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At least 919 records · Page 51Linked to original sources
PubMed1985

Reticuloendothelial system and glomerular deposition of heat-aggregated human IgG.

The influence of functional impairment of reticuloendothelial system on glomerular deposition of heat aggregated human IgG (HAIgG) was studied. I-125 HAIgG was injected to mice treated either with dextran-containing 0.9% saline or with the saline alone. The HAIgG clearance rate from the blood decreased in the dextran-treated mice. The chronologically measured HAIgG contents in the liver, spleen and glomeruli increased in the dextran-treated animals. Immunofluorescent technique also demonstrated an increase in HAIgG and host C3 in the glomeruli. The glomerular hypercellularity was not demonstrated morphologically. Assuming that the function of the hepatic Kupffer cells principally affect the clearance rate of the foreign macromolecules from the blood, it is likely that the dextran administration impaired the function of these cells to digest the phagocytosed HAIgG, and that consequently the injected HAIgG stayed longer in the blood. Thus, increased supply of the HAIgG from the blood and/or the dextran-induced reduction of digesting function of the mesangial cell per se might have led to the accumulation of glomerular HAIgG. We suggest, therefore, that even small amount of immune complex may induce immune complex-mediated glomerular lesion, when associated with long lasting functional impairment of the Kupffer cells.

Animals↗
PubMed1981

Cutaneous vasculitis associated with acute and chronic hepatitis.

We encountered 11 patients who had rashes associated with hepatitis. Five of six acute hepatitis cases, but only one of five chronic hepatitis cases, were related to hepatitis B. Nine of the 11 patients had rash in the absence of clinically overt liver disease. Skin biopsy specimens showed histologic evidence of cutaneous vascular injury; specimens of urticarial and maculopapular rashes, which were seen in this series only with acute hepatitis, showed a primarily lymphocytic venulitis with focal necrosis, while palpable purpura, which was seen in this series only in chronic hepatitis, showed a primarily neutrophilic necrotizing vasculitis involving small vessels. One patient had lichen planus-like lesions. Demonstration of vascular deposits of immunoglobulins, complement, and fibrin in skin, as well as hypocomplementemia, circulating immune complexes, and mixed cryoglobulinemia, in these patients suggests that cutaneous lesions associated with liver disease resulted from immune complex-mediated vascular injury.

Adult↗
PubMed1993

[Suppressive effect of methylprednisolone on bovine serum albumin nephritis in mice].

Experiments were undertaken to study whether progressive processes of bovine serum albumin (BSA) nephritis in C57BL/B10-BR mice could be prevented by the treatment with methylprednisolone (MPSL), a glucocorticoid. Crescentic glomerulonephritis could be induced in 22 mice with high 95 per cent reproducibility by preimmunization of 0.2 mg of BSA four times every 2 weeks, followed by daily intraperitoneal injections of 50 mg/kg of BSA for 4 weeks (group IV, a control). In groups of 8 mice each, intraperitoneal injection of 50 mg/kg of MPSL was initiated 3 days before preimmunization (group I), before daily intraperitoneal injection of BSA (group II), and after daily intraperitoneal injection of BSA (group II), and after daily intraperitoneal injection of BSA (group III). In each group, the treatment was continued until the final day of the experiment. In group I, anti-BSA antibody titers, the levels of circulating immune complexes (CIC) and urinary protein was significantly suppressed in comparison with those in group IV. Histologically, diffuse intra- and extra-capillary proliferation observed in group IV was apparently inhibited. In group II and III, urinary protein and intra-/extracapillary proliferation were significantly diminished compared with those of group IV in spite of minor or no decrease in antibody titers and the CIC levels. These results suggest that MPSL has a suppressive effect on the progressive processes of immune complex mediated glomerulonephritis through both its immunosuppressive and antiinflammatory actions, especially when used in the early stage of immune reaction.

Animals↗
PubMed2005

Drosophila BAP60 is an essential component of the Brahma complex, required for gene activation and repression.

The SWI/SNF-like chromatin remodeling complex of Drosophila, the Brahma complex, contains four subunits (Brahma, BAP155/Moira, SNR1 and BAP60) conserved from yeast to humans. A reconstituted human complex lacking the BAP60 homolog shows full remodeling activity, suggesting that BAP60 is not essential for the core function. We generated Drosophila mutants and found that BAP60 carries a vital function and participates in complex-mediated transcriptional activation and repression. BAP60 binds DNA and shows genetic and physical interactions with the sex-determining transcription factors encoded by sisterless A and scute. The results support the conclusion that BAP60 participates in site-specific recruitment of the Brahma complex in Drosophila.

