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PubMed1988

Determinants of immune complex-mediated glomerulonephritis.

We have studied the influence of steric factors on the clinico-pathologic expression of immune complex-mediated glomerular diseases, utilizing ferritin as an exogenous antigen. The tracer was planted in the left kidney either in the subepithelial layer of the glomerular capillary wall or on the endothelium and lamina rara interna. Subepithelial immune complex formation resulted in non-inflammatory injury with heterologous and autologous proteinuric phases (115 +/- 16 mg/24 hrs on day 2; 183 +/- 16 mg/24 hrs on day 9) lasting four to five weeks. The glomerular filtration rate of the experimental left kidney was reduced by 19% at day 3, and was increased by 20% at day 12 over right kidney values. Immune complexes persisted for more than seven weeks in the lamina rara externa. In contrast, immune complex deposition on the endothelium and in the lamina rara interna led to acute transient anuria, with a 38% drop in glomerular filtration rate at one hour, massive platelet accumulation, followed by a strong inflammatory response. Proteinuria did not develop. Functional and structural integrity was restored within 24 hours, with complete clearing of immune deposits. We conclude that the distribution of exogenous antigens within the capillary wall determines the structural and functional expression of immune-mediated glomerular diseases.

Animals↗
PubMed2002

Local overexpression of adeno-viral IL-4 protects cartilage from metallo proteinase-induced destruction during immune complex-mediated arthritis by preventing activation of pro-MMPs.

OBJECTIVE: To determine whether IL-4 protects against metalloproteinase-induced cartilage destruction during immune complex mediated arthritis and to elucidate its mechanism. METHODS: Experimental immune complex arthritis (ICA) was raised by injecting lysozyme into the knee joints of mice which previously were given anti-lysozyme antibodies. Three days before ICA induction, mice were injected into the right knee joint with either IL-4 expressing or empty control recombinant human type 5 adenovirus. Joint inflammation and cartilage destruction (PG depletion, erosion) was measured by histology of total knee joints. Aggrecan breakdown in cartilage caused by metalloproteinases (MMPs) was studied by immunolocalization using anti-VDIPEN antibodies. RESULTS: Four days after ICA induction, histological analysis showed comparable exudate and infiltrate in both groups. Depletion of proteoglycans as measured by loss of red staining was also comparable in both groups. IL-4 treatment inhibited MMP-mediated neoepitope expression by 90%. Moreover, cartilage matrix erosion was evident in all animals (10 out of 10 mice) in the control group and significantly diminished (only two out of ten mice) in the IL-4 treated group. Incubation of patellae with APMA, which activates latent MMPs resulted in VDIPEN expression which was not significantly different from control ICA indicating that comparable amounts of latent pro-MMPs are present in IL-4 treated arthritic knee joints. CONCLUSION: This study indicates that during ICA, IL-4 largely prevents MMP-mediated aggrecan breakdown and severe cartilage erosion. IL-4 does not inhibit production of latent MMPs by the chondrocyte but predominantly interferes with its activation.

Adenoviridae↗
PubMed1991

Immune complex-mediated glomerulopathy in experimental Chagas' disease.

To investigate the development of glomerulopathy during the chronic phase of experimental Chagas' disease, C3H-Hej mice were infected with Trypanosoma cruzi trypomastigotes. Deposits of IgG, IgM, and C3 in renal mesangium were observed by immunofluorescence (IF) to increase in size as a function of time after infection (4-6 months). T. cruzi antigens were codeposited in glomeruli with Ig and C3. Electron-dense deposits were visualized in mesangial and paramesangial areas by electron microscopy. Anti-T. cruzi and rheumatoid factor (RF) antibodies (of IgG isotypes) were detected both in serum and in renal eluates. In serum, the titers of both antibodies progressively decreased as a function of time after infection. In renal eluates, titers of anti-T. cruzi antibodies appeared to be stable during the three time periods after infection. By contrast, titers of RF antibodies in renal eluates were shown to increase progressively during these same time periods, paralleling the increase in size of mesangial Ig deposits observed by IF. Several T. cruzi proteins were immunoprecipitated from radiolabeled renal eluates by a control anti-T. cruzi antibody. In addition, antibodies from renal eluates specifically precipitated a 85-kDa protein from radiolabeled T. cruzi lysates, whereas serum antibodies precipitated a broad pattern of T. cruzi proteins. These results demonstrate that mice experimentally infected with T. cruzi can develop a mesangial glomerulopathy during the chronic phase of the disease, which appears to be mediated through immune complexes containing parasite antigens associated with secondary deposition of RF.

