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PubMed1978

Immune-complex-mediated glomerulonephritis and pulmonary hemorrhage simulating Goodpasture syndrome.

Two female children whose clinical presentations and renal light-microscopic findings were consistent with Goodpasture syndrome are described. Immunopathologic studies demonstrated granular deposition of immunoglobulins and complement, suggesting that the renal disease was mediated by circulating immune complexes and not by anti-glomerular basement membrane antibody. Anti-GBM antibody was absent in both patients. These patients represent the first report in children of idiopathic nephritis due to immune complexes with associated pulmonary hemorrhage. The findings raise some doubt as to the accuracy of previous reports of Goodpasture syndrome in children, and also demonstrate the diagnostic and therapeutic importance of evaluation the renal immunopathology in the child with nephritis and pulmonary hemorrhage.

Anti-Glomerular Basement Membrane Disease↗
PubMed2004

Blood and endothelium in immune complex-mediated tissue injury.

Antigen-antibody complexes can be formed both intravascularly and perivascularly and damage tissues by inducing inflammatory mechanisms. Recent studies have characterized a definite sequence of steps involved in these inflammatory mechanisms, and identified the predominance of particular chemical mediator(s) in each step. The lesions associated with this type of inflammation are characterized by the early development of plasma leakage, followed by the recruitment of polymorphonuclear leukocytes mediated by chemokines generated by FcgammaR-dependent mechanisms. The development of these lesions is modulated by endothelial cell-derived paracrine mediators, and activation of the coagulation system can ensue. The activation of platelets and coagulation, if not properly counterbalanced by fibrinolysis, might be a major factor for the late development of fibrotic changes and organ remodeling.

Animals↗
PubMed2005

The mammalian Mediator complex and its role in transcriptional regulation.

Mediator is an essential component of the RNA polymerase II general transcriptional machinery and plays a crucial part in the activation and repression of eukaryotic mRNA synthesis. The Saccharomyces cerevisiae Mediator was the first to be defined and is a high molecular mass complex composed of >20 distinct subunits that performs multiple activities in transcription. Recent studies have defined the subunit composition and associated activities of mammalian Mediator, and revealed a striking evolutionary conservation of Mediator structure and function from yeast to man.

Animals↗
PubMed2005

Immune complex-mediated tissue injury: a multistep paradigm.

Antigen-antibody complexes can damage tissues by triggering inflammation. Recent studies have enabled the description of a sequence of steps, which depend on the intra- or perivascular location of complex formation. Acute lethal toxicity and circulatory shock as a result of the acute release of inflammatory mediators can occur after intravascular complex formation. The lesions associated with perivascular complexes are characterized by plasma leakage and the recruitment of polymorphonuclear leukocytes. These lesions are modulated by mediators released from endothelial cells, namely nitric oxide, endothelins and lipid mediators, and provide an appropriate basis for the activation of both arms of hemostasis: coagulation and fibrinolysis. The balance between both activation systems can explain the late occurrence of both tissue fibrosis and organ remodeling.

Animals↗
PubMed2006

R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation.

Recent compelling evidence has lead to renewed interest in the role of antibodies and immune complexes in the pathogenesis of several autoimmune disorders, such as rheumatoid arthritis. These immune complexes, consisting of autoantibodies to self-antigens, can mediate inflammatory responses largely through binding and activating the immunoglobulin Fc receptors (FcRs). Using cell-based structure activity relationships with cultured human mast cells, we have identified the small molecule R406 [N4-(2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine] as a potent inhibitor of immunoglobulin E (IgE)- and IgG-mediated activation of Fc receptor signaling (EC(50) for degranulation = 56-64 nM). Here we show that the primary target for R406 is the spleen tyrosine kinase (Syk), which plays a key role in the signaling of activating Fc receptors and the B-cell receptor (BCR). R406 inhibited phosphorylation of Syk substrate linker for activation of T cells in mast cells and B-cell linker protein/SLP65 in B cells. R406 bound to the ATP binding pocket of Syk and inhibited its kinase activity as an ATP-competitive inhibitor (K(i) = 30 nM). Furthermore, R406 blocked Syk-dependent FcR-mediated activation of monocytes/macrophages and neutrophils and BCR-mediated activation of B lymphocytes. R406 was selective as assessed using a large panel of Syk-independent cell-based assays representing both specific and general signaling pathways. Consistent with Syk inhibition, oral administration of R406 to mice reduced immune complex-mediated inflammation in a reverse-passive Arthus reaction and two antibody-induced arthritis models. Finally, we report a first-inhuman study showing that R406 is orally bioavailable, achieving exposures capable of inhibiting Syk-dependent IgE-mediated basophil activation. Collectively, the results show R406 potential for modulating Syk activity in human disease.

