of glomerulonephritis that has been described in the HIV-infected population is immune complex glomerulonephritis with "lupus-like" features, characterized by histologic, immunohistologic, and ultrastructural features resembling lupus nephritis, but occurring in patients without evidence of systemic lupus erythematosus (SLE). Data regarding clinical outcomes in patients with this form of glomerulonephritis are very limited. METHODS: We reviewed pathology reports for all native renal biopsy specimens from HIV-positive patients processed at our center from January 1999 through December 2003. Of 77 total specimens, 14 met the following criteria for lupus-like glomerulonephritis: (1) immunofluorescence microscopy showed granular glomerular staining for IgG, IgA, IgM, C3 and C1q, with > or=1+ (0 to 4+ scale) staining for C1q; and (2) the patient's serum was negative for antinuclear antibodies (ANA), or weakly positive (titer < or =1:80) for ANA and negative for antidouble-stranded DNA. RESULTS: Clinically, ten of the 14 patients with lupus-like glomerulonephritis presented with nephrotic syndrome, all had microscopic hematuria, and nine had serum creatinine >3.0 mg/dL. All but one were African American. Histologically, seven biopsies showed diffuse proliferative glomerulonephritis, six focal proliferative glomerulonephritis, and one membranous nephropathy. All but two biopsies showed moderate or severe chronic change, and three showed concurrent HIVAN. Ten of the 14 patients developed end-stage renal disease (ESRD) within 1 year of the biopsy. Nine of these ten patients presented with proteinuria >5.0 g/24 hours and nephrotic syndrome, while three of four patients who did not develop ESRD had proteinuria < or =3.0 g/24 hours. CONCLUSION: Lupus-like glomerulonephritis, defined by immunohistologic features and absence of serologic evidence of SLE, is not an uncommon form of glomerular disease in HIV-infected patients undergoing a renal biopsy. Renal outcomes in these patients were poor, although this may be due largely to most patients presenting with advanced disease.

AIDS-Associated Nephropathy↗
PubMed2004

Less thought, more punishment: need for cognition predicts support for punitive responses to crime.

Three studies examined the relationship between need for cognition and support for punitive responses to crime. The results of Study 1 (N = 110) indicated that individuals high in need for cognition were less supportive of punitive measures than their low need for cognition counterparts. This finding was replicated in Study 2 (N = 1,807), which employed a nationally representative probability sample and included a more extensive battery of control variables. The purpose of Study 3 (N = 255) was to identify a third variable that might explain this relationship. This final study's results suggest that attributional complexity mediates the relationship between need for cognition and punitiveness. High need for cognition individuals are less supportive of punitive measures because they endorse more complex attributions for human behavior than their low need for cognition peers.

Attitude↗
PubMed1982

Absence of circulating IgG immune Complexes in C57Bl/6 mice with age-associated renal IgG deposits.

The L1210 enzyme-linked immunoassay (ELIA) for circulating immune complexes, previously developed for use in humans, has been adapted for use in mice. The assay detected elevated levels of immune complexes in 100% of NZB/W female mice (6-10 months old) with age-related immune complex-mediated glomerulonephritis. Application of the assay to the serum of one year old C57Bl/6 male mice failed to demonstrate elevated levels of serum immune complexes in spite of the routine finding of renal deposition of IgG plus proteinuria in aged mice of this strain. Since the L1210 ELIA detects all IgG-containing immune complexes, regardless of size or complement fixing capacity, these results suggest that the renal IgG deposits seen in aged C57Bl/6 mice are not derived from circulating IgG immune complexes.

Aging↗
PubMed2005

Ig alpha/Ig beta complexes generate signals for B cell development independent of selective plasma membrane compartmentalization.