Amino Acid Sequence↗
PubMed2005

Activator Gcn4p and Cyc8p/Tup1p are interdependent for promoter occupancy at ARG1 in vivo.

The Cyc8p/Tup1p complex mediates repression of diverse genes in Saccharomyces cerevisiae and is recruited by DNA binding proteins specific for the different sets of repressed genes. By screening the yeast deletion library, we identified Cyc8p as a coactivator for Gcn4p, a transcriptional activator of amino acid biosynthetic genes. Deletion of CYC8 confers sensitivity to an inhibitor of isoleucine/valine biosynthesis and impairs activation of Gcn4p-dependent reporters and authentic amino acid biosynthetic target genes. Deletion of TUP1 produces similar but less severe activation defects in vivo. Although expression of Gcn4p is unaffected by deletion of CYC8, chromatin immunoprecipitation assays reveal a strong defect in binding of Gcn4p at the target genes ARG1 and ARG4 in cyc8Delta cells and to a lesser extent in tup1Delta cells. The defects in Gcn4p binding and transcriptional activation in cyc8Delta cells cannot be overcome by Gcn4p overexpression but are partially suppressed in tup1Delta cells. The impairment of Gcn4p binding in cyc8Delta and tup1Delta cells is severe enough to reduce recruitment of SAGA, Srb mediator, TATA binding protein, and RNA polymerase II to the ARG1 and ARG4 promoters, accounting for impaired transcriptional activation of these genes in both mutants. Cyc8p and Tup1p are recruited to the ARG1 and ARG4 promoters, consistent with a direct role for this complex in stimulating Gcn4p occupancy of the upstream activation sequence (UAS). Interestingly, Gcn4p also stimulates binding of Cyc8p/Tup1p at the 3' ends of these genes, raising the possibility that Cyc8p/Tup1p influences transcription elongation. Our findings reveal a novel coactivator function for Cyc8p/Tup1p at the level of activator binding and suggest that Gcn4p may enhance its own binding to the UAS by recruiting Cyc8p/Tup1p.

Argininosuccinate Lyase↗
PubMed1985

[Immune complexes: studies on animal models].

A review is presented of some selected experiments conducted on animal models of immune complex-mediated diseases. The immune response and kinetics of antigen deposition are analysed in the model of systemic chronic serum sickness of rabbits and chickens. Experimental nephritis, induced by mercuric chloride, illustrates a pathogenesis in which autoantibodies to basement membranes become components of immune complexes. A recently developed Streptococcus mutans-induced nephritis in rabbits should make it possible to obtain some understanding of early pathogenetic mechanisms. These could very well be analogous to aspects of the pathogenesis of streptococcus-associated nephritides of man.

Animals↗
PubMed1978

Acute massive pulmonary hemorrhage in systemic lupus erythematosus.

Acute massive pulmonary hemorrhage is described as part of the clinical picture of SLE. Seven patients had sudden onset of high fever, dyspnea, tachycardia, and cough with blood-tinged sputum that within hours progressed to massive hemoptysis and death. There were no vasculitis or other inflammatory lung changes found at autopsy. Only one of the seven reported cases survived when treated with 2 g of intravenous hydrocortisone daily. The mechanism of this pulmonary bleeding is unknown but seems to be an immune complex mediated phenomenon.

Adolescent↗
PubMed1990

Divalent cation-dependent structure in the platelet membrane glycoprotein Ia-IIa (VLA-2) complex.

Recent studies have shown that the platelet membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg(++)-dependent adhesion of platelets to collagen and that this adhesion is inhibited by Ca++ in a simple, linear, noncompetitive manner. These findings suggested that separate binding sites for Mg++ and Ca++ stabilize different divalent cation-dependent structures within the receptor complex. To provide evidence for the existence of such structures purified platelet Ia-IIa complex was subjected to limited proteolytic digestion in the presence of Mg++, Ca++, Mg++ and Ca++, or EDTA and the resulting peptides mapped by SDS-PAGE using both one and two-dimensional techniques. Unique patterns of tryptic peptides were produced under each of the conditions. The results indicate that Mg++ and Ca++ stabilize different structures within the Ia-IIa (VLA-2) complex and that these structures influence both the collagen binding activity and proteolytic susceptibility of the complex.

Blood Platelets↗
PubMed2002

Smads "freeze" when they ski.