Animals↗
PubMed2005

An Os(II)--bisbipyridine--4-picolinic acid complex mediates the biocatalytic growth of au nanoparticles: optical detection of glucose and acetylcholine esterase inhibition.

The complex Os(II)-bisbipyridine-4-picolinic acid, [Os(bpy)(2)PyCO(2)H](2+) (1), mediates the biocatalyzed growth of Au nanoparticles, Au NPs, and enables the spectroscopic assay of biocatalyzed transformations and enzyme inhibition by following the Au NP plasmon absorbance. In one system, [Os(bpy)(2)PyCO(2)H](2+) mediates the biocatalyzed oxidation of glucose and the growth of Au NPs in the presence of glucose oxidase, GOx, AuCl(4) (-), citrate and Au NP seeds. The mechanism of the Au NPs growth involves the oxidation of the [Os(bpy)(2)PyCO(2)H](2+) complex by AuCl(4) (-) to form [Os(bpy)(2)PyCO(2)H](3+) and Au(I). The [Os(bpy)(2)PyCO(2)H](3+) complex mediates the GOx biocatalyzed oxidation of glucose and the regeneration of the mediator 1. Citrate reduces Au(I) and enlarges the Au seeds by the catalytic deposition of gold on the Au NP seeds. In the second system, the enzyme acetylcholine esterase, AChE, is assayed by the catalytic growth of the Au NPs. The hydrolysis of acetylcholine (2) by AChE to choline is followed by the [Os(bpy)(2)PyCO(2)H](3+) mediated oxidation of choline to betaine and the concomitant growth of the Au NPs. The mediated growth of the Au NPs is inhibited by 1,5-bis(4-allyldimethylammonium-phenyl)pentane-3-one dibromide (3). A competitive inhibition process was demonstrated (K(M)=0.13 mM, K(I)=2.6 microM) by following the growth of the Au NPs.

2,2'-Dipyridyl↗
PubMed2002

Interconversion between bis(mu-thiolato)dicopper(II) and disulfide-bridged dicopper(I) complexes mediated by chloride ion.

An unprecedented clean interconversion between a novel bis(mu-thiolato)dicopper(II) complex (1) and a disulfide-bridged dicopper(I) complex (3) through a disulfide-bridged (mu-chloro)dicopper(I) complex (2) mediated by chloride ion has been established for the first time, providing a new redox chemistry of the transition metal-sulfur complexes. Crystal structures of 1 and 3 as well as spectroscopic features of the compounds are reported.

Journal Article↗
PubMed1988

Immune complex-mediated glomerulopathy in Marek's disease.

Chickens infected with Marek's disease (MD) virus developed immune complex (IC)-mediated glomerulopathy. Fluorescent antibody staining technique using antichicken globulin and antichicken complement was used to demonstrate IC in the kidney glomeruli. During the initial stages of MDV infection, IC deposits were seen on the glomerular basement membrane, but subsequently the entire glomerulus was involved. Mesangial cells also had IC deposits. Chicken complement was demonstrated in the glomeruli which had IC deposits. The number of glomeruli with IC deposition was higher in tumor-bearing birds than in non-tumor-bearing birds. Histologically, kidney lesion were characterized by thickening of basement membrane and proliferation of mesangial cells. It is suggested that IC-mediated glomerulopathy might be one of the major causes of death in MD.