Ligand-induced BCR association with detergent-resistant plasma membrane compartments (lipid rafts) has been argued to be essential for initiating and/or sustaining Igalpha/Igbeta-dependent BCR signaling. Because a fraction of the BCR and an even larger fraction of the preBCR associates with lipid rafts in the apparent absence of ligand stimulation, it has been proposed that raft-associated receptor complexes mediate the ligand-independent basal signaling events observed in resting B lineage cells. However, there is no direct evidence that localization of Igalpha/Igbeta-containing complexes to detergent-resistant membrane compartments is absolutely required for the signaling events that drive B cell development. To address these issues we have designed surrogate preBCR/Igalpha/Igbeta complexes that are incapable of ligand-induced aggregation and that are preferentially targeted to either raft or nonraft compartments. An analysis of their ability to promote the preBCR-dependent proB-->preB cell transition of murine B cell progenitors revealed that expression of these surrogate receptor complexes at levels that approximate that of the conventional preBCR can drive B cell development in a manner independent of both aggregation and lipid raft localization.

Animals↗
PubMed1999

Reactive oxygen intermediates enhance Fc gamma receptor signaling and amplify phagocytic capacity.

Receptors for the Fc region of IgG (Fc gamma R) mediate internalization of opsonized particles by human neutrophils (PMN) and mononuclear phagocytes. Cross-linking of Fc gamma R leads to activation of protein tyrosine kinases and phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) within Fc gamma R subunits, both obligatory early signals for phagocytosis. Human PMN constitutively express two structurally distinct Fc gamma R, Fc gamma RIIa and Fc gamma RIIIb, and can be induced to express Fc gamma RI by IFN-gamma. We have previously shown that stimulation of PMN through Fc gamma RIIIb results in enhanced Fc gamma RIIa-mediated phagocytic activity that is inhibited by catalase. In the present study, we have tested the hypothesis that reactive oxygen intermediates (ROI) have the capacity to regulate Fc gamma R responses and defined a mechanism for this effect. We show that H2O2 augmented phagocytosis mediated by Fc gamma RIIa and Fc gamma RI in PMN and amplified receptor-triggered tyrosine phosphorylation of Fc gamma R-associated ITAMs and signaling elements. Generation of endogenous oxidants in PMN by cross-linking Fc gamma RIIIb similarly enhanced phosphorylation of Fc gamma RIIa and Syk, a tyrosine kinase required for phagocytic function, in a catalase-sensitive manner. Our results provide a mechanism for priming phagocytes for enhanced responses to receptor-driven effects. ROI generated in an inflammatory milieu may stimulate quiescent cells to rapidly increase the magnitude of their effector function. Indeed, human monocytes incubated in the presence of stimulated PMN showed oxidant-induced increases in Fc gamma RIIa-mediated phagocytosis. Definition of the role of oxidants as amplifiers of Fc gamma R signaling identifies a target for therapeutic intervention in immune complex-mediated tissue injury.

Adjuvants, Immunologic↗
PubMed1991

Interactions of immunoglobulins and chondrocytes.

Our study relates to damage of articular cartilage by deposition of immune complexes. Addition of IgG to cultured chondrocytes affected their metabolism--boosting metalloprotease synthesis, generating superoxide anion (O2-), and reducing the synthesis of sulfated glycosaminoglycans (S-GAG). Heat aggregation of the IgG enhanced its effect on O2- and S-GAG. Some interleukin 1 beta (38 pg/ml) was detected by ELISA after exposure to heat aggregated IgG. There was no cytotoxic effect due to IgG alone, but addition of complement (5% bovine serum) caused significant loss of intracellular 51Cr, which was further increased by addition of heat aggregated IgG. Similar responses of chondrocytes in vivo might account for immune complex mediated damage of cartilage.

Animals↗
PubMed1989

Surfactant replacement: immunological considerations.

We sought to analyse the potential immunogenicity of human alveolar surfactant as it is currently used in the treatment of neonatal respiratory distress syndrome (RDS). An enzyme linked immunosorbant assay capable of detecting specific immune complexes between surfactant and antibodies directed to surfactant was developed. Premature infants with RDS were divided into groups: one group received surfactant replacement and one received conventional therapy. Plasma samples obtained from these infants at birth and thereafter were examined for specific circulating immune complexes between surfactant and anti-surfactant antibodies. All babies were also examined for clinical and serological evidence of immune complex-mediated tissue damage. We found that almost all infants with RDS, regardless of their therapy, showed evidence of circulating surfactant-anti-surfactant immune complexes. Plasma samples from infants without RDS showed no such complexes. Immune complexes appeared early in postnatal life, usually within the first week, and diminished thereafter. We detected no evidence of altered plasma complement levels or end organ damage attributable to these immune complexes. Thus, circulating immune complexes between surfactant and antibodies to surfactant are common in neonatal respiratory distress syndrome, though they do not appear to cause injury. Since not only human but heterologous surfactants are now used in treating RDS, we feel that cautious evaluation of potential immune reactions to the administered materials should be undertaken.