The transforming growth factor-beta (TGF-beta) signal is manifest through activated heteromeric Smad complex-mediated transcriptional modulation of target genes that translates into diverse, context-specific biologic effects, such as the potent TGF-beta-initiated cytostatic program. The TGF-beta pathway is effectively antagonized through the direct binding and subsequent repression of activated Smad heteromeric complexes by the Ski family of proto-oncoproteins.

DNA-Binding Proteins↗
PubMed1998

Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76.

Tyrosine phosphorylation of linker proteins enables the T cell antigen receptor (TCR)-associated protein tyrosine kinases to phosphorylate and regulate effector molecules that generate second messengers. We demonstrate here that the SLP-76 linker protein interacts with both nck, an adaptor protein, and Vav, a guanine nucleotide exchange factor for Rho-family GTPases. The assembly of this tri-molecular complex permits the activated Rho-family GTPases to regulate target effectors that interact through nck. In turn, assembly of this complex mediates the enzymatic activation of the p21-activated protein kinase 1 and facilitates actin polymerization. Hence, phosphorylation of linker proteins not only bridges the TCR-associated PTK, ZAP-70, with downstream effector proteins, but also provides a scaffold to integrate distinct signaling complexes to regulate T cell function.

Actins↗
PubMedDate not supplied

Glutathione depletion in a midbrain-derived immortalized dopaminergic cell line results in limited tyrosine nitration of mitochondrial complex I subunits: implications for Parkinson's disease.

Oxidative stress and mitochondrial dysfunction signify two important biochemical events associated with the loss of dopaminergic neurons in Parkinson's disease (PD). Studies using in vitro and in vivo PD models and in affected tissues from the disease itself have demonstrated a selective inhibition of mitochondrial complex I activity that appears to affect normal mitochondrial physiology leading to neuronal cell death. Earlier experiments from our laboratory have demonstrated that induced depletion of glutathione (GSH + GSSG) in cultured dopaminergic cells resulted in increased oxidative stress and a decrease in mitochondrial function. Furthermore, this dysfunction was linked to a selective decrease in mitochondrial complex I activity that appears to be due to oxidation of this complex. Glutathione depletion is the earliest detectable biochemical event during PD progression and occurs prior to complex I inhibition. Recent observations have also indicated that oxidative damage to complex I via naturally occurring free radicals such as peroxynitrite leads to modification of tyrosine and/or cysteine residues resulting in complex I inhibition. Using the sucrose gradient method, we detected in complex I-enriched fractions from a glutathione-depleted dopaminergic cell line two bands corresponding to approximately 25-kDa and approximately 30-kDa polypeptides that demonstrate anti-nitrotyrosine immunoreactivity, suggesting the possible involvement of protein nitration by peroxynitrite in glutathione depletion-mediated complex I inhibition.

Animals↗
PubMed1995

Effects of an aminosteroid inhibitor of phospholipase C-dependent processes on the TCR-mediated signal transduction pathway in human T cells.

Phospholipase C (PLC) is a key enzyme in the T cell antigen receptor (TCR)-mediated signal transduction pathway in human T cells. Agonist-induced PLC activation leads to a cascade of intracellular events that ultimately regulate gene transcription and T cell activation. We studied the effects of U-73122, a putative inhibitor of PLC-dependent events, on TCR/CD3 complex-mediated early and late events in human T cells. Both anti-CD3 monoclonal antibody-induced 1,4,5-inositol trisphosphate (IP3) and free intracytoplasmic calcium [Ca2+]i increases were inhibited by U-73122 (0.05-0.1 microM), but not by the related inactive analog, U-73343. U-73122 did not affect thapsigargin-evoked [Ca2+]i increase in T cells, indicating a specific mode of inhibition of CD3 signaling. Late events in T cell activation like CD3-mediated T cell proliferation and mitogen-induced interleukin 2 receptor (IL2-R) expression were also inhibited by this agent. T cell proliferation induced by a combination of a phorbol ester and ionomycin was not affected by U-73122. Although an agonist effect on basal IP3 and [Ca2+]i levels was observed with high concentrations of U-73122, the inhibitor alone did not induce any proliferative effect or IL2-R expression in T cells. Our results demonstrate for the first time that U-73122 is a specific inhibitor of PLC-dependent processes in human T cells and could serve as a valuable tool for studying T cell signal transduction pathways.

Adjuvants, Immunologic↗
PubMed1996

Single nuclear pores visualized by confocal microscopy and image processing.