Animals↗
PubMed1997

Immune complex-mediated haemolytic anaemia and Evans syndrome induced by diclofenac.

BACKGROUND AND OBJECTIVES: Sodium diclofenac is one of the most widely used nonsteroidal anti-inflammatory drugs. Cases of acute haemolytic anaemia have been ascribed to the drug. We describe such a case, mediated by immune complexes. MATERIALS AND METHODS: Standard serologic tests were carried out for blood grouping and the detection and identification of red cell allo- and autoantibodies. Drug-anti-drug complexes were detected with an ex-vivo method. RESULTS: Warm IgG drug-independent red cell and platelet autoantibodies were detected in the serum. At first, the patient was diagnosed as having the Evans syndrome, and corticosteroids were administered. Later, because of the severity of the anaemia, the possibility of an immune complex mechanism was considered. This was confirmed by the detection of diclofenac-dependent antibodies that reacted with RBC only in the presence of urine from a volunteer receiving diclofenac as a source of ex-vivo antigen. The antibodies neither reacted with an in-vitro solution of the drug nor with the volunteer's serum. Diclofenac and corticosteroids were stopped, and the clinical condition of the patient completely normalised within 15 days. CONCLUSIONS: We describe a patient with acute haemolytic anaemia caused by diclofenac through an immune complex mechanism.

Anemia, Hemolytic, Autoimmune↗
PubMed1999

Biopsy-proven resolution of immune complex-mediated crescentic glomerulonephritis with mycophenolate mofetil therapy in an allograft.

We report biopsy-proven resolution of immune-complex-mediated crescentic glomerulonephritis (ICMCGn) using mycophenolate mofetil (MMF). Therapy with steroids and cyclophosphamide failed twice in a 39-year-old white man who developed ICMCGn in his native kidneys, and subsequently in a human lymphocyte antigen-identical renal allograft. When he developed ICMCGn in a second, now cadaver, allograft, he was treated with steroids and MMF instead. His serum creatinine (Cr) improved from 4.4 mg/dL to 2.1 mg/dL. A biopsy 21 months later showed him to be free of glomerular disease. MMF is known to be an effective immunosuppressant. In our patient, ICMCGn, a notoriously difficult entity to treat effectively, seemingly resolved with MMF therapy. We suggest that MMF may be effective in the treatment of immunologically mediated pre-end-stage renal disease (ESRD). It should be considered in any posttransplantation setting where the original cause of organ failure is known to be immunologically mediated and likely to recur.

Adult↗
PubMed2001

Uptake of apoptotic leukocytes by synovial lining macrophages inhibits immune complex-mediated arthritis.

Previously we have shown that synovial lining macrophages (SLMs) determine the onset of experimental immune complex-mediated arthritis (ICA). During joint inflammation, many leukocytes undergo apoptosis, and removal of leukocytes by SLMs may regulate resolution of inflammation. In this study we investigated binding and uptake of apoptotic leukocytes by SLMs and its impact on the onset of murine experimental arthritis. We used an in vitro model to evaluate phagocytosis of apoptotic cells on chemotaxis. Phagocytosis of apoptotic thymocytes resulted in a significant decrease (58%) of chemotactic activity for polymorphonuclear neutrophils (PMNs). If apoptotic cells were injected directly into a normal murine knee joint, SLMs resulted in a prominent uptake of cells. After ICA induction, electron micrographs showed that apoptotic leukocytes were evidently present in SLMs on days 1 and 2. Injection of apoptotic leukocytes into the knee joint 1 h before induction of ICA significantly inhibited PMN infiltration into the knee joint at 24 h (61% decrease). This study indicates that uptake of apoptotic leukocytes by SLM reduces chemotactic activity and inhibits the onset of experimental arthritis. These findings indicate an important mechanism in the resolution of joint inflammation.