Antigen-Antibody Complex↗
PubMed1997

HER2-targeted gene transfer.

Selective transfer of genes to specific cells remains a barrier to successful utilization of somatic gene therapy. We hypothesized that the human epidermal growth factor receptor-2 (HER2, also called ErbB2), a membrane tyrosine kinase highly expressed in many epithelial tumors, could be an immunological target for gene transfer. To test this hypothesis in vitro, we non-covalently linked a luciferase expression vector (pRSVLuc) to a humanized HER2 antibody (rhuMAbHER2) covalently modified with poly-L-lysine bridges (PL). This complex (PL-rhuMAbHER2) was tested for its ability to direct gene transfer to HER2 expressing cells in vitro using NIH3T3 (HER2 nonexpressing) and NIH3T3.HER2 (HER2 expressing) cell lines as a model system. Twenty-four hours after exposing NIH3T3.HER2 cells to the PL-rhuMAbHER2-pRSVLuc complexes and 100 microM chloroquine, luciferase expression was 180-fold higher than that obtained from a conjugate made with an isotype-matched antibody against an irrelevant target. Exposing the HER2-expressing adenocarcinoma cell lines BT474 and SKBR3 to the HER2-targeted complexes also resulted in successful gene transfer and expression. Gene transfer was specific for the HER2 receptor, because preincubation of HER2-expressing cells with unconjugated rhuMAbHER2 decreased complex-mediated luciferase expression by 95%. These studies suggest that HER2 may be an appropriate target for selective gene transfer and that PL-rhuMAbHER2-DNA complexes may be a useful vehicle for directing gene transfer to cells that express HER2.

3T3 Cells↗
PubMed1998

Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate.

A large protein complex mediates the phosphorylation of the inhibitor of kappaB (IkappaB), which results in the activation of nuclear factor kappaB (NF-kappaB). Two subunits of this complex, IkappaB kinase alpha (IKKalpha) and IkappaB kinase beta (IKKbeta), are required for NF-kappaB activation. Purified recombinant IKKalpha and IKKbeta expressed in insect cells were used to demonstrate that each protein can directly phosphorylate IkappaB proteins. IKKalpha and IKKbeta were found to form both homodimers and heterodimers. Both IKKalpha and IKKbeta phosphorylated IkappaB bound to NF-kappaB more efficiently than they phosphorylated free IkappaB. This result explains how free IkappaB can accumulate in cells in which IKK is still active and thus can contribute to the termination of NF-kappaB activation.

Animals↗
PubMed1986

Lack of circulating immune complexes in inflammatory bowel disease.

Multi-organ involvement and especially extraintestinal manifestations have suggested an immune complex-mediated pathogenesis of ulcerative colitis and Crohn's disease. Using various techniques controversial data have been reported on the incidence and levels of circulating immune complexes and their correlation to clinical presentation. Sera of 131 patients with inflammatory bowel disease (78 Crohn's disease, 53 ulcerative colitis) representing a wide spectrum of disease activity, treatment and presence or absence of extraintestinal manifestations were tested for circulating immune complexes using Raji cell indirect immunofluorescence assay, Raji cell radioimmunoassay, C1q solid phase assay and polyethylene glycol precipitation coupled with measurements of optical density and subsequent immunoelectrophoresis or radial immunodiffusion. Circulating immune complexes in low concentrations were observed in a small number of patients with inflammatory bowel disease, the frequency and concentrations being slightly higher in patients with Crohn's disease than in those with ulcerative colitis. No association of concentrations of circulating immune complexes with disease activity or presence of extraintestinal manifestations could be demonstrated. These data do not support the claim for a major role of circulating immune complexes in the pathogenesis of inflammatory bowel disease.