How nuclear pore complexes, mediating the transport of nucleic acids, proteins, and metabolites between cell nucleus and cytoplasm, are arranged in the nuclear envelope is essentially unknown. Here we describe a method combining high-resolution confocal imaging with image processing and pattern recognition to visualize single nuclear pore complexes (120 nm diameter), determine their relative positions with nanometer accuracy, and analyze their distribution in situ. The method was tested by means of a model system in which the very same sample areas could be imaged by confocal and electron microscopy. It was thus found that single fluorescent beads of 105 nm nominal diameter could be localized with a lateral accuracy of <20 nm and an axial accuracy of approximately 20 nm. The method was applied to digitonin-permeabilized 3T3 cells, whose nuclear pore complexes were fluorescently labeled with the anti-nucleoporin antibody mAb414. Stacks of optical sections were generated by confocal imaging at high resolution. Herein the nuclear pore complexes appeared as bright diffraction-limited spots whose centers were localized by fitting them by three-dimensional gaussians. The nearest-neighbor distribution function and the pair correlation function were calculated and found to agree well with those of randomly distributed hard cylinders of 138 +/- 17 nm diameter, but not with those of randomly distributed points or nonrandomly distributed cylinders. This was supported by a cluster analysis. Implications for the direct observation of the transport of single particles and molecules through individual nuclear pore complexes are discussed.

3T3 Cells↗
PubMed2004

Immature nicastrin stabilizes APH-1 independent of PEN-2 and presenilin: identification of nicastrin mutants that selectively interact with APH-1.

Gamma-secretase is a high molecular mass aspartyl protease complex composed of presenilin (PS1 or PS2), nicastrin (Nct), anterior pharynx-defective-1 (APH-1) and presenilin enhancer-2 (PEN-2). The complex mediates the intramembraneous proteolysis of beta-secretase cleaved beta-amyloid precursor protein (APP) leading to the secretion of the Alzheimer's disease-associated amyloid beta-peptide (Abeta). In order to dissect functionally important domains of Nct required for gamma-secretase complex assembly, maturation, and activity we mutated evolutionary conserved amino acids. The mutant Nct variants were expressed in a cellular background with significantly reduced endogenous Nct. Mutant Nct was functionally investigated by its ability to restore PS, APH-1 and PEN-2 expression as well as by monitoring the accumulation of the APP C-terminal fragments, the immediate substrates of gamma-secretase. We identified three independent mutations within the ectodomain of Nct, which rescued expression of APH-1 but not of PEN-2 or PS and thus failed to restore gamma-secretase activity. Interestingly, these immature Nct variants selectively bound to APH-1, suggesting a stable Nct/APH-1 interaction independent of PS and PEN-2. Consistent with this finding, expression of APH-1 remained largely unaffected in the PS double knock-out and immature Nct co-immunoprecipitated with APH-1 in the absence of PS and PEN-2. Taken together, our findings suggest that immature Nct can stably interact with APH-1 to form a potential scaffold for binding of PS and PEN-2. Moreover, binding of the latter two complex partners critically depends on the integrity of the Nct ectodomain.

Alzheimer Disease↗
PubMedDate not supplied

[Immune complexes and peripheral neuropathy: about two cases (author's transl)].

Two female patients aged 64 and 54 were studied, affected by a progressive, distal sensori-motor mononeuritis multiplex. A nerve biopsy specimen from the first patient, suffering from chronic active hepatitis without detectable serum hepatitis B surface antigen (HBsAg) or antibody (anti-HBs), showed segmental demyelination and widespread inflammatory and necrotizing vasculitis and perivasculitis. The second patient, affected by a localized, caeseating tuberculous infection of the right kidney, refused to undergo a nerve biopsy. Serum levels of circulating immune complexes, detected by C1q BA binding method were strongly positive in both subjects; activation of the complement system (decreased serum level of C3 and/or C4) was also present. The course of the peripheral neuropathy was progressive and worsened in the first patient whose circulating immune complexes were always detectable. On the contrary the second patient showed improvement after the nephrectomy, which coincided with a quick disappearance of the circulating immune complexes. The findings may suggest in these two patients an immune complex mediated pathogenetic mechanism like the one recently accepted for the peripheral neuropathies in the course of chronic hepatitis B.

Antigen-Antibody Complex↗
PubMed2007

C-reactive protein-mediated suppression of nephrotoxic nephritis: role of macrophages, complement, and Fcgamma receptors.