Animals↗
PubMed2004

Activating the PARP-1 sensor component of the groucho/ TLE1 corepressor complex mediates a CaMKinase IIdelta-dependent neurogenic gene activation pathway.

Switching specific patterns of gene repression and activation in response to precise temporal/spatial signals is critical for normal development. Here we report a pathway in which induction of CaMKIIdelta triggers an unexpected switch in the function of the HES1 transcription factor from a TLE-dependent repressor to an activator required for neuronal differentiation. These events are based on activation of the poly(ADP-ribose) polymerase1 (PARP-1) sensor component of the groucho/TLE-corepressor complex mediating dismissal of the corepressor complex from HES1-regulated promoters. In parallel, CaMKIIdelta mediates a required phosphorylation of HES1 to permit neurogenic gene activation, revealing the ability of a specific signaling pathway to modulate both the derepression and the subsequent coactivator recruitment events required for transcriptional activation of a neurogenic program. The identification of PARP-1 as a regulated promoter-specific exchange factor required for activation of specific neurogenic gene programs is likely to be prototypic of similar molecular mechanisms.

Animals↗
PubMed1995

TCR/CD3 complex-mediated signal transduction pathway in T cells and T cell lines from patients with systemic lupus erythematosus.

We studied the TCR/CD3 complex-mediated signal transduction pathway in freshly isolated T cells and T cell lines from patients with systemic lupus erythematosus (SLE). The peak and 5-min anti-CD3 mAb-mediated free intracytoplasmic Ca2+ concentration ([Ca2+]i) increase was statistically significant higher in fresh T cells from SLE patients than in control T cells. Increased CD3-mediated [Ca2+]i responses were observed in T cells from patients with SLE but not in T cells from other rheumatic diseases. Furthermore, significantly increased CD3-mediated [Ca2+]i responses were observed in T cell lines from SLE patients but not from controls. Although the [Ca2+]i response did not correlate with the global SLE disease activity or individual clinical manifestations, it was significantly higher in the group of patients who were not on treatment. Both CD4+ and CD8+ T cell subsets from peripheral blood cells and T cell lines displayed higher CD3-mediated [Ca2+]i responses than their normal counterparts. The peak of the response occurred earlier in the patient than in the normal group. The amount of Ca2+ that was released from the intracellular stores was higher in lupus than control T cells. The TCR/CD3-induced production of inositol phosphate metabolites in SLE cells was comparable with controls. The sarcoplasmic and endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin-induced [Ca2+]i response was similar in both SLE and normal T cells. Our experiments demonstrate for the first time a definite abnormality in the early steps of the TCR/CD3-mediated signal transduction pathway in T cells from SLE patients that involves increased release of Ca2+ from intracellular stores.

Adolescent↗
PubMed2000

Fc gamma R expression on macrophages is related to severity and chronicity of synovial inflammation and cartilage destruction during experimental immune-complex-mediated arthritis (ICA).

STATEMENT OF FINDINGS: We investigated the role of Fc gamma receptors (Fc gamma Rs) on synovial macrophages in immune-complex-mediated arthritis (ICA). ICA elicited in knee joints of C57BL/6 mice caused a short-lasting, florid inflammation and reversible loss of proteoglycans (PGs), moderate chondrocyte death, and minor erosion of the cartilage. In contrast, when ICA was induced in knee joints of Fc receptor (FcR) gamma-chain(-/-) C57BL/6 mice, which lack functional Fc gamma RI and RIII, inflammation and cartilage destruction were prevented. When ICA was elicited in DBA/1 mice, a very severe, chronic inflammation was observed, and significantly more chondrocyte death and cartilage erosion than in arthritic C57BL/6 mice. The synovial lining and peritoneal macrophages of naïve DBA/1 mice expressed a significantly higher level of Fc gamma Rs than was seen in C57BL/6 mice. Moreover, elevated and prolonged expression of IL-1 was found after stimulation of these cells with immune complexes. Zymosan or streptococcal cell walls caused comparable inflammation and only mild cartilage destruction in all strains. We conclude that Fc gamma R expression on synovial macrophages may be related to the severity of synovial inflammation and cartilage destruction during ICA.