Adolescent↗
PubMed2005

Polarized development of memory cell-like IFN-gamma-producing cells in the absence of TCR zeta-chain.

TCR/CD3 complex-mediated signals play critical roles in regulating CD4(+) Th cell differentiation. In this report, we have examined the in vivo role of a key TCR/CD3 complex molecule zeta-chain in regulating the differentiation of Th cells. We have studied T cells from zeta-chain-deficient mice (zetaKO mice), zeta-chain-bearing mice (zeta(+) mice), and from zetaKO mice expressing a FcRgamma chain transgene (FcRgammaTG, zetaKO mice). Our results demonstrated that, compared with those of control mice, CD4(+) T cells and not CD8(+) T cells from zetaKO mice were polarized into IFN-gamma-producing cells. Some of these IFN-gamma-producing cells could also secrete IL-10. Interestingly, zetaKO mouse T cells produced IFN-gamma even after they were cultured in a Th2 condition. Our studies to determine the molecular mechanisms underlying the polarized IFN-gamma production revealed that the expression level of STAT4 and T-bet were up-regulated in freshly isolated T cells from zetaKO mice. Further studies showed that noncultured zetaKO mice CD4(+) T cells and thymocytes bore a unique memory cell-like CD44(high), CD62L(low/neg) phenotype. Altogether, these results suggest that, in the absence of the zeta-chain, CD4(+) T cells develop as polarized IFN-gamma-producing cells that bear a memory cell-like phenotype. The zeta-chain-bearing T cells may produce a large amount of IFN-gamma only after they are cultured in a condition favoring Th1 cell differentiation. This study may provide important implications for the down-regulation of zeta-chain in T cells of patients bearing a variety of tumors, chronic inflammatory and infectious diseases.

Animals↗
PubMed2004

Mutual targeting of mediator and the TFIIH kinase Kin28.

In Saccharomyces cerevisiae, Kin28 is a member of the cyclin-dependent kinase family. Kin28 is a subunit of the basal transcription factor holo-TFIIH and its trimeric sub-complex TFIIK. Kin28 is the primary kinase that phosphorylates the RNA polymerase II (RNA pol II) C-terminal domain (CTD) within a transcription initiation complex. Mediator, a global transcriptional co-activator, dramatically enhances the phosphorylation of the CTD of RNA pol II by holo-TFIIH in vitro. Using purified proteins we have determined that the subunits of TFIIK are sufficient for Mediator to enhance Kin28 CTD kinase activity and that Mediator enhances phosphorylation of a glutathione S-transferase-CTD fusion protein, despite the absence of multiple Mediator and/or TFIIH interactions with polymerase. Mediator does not stimulate the activity of several other CTD kinases, suggesting that the specific enhancement of TFIIH kinase activity results in Kin28 being the primary CTD kinase at initiation. In addition, we have found that Kin28 phosphorylates Mediator subunit Med4 in an assay, including purified holo-TFIIH, and either Mediator or recombinant Med4 alone. Furthermore, Kin28 appears to be, at least in part, responsible for the phosphorylation of Med4 in vivo. We have identified Thr-237 as the site of phosphorylation of Med4 by Kin28 in vitro. The mutation of Thr-237 to Ala has no effect on the growth of a yeast strain under normal conditions but confirms that Thr-237 is also the site of Med4 phosphorylation in vivo.

Casein Kinases↗
PubMed2002

Biogenesis of the mitochondrial TOM complex.

The translocase at the outer membrane of mitochondria (TOM complex) mediates the initial steps of the import of preproteins into the organelle, which are essential for mitochondrial biogenesis and, therefore, for eukaryotic cell viability. The TOM complex is a multisubunit molecular machine with a dynamic structure. The biogenesis of TOM is of special interest because the complex is required for its own biogenesis. This article describes the mechanisms by which Tom components are targeted to the mitochondria and inserted into the outer membrane. The assembly of newly synthesized subunits into the functional TOM complex might occur via assembly intermediates that are in equilibrium with the mature complex.