Animals↗
PubMed1991

Experimental immune complex-mediated glomerulonephritis in the nonhuman primate.

This study was undertaken to develop a model of immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate that could be used in subsequent studies to examine critically the role of the erythrocyte complement receptor (E-CR) in the pathogenesis of IC-mediated disease. Cynomolgus monkeys were chosen for study because they constitutively express E-CR levels that are either less than, equal to, or greater than that seen in normal man. After immunization with bovine gamma globulin (BGG), the GN induction protocol was begun in 10 cynomolgus by initiating daily i.v. administration of BGG in amounts sufficient to achieve or exceed antigen/antibody equivalence (assessed by the quantitative precipitin assay) for precipitating antibody present in the plasma volume. We found that within eight weeks of daily BGG administration of all the cynomolgus developed IC-mediated GN, irrespective of the initial E-CR level of the animals. However, the high E-CR cynomolgus tended to receive the higher BGG doses because of higher initial antibody levels to BGG. When the total number of glomerular deposits (determined by morphometric studies) per total BGG dose for each animal was plotted against the initial CR/E of that animal, there was a tendency for the animals with higher CR/E levels to have a lower number of glomerular deposits/BGG dose (r = 0.62, P = 0.06). Also, the total number of glomerular deposits correlated with the severity of the GN. During the early weeks of the GN induction protocol, the IC that formed in vivo (assessed by infusion of 125I-BGG) bound in large amounts to the circulating erythrocytes of the cynomolgus with medium or high E-CR levels. However, when tested after the onset of heavy proteinuria, which occurred between weeks 5 and 8 of daily BGG administration, the IC that formed in the circulation bound only poorly to circulating erythrocytes. By this time the E-CR levels had declined to 43 +/- 9% of initial values (P less than 0.01). This study demonstrates that: 1) A workable model of IC-mediated GN has been developed in the nonhuman primate. 2) During the induction of GN, CR/E and the ability of the erythrocyte to bind IC in vivo are decreased significantly. This suggests that an intact E-CR system could play a role in the protection against IC-mediated disease. However, further study will be needed to test that hypothesis critically. The present model should be useful in such studies.

Animals↗
PubMed2026

BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance.

Extrachromosomal circular DNA (ecDNA) is frequently generated within the nucleus, contributing to genome dynamics and heterogeneity, thereby promoting cancer cell evolution and adaptation. However, the mechanisms underlying ecDNA biogenesis remain poorly understood. Here, using genome-wide CRISPR screening in human cells, we identified the BRCA1-A and the LIG4 complexes as key drivers of ecDNA production. Following DNA segmentation, the upstream BRCA1-A complex protects DNA ends from excessive resection, promoting end-joining for circularization. Conversely, the MRN complex, which mediates end resection and thus antagonizes the BRCA1-A complex, suppresses ecDNA formation. Downstream, LIG4 conservatively mediates ecDNA production by joining the free ends of the DNA fragments. Furthermore, ecDNA from patient tumors harbors junction sites with a LIG4 signature. Notably, disruption of either LIG4 or the BRCA1-A complex in cancer cells impairs ecDNA-mediated adaptation, hindering the development of resistance to both chemotherapy and targeted therapies. Together, our study reveals the roles of the LIG4 and BRCA1-A complexes in ecDNA biogenesis, and uncovers therapeutic targets to block ecDNA-mediated adaptation for cancer treatment.

Humans↗
PubMed1989

Enzyme histochemistry of monocytes/macrophages: a study in a murine model of immune complex-mediated glomerulonephritis.