C-reactive protein (CRP) is a member of the pentraxin family of proteins and an acute phase reactant. CRP modulates the response to inflammatory stimuli including LPS and C5a. We recently demonstrated that CRP prevents and reverses proteinuria in accelerated nephrotoxic nephritis (NTN). NTN is a model of active inflammatory immune complex-mediated nephritis induced by injection of antiglomerular basement membrane. CRP treatment prevented the induction of NTN in C57BL/6 (B6) mice, increased survival, and reversed ongoing nephritis. Protection was associated with a decrease in IL-1beta and chemokines in the kidney and peritoneal cells as measured by quantitative RT-PCR. However, IL-10(-/-) mice were not protected by CRP either when given before disease onset or when disease activity was maximal. FcgammaRI(-/-) mice developed NTN, but were only transiently protected by CRP treatment. This transient protection was abrogated by cobra venom factor depletion of complement from FcgammaRI(-/-) mice. However, complement depletion did not prevent CRP-mediated protection in B6 mice, and CRP was protective in C3(-/-) mice. The role of macrophages in the protection provided by CRP was tested by treating B6 mice with liposomes containing clodronate. Clodronate-containing liposomes deplete mice of splenic and hepatic macrophages for 5-7 days. Pretreatment of NTN mice with clodronate but not control liposomes completely prevented CRP-mediated protection. These studies suggest that CRP mediates protection from NTN through the induction of IL-10 and that macrophages are required. In addition, FcgammaRI plays an important role but is not the sole mediator of CRP-mediated protection.

Animals↗
PubMed1992

Alpha 2-macroglobulin, a multifunctional binding protein with targeting characteristics.

Alpha 2-macroglobulin (alpha 2M) and related proteins share the function of binding host or foreign peptides and particles, thereby serving as humoral defense barriers against pathogens in the plasma and tissues of vertebrates. In human alpha 2M, several reactive sites including high-affinity sites for zinc, transglutaminase cross-linking sites, and reactive sites derived from the activated thiol ester can mediate reversible or irreversible capture of proteins of diverse biological functions. Alpha 2M interacts and captures virtually any proteinase whether self or foreign, suggesting a function as a unique "panproteinase inhibitor." Activation of alpha 2M generates novel binding sites, which mediate complex formation with cytokines and other peptides. Direct evidence of physical association of cytokines with activated alpha 2M indicated its role as biological response modifier in cell cultures. A mechanism commonly referred to as "clearance of activated alpha 2M" involves Ca(2+)-dependent binding to a specific cell surface receptor, a member of the low-density lipoprotein receptor supergene family, that mediates cellular uptake by endocytosis and delivery to endosomes and lysosomes. The peptide binding function of alpha 2M, therefore, may also be viewed as a mechanism that allows targeting of biologically active peptides to different cell types expressing the alpha 2M receptor. Internalized complexes may be dispatched into different pathways of endocytic/lysosomal pathways in a cell type-specific manner. In addition, bioactive peptides bound to alpha 2M may dissociate in the process of intracellular ligand sorting, thereby modulating cell function, or remain bound and share the catabolic fate of alpha 2M. The diversified and probably programmed binding functions of alpha 2M indicate that in addition to its role in trapping proteinases, it has other biological activities that remain to be fully defined. That alpha 2M may function as a binding and carrier protein with targeting characteristics is predicted from 1) the known functions of alpha 2M, and 2) the similarity of the fate of alpha 2M with proteins whose significance in targeting and intracellular trafficking has been studied in more detail.

Animals↗
PubMed2001

Cutting edge: differential signaling requirements for activation of assembled cyclin D3-cdk4 complexes in B-1 and B-2 lymphocyte subsets.

B-1 lymphocytes represent a distinct B cell subset with unusual mitogenic responses. PMA alone promotes proliferation in B-1 cells, but not in splenic B-2 cells. Although cyclin D2-cyclin-dependent kinase 4 (cdk4) complexes mediate early retinoblastoma gene product (pRb) phosphorylation in B-1 cells, the transient nature of their accumulation cannot account for the continued increase in pRb phosphorylation, which is maximal at 24 h. We show herein that PMA promotes the accumulation of functional cyclin D3-cdk4 complexes in B-1 cells following loss of cyclin D2. PMA also induces accumulation of cyclin D3-cdk4 complexes in B-2 cells; however, these complexes do not phosphorylate pRb. Thus, PMA is sufficient to induce synthesis and assembly of cyclin D3-cdk4 complexes in B-1 and B-2 cells; however, PMA triggers cyclin D3-cdk4 activation only in B-1 cells. These results reveal a novel regulatory step that controls activation of cyclin D3-cdk4 complexes whose function segregates differentially in B cell subsets.

Animals↗