Chromatography, Gel↗
PubMed2007

Mitochondrial complex I inhibition in Parkinson's disease: how can curcumin protect mitochondria?

Selective damage of mitochondrial complex I within the dopaminergic neurons of the substantia nigra is the central event during Parkinson disease. Peroxynitrite is one of the important free radicals probably mediating complex I damage. Peroxynitrite inhibits brain complex I mainly by 3-nitrotyrosine and nitrosothiol formation, but how these modifications alter the structure-function relation of complex I is unclear. Curcumin pretreatment protects brain mitochondria against peroxynitrite in vitro by direct detoxification and prevention of 3-nitrotyrosine formation and in vivo by elevation of total cellular glutathione levels. These results suggest a potential therapeutic role for curcumin against nitrosative stress in neurological disorders.

Curcumin↗
PubMed2003

Structural analyses of purified human immunodeficiency virus type 1 intracellular reverse transcription complexes.

Retroviruses copy their RNA genome into a DNA molecule, but little is known of the structure of the complex mediating reverse transcription in vivo. We used confocal and electron microscopy to study the structure of human immunodeficiency virus type 1 (HIV-1) intracellular reverse transcription complexes (RTCs). Cytoplasmic extracts were prepared 3, 4, and 16 h after acute infection by Dounce homogenization in hypotonic buffer. RTCs were purified by velocity sedimentation, followed by density fractionation in linear sucrose gradients and dialysis in a large pore cellulose membrane. RTCs had a sedimentation velocity of approximately 350 S and a density of 1.34 g/ml and were active in an endogenous reverse transcription assay. Double labeling of nucleic acids and viral proteins allowed specific visualization of RTCs by confocal microscopy. Electron microscopy revealed that RTCs are large nucleoprotein structures of variable shape consisting of packed filaments ca. 6 nm thick. Integrase and Vpr are associated with discrete regions of the 6-nm filaments. The nucleic acids within the RTC are coated by small proteins distinct from nucleocapsid and are partially protected from nuclease digestion.

Cell Line↗
PubMed1993

[Arthritis as complication of acute meningococcal infection].

The incidence of meningococcal disease appears to be increasing in the Netherlands. Numerous complications, mostly involving the central nervous system, have been reported. We focus attention on arthritis by describing the case history of a 2-year-old boy who developed oligoarthritis 8 days after a disease onset characterised by general malaise, fever, signs of meningeal irritation and positive cultures of Neisseria meningitidis in CSF, blood and nasopharynx. The arthritis was probably immune complex mediated. He recovered after antibiotic therapy. There are three forms of arthritis as a complication of meningococcal disease: primary meningococcal arthritis, purulent metastatic arthritis, and immune complex arthritis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1980

Chemiluminescence of guinea pig peritoneal macrophages stimulated by immune precipitates and soluble immune complexes.

The chemiluminescence (CL) response of guinea pig peritoneal macrophages to immune precipitates and soluble immune complexes has been investigated. The rapid burst of intense light emission observed in response to both stimuli, was inhibited by superoxide dismutase (SOD). With soluble immune complexes, this was followed by prolonged CL of lower intensity susceptible to both SOD and catalase inhibition. The magnitude of the CL response was directly related to seize the size of the soluble complexes reacting with the macrophages. These findings suggest that circulating, as distinct from deposited immune complexes, may play a role in the pathogenesis of complex-mediated diseases.

Animals↗
PubMed1986

Retrobulbar optic neuritis in a patient with acute type B hepatitis.

A case is described of retrobulbar optic neuritis in a 33-year-old female with acute type B hepatitis. The ocular distress, principally affecting the left eye, followed the normalisation of liver function tests and subsided after steroid therapy. At the onset of ocular symptomatology, complement activation, involving both classic and alternative pathways, and high levels of circulating immune complexes were present. HBsAg was positive. No relapse was observed during follow-up for 3 years. An association between HBV-infection, optic neuritis and an immune complexes-mediated neurotoxic activity are hypothetized.

Adult↗