In a model of immune complex glomerulonephritis in BALB/c mice, cells of monocyte/macrophage lineage (M phi), identifiable by electron microscopy, infiltrate the glomerulus. In spite of this, no unequivocal nonspecific esterase activity can be demonstrated histochemically in the glomeruli. On the other hand, many mononuclear cells with strong acid phosphatase activity are consistently present. This observation is in line with other studies that have demonstrated the heterogeneity of enzyme profiles in different M phi populations. Despite the wide acceptance of nonspecific esterases as markers for M phi, the present study indicates that exclusive reliance on a single marker in investigating the participation of M phi in a pathological process can lead to erroneous conclusions. Use of multiple markers and preferably multiple investigative modalities is recommended.

Animals↗
PubMed2005

Joint inflammation and chondrocyte death become independent of Fcgamma receptor type III by local overexpression of interferon-gamma during immune complex-mediated arthritis.

OBJECTIVE: It has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)-mediated arthritis depend on Fcgamma receptor type III (FcgammaRIII). Local adenoviral overexpression of interferon-gamma (IFNgamma) in the knee joint prior to onset of IC-mediated arthritis aggravated severe cartilage destruction. In FcgammaRI(-/-) mice, however, chondrocyte death was not enhanced by IFNgamma, whereas matrix metalloproteinase (MMP)-mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating FcgammaRIII in the latter process. We undertook this study to determine the role of FcgammaRIII in joint inflammation and severe cartilage destruction in IFNgamma-stimulated IC-mediated arthritis, using FcgammaRIII(-/-) mice. METHODS: FcgammaRIII(-/-) and wild-type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFNgamma (AdIFNgamma) or with adenovirus encoding enhanced green fluorescent protein 1 day prior to induction of IC-mediated arthritis. Histologic sections were obtained 3 days after arthritis onset to study inflammation and cartilage damage. MMP-mediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and FcgammaR expression levels were determined in synovial washouts and synovium, respectively. RESULTS: Injection of AdIFNgamma in naive knee joints markedly increased levels of messenger RNA for FcgammaRI, FcgammaRII, and FcgammaRIII. Upon IFNgamma overexpression prior to induction of IC-mediated arthritis, joint inflammation was similar in FcgammaRIII(-/-) and WT mice. The percentage of macrophages in the knee joint was increased, which correlated with high concentrations of the macrophage attractant macrophage inflammatory protein 1alpha. Furthermore, IFNgamma induced 2-fold and 3-fold increases in chondrocyte death in WT controls and FcgammaRIII(-/-) mice, respectively. Notably, VDIPEN expression also remained high in FcgammaRIII(-/-) mice. CONCLUSION: IFNgamma bypasses the dependence on FcgammaRIII in the development of IC-mediated arthritis. Furthermore, both FcgammaRI and FcgammaRIII can mediate MMP-dependent cartilage matrix destruction.

Aggrecans↗
PubMed1993

Platelet involvement in experimental immune complex-mediated glomerulonephritis in the nonhuman primate.

Abundant glomerular platelet deposition is a hallmark of certain animal models of immune complex (IC)-mediated glomerulonephritis (GN). By contrast, conspicuous platelet deposition is uncommon in the IC-GN seen in humans. This could result from intrinsic differences between human and animal platelets, which are known to be present. To assess whether abundant glomerular platelet deposition can occur in humans with IC-GN, the present studies were undertaken in nonhuman primates (cynomolgus monkeys, CYN), with active experimental IC-GN induced by 12 weeks of daily intravenous infusion of bovine gamma globulin (BGG). CYN are appropriate for these studies because, like humans, CYN platelets do not express the C3b receptor but do express receptors for the Fc region of IgG (FcR gamma II). Furthermore, in this model of IC-GN, which is indistinguishable from IC-GN seen in humans, it is possible to time the biopsy to coincide with a period of peak activity of the GN. The present studies proceeded as follows: ten CYN were studied before and after intravenous infusion of BGG sufficient to achieve conditions near antigen/antibody equivalence for circulating precipitating antibody to BGG. The infusion of BGG, which was given over 10 minutes, resulted in an acute reduction in circulating platelets (mean 43% +/- 5 SE, P < 0.001). However, renal biopsies performed before and five minutes after the acute reduction in circulating platelets showed that relatively few of the platelets removed from the circulation lodged in glomeruli (platelets/glomerular cross section: 0.2 +/- 0.06 before BGG vs. 0.88 +/- 0.31 after BGG, P = 0.035). In five of the CYN studied under the above protocol, autologous platelets were labeled with 111In and reinfused into the CYN just prior to the BGG infusion. These studies confirmed the paucity of platelet deposition in kidney but showed major uptake of the 111In-labeled platelets by liver and spleen (mean +/- SE 111In CPM/mg of tissue: kidney cortex 18 +/- 8, liver 132 +/- 42, and spleen 808 +/- 127, P = 0.038, comparing kidney to liver or spleen by paired t-test). Thus, the platelets removed from the circulation were taken up at the sites which are also the principal sites of IC uptake (liver and spleen), and over the time interval that coincides with the period of maximum uptake of IC by liver and spleen, after BGG infusion. In vitro studies, discussed herein, showed that BGG anti-BGG IC bind to CYN platelets via FcR gamma II.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2000

Drosophila homologs of transcriptional mediator complex subunits are required for adult cell and segment identity specification.

The origins of specificity in gene expression are a central concern in understanding developmental control. Mediator protein complexes regulate transcriptional initiation, acting as modular adaptors linking specific transcription factors to core RNA polymerase II. Here, we identified the Drosophila homologs of 23 human mediator genes and mutations of two, dTRAP240 and of dTRAP80 (the putative fly homolog of yeast SRB4). Clonal analysis indicates a general role for dTRAP80 necessary for cell viability. The dTRAP240 gene is also essential, but cells lacking its function are viable and proliferate normally. Clones reveal localized developmental activities including a sex comb cell identity function. This contrasts with the ubiquitous nuclear accumulation of dTRAP240 protein in imaginal discs. Synergistic genetic interactions support shared developmental cell and segment identity functions of dTRAP240 and dTRAP80, potentially within a common complex. Further, they identify the homeotic Sex combs reduced product, required for the same cell/tissue identities, as a functional partner of these mediator proteins.

Amino Acid Sequence↗
PubMed1989

The membrane glycoprotein Ia-IIa (VLA-2) complex mediates the Mg++-dependent adhesion of platelets to collagen.

We have purified the platelet membrane glycoprotein Ia-IIa complex by detergent solubilization and sequential affinity chromatography on Concanavalin A-Sepharose and collagen-Sepharose. The complex, which is identical to the VLA-2 complex of lymphocytes and other cells and contains subunits of 160 and 130 kD on SDS-PAGE, was labeled with 125I and incorporated into phosphatidyl choline liposomes. The liposomes, like intact platelets, adhered to collagenous substrates in an Mg++-dependent manner with a K'a(Mg++) of 3.5 mM. Little adhesion of the liposomes to collagen occurred when Mg++ was replaced by Ca++ or EDTA. Calcium ions inhibited the Mg++-dependent adhesion with a K'i(Ca++) of 5.5 mM. Liposomes containing the Ia-IIa complex adhered to substrates composed of types I, II, III, and IV collagen, but did not effectively adhere to substrates composed of type V collagen or gelatin. Adhesion to collagen was specific. The liposomes did not adhere to fibronectin, vitronectin, laminin, thrombospondin, fibrinogen, or von Willebrand factor substrates. The monoclonal antibody P1H5, which specifically immunoprecipitated the Ia-IIa complex, also specifically inhibited the Mg++-dependent adhesion of both platelets and Ia-IIa-containing liposomes to collagen substrates. These findings provide additional evidence that the platelet membrane Ia-IIa complex is the mediator of Mg++-dependent platelet adhesion to collagen and suggest that the VLA-2 complex may also function as an Mg++-dependent collagen receptor in other cells.

Blood Platelets↗
PubMed2006

p66alpha and p66beta of the Mi-2/NuRD complex mediate MBD2 and histone interaction.

The Mi-2/NuRD complex is a multi-subunit protein complex with enzymatic activities involving chromatin remodeling and histone deacetylation. Targeting of Mi-2/NuRD to methylated CpG sequences mediates gene repression. The function of p66alpha and of p66beta within the multiple subunits has not been addressed. Here, we analyzed the in vivo function and binding of both p66-paralogs. Both factors function in synergy, since knocking-down p66alpha affects the repressive function of p66beta and vice versa. Both proteins interact with MBD2 functionally and biochemically. Mutation of a single amino acid of p66alpha abolishes in vivo binding to MBD2 and interferes with MBD2-mediated repression. This loss of binding results in a diffuse nuclear localization in contrast to wild-type p66alpha that shows a speckled nuclear distribution. Furthermore, wild-type subnuclear distribution of p66alpha and p66beta depends on the presence of MBD2. Both proteins interact with the tails of all octamer histones in vitro, and acetylation of histone tails interferes with p66 binding. The conserved region 2 of p66alpha is required for histone tail interaction as well as for wild-type subnuclear distribution. These results suggest a two-interaction forward feedback binding mode, with a stable chromatin association only after deacetylation of the histones has occurred.

Acetylation↗
PubMed2001

Plasma membrane resident 'fusion complexes' mediate reconstituted exocytosis.

Calcium-triggered exocytosis is thought to be mediated by membrane-associated protein complexes. In sea urchin eggs, high concentrations of calcium activate multiple 'fusion complexes' per cortical vesicle-plasma membrane docking site. Some of these fusion complexes are known to reside in the vesicle membrane. It is not known if fusion complexes also reside in the plasma membrane, or if plasma membrane-resident fusion complexes require cognate partners in the vesicle membrane. Using reconstitution, we show that N-ethylmaleimide treatment of either vesicles or plasma membrane fragments prior to reconstitution does not completely inhibit exocytosis. Treatment of both components did result in complete inhibition. Upon reconstitution, cortical vesicles and the early endosomes formed by compensatory endocytosis both contributed, on average, two fusion complexes per reconstituted docking site. The plasma membrane contributed, on average, two fusion complexes per docking site when assembled with cortical vesicles, but only one complex when reconstituted with endosomes. We conclude that there are at least two types of plasma membrane-resident fusion complexes that participate in reconstituted cortical vesicle-plasma membrane fusion. The activity of one of these fusion complexes is target-specific for cortical vesicles, while the second type also supports fusion with endosomes.

Actins↗
PubMed1980

Loss of Fc receptor activity after culture of human monocytes on surface-bound immune complexes. Mediation by cyclic nucleotides.

Human monocytes cultured on surface-bound immune complexes exhibited a loss of ability to form rosettes with IgG-sensitized sheep erythrocytes (EA). This loss was not a result of inhibition of Fc receptors by solubilized complexes nor of release of soluble factors by the cells. Loss of EA rosetting was not prevented by culture of monocytes at 4 degrees C, or by treatment with colchicine, cytochalasin B, or local anethetic agents. These results suggested that the loss was not secondary to capping or interiorization of Fc receptors. The results of other studies indicated that the Fc receptors were not damaged by lysosomal enzymes or oxygen radicals. Maintenance of EA rosetting ability of monocytes cultured on surface-bound immune complexes was seen after a 3-h preincubation of the cells in 100 mM 2-deoxy-D-glucose (2dG). A similar preincubation in ATP or in 8-bromoadenosine 3':5'-cyclic monophosphoric acid plus the phosphodiesterase inhibitor methyl isobutyl xanthine led to a partial loss of EA rosetting of cells on plain fibrin and to a partial reversal of the effects of 2dG seen with cells on complexes. We conclude that EA rosetting of monocytes cultured on surface-bound immune complexes is reduced by cyclic nucleotide-mediated effects on Fc receptor number or function.

Antigen-Antibody Complex↗