Animals↗
PubMed1989

Mechanism of immune complex-mediated damage: induction of interleukin 1 by immune complexes and synergy with interferon-gamma and tumor necrosis factor-alpha.

The ability of immune complexes derived from patients with type II mixed essential cryoglobulinemia to trigger the production of interleukin 1 (IL 1) was investigated. Immune complexes containing either IgM/IgG or IgA/IgG aggregates were shown to induce IL 1 production in human peripheral blood monocyte-enriched populations. Interferon-gamma alone did not induce detectable IL 1, but increased the IL 1 production induced by the immune complexes. Tumor necrosis factor-alpha, which is a potent inducer of IL 1, also enhanced IL 1 production following stimulation with suboptimal doses of the immune complex. The findings suggest that immune complexes may induce inflammation partly due to their capacity to induce the synthesis of IL 1.

Antigen-Antibody Complex↗
PubMed2001

Inhibition of immune-complex mediated dermal inflammation in rats following either oral or topical administration of a small molecule C5a receptor antagonist.

1. Initiation of a peritoneal Arthus reaction by deposition of immune-complexes results in vascular leakage, polymorphonuclear leukocyte (PMN) infiltration, and tumour necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production. We now demonstrate in rats that oral administration of the C5a receptor antagonist AcPhe[Orn-Pro-D-Cyclohexylalanine-Trp-Arg] (AcF-[OPdChaWR]; 1 - 10 mg kg(-1) 30 min prior to immune-complex deposition) inhibits these inflammatory markers in the peritoneal Arthus reaction. 2. Initiation of a dermal Arthus reaction resulted in a significant increase in vascular leakage, PMN infiltration, systemic production of TNFalpha and pathological changes in the dermis. 3. Pretreatment of rats with AcF-[OPdChaWR] either intravenously (1 mg kg(-1) 10 min prior to immune-complex deposition) or orally (1 - 10 mg kg(-1) 30 min prior to immune-complex deposition) significantly inhibited immune-complex mediated dermal vascular leakage and systemic cytokine production. Topical pretreatment with AcF-[OPdChaWR] (400 microg site(-1) in 10% dimethyl sulphoxide 10 min prior to immune-complex deposition) also inhibited vascular leakage, as well as histopathological changes associated with a dermal Arthus reaction. 4. Oral administration of 3 mg kg(-1) AcF-[OPdChaWR] resulted in the appearance of the drug in plasma within 5 min, with peak blood levels approximately 0.3 microM reached within 20 min. The plasma elimination half-life was approximately 70 min. The oral activity and bioavailability of AcF-[OPdChaWR], its activity when applied topically to the skin, suggest that small molecule C5a receptor antagonists may have therapeutic utility in dermal inflammatory disorders involving complement activation. 5. This is the first demonstration for either an orally or topically active C5a receptor antagonist, and suggests that small molecule C5a antagonists may have therapeutic utility when given by multiple routes of application.

Administration, Oral↗
PubMed2003

Coordinate expression of activating Fc gamma receptors I and III and inhibiting Fc gamma receptor type II in the determination of joint inflammation and cartilage destruction during immune complex-mediated arthritis.

OBJECTIVE: To study the role of the activating Fc gamma receptor types I and III (Fc gamma RI and Fc gamma RIII, respectively) and the inhibiting Fc gamma receptor II (Fc gamma RII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune complexes. METHODS: Immune complex-mediated arthritis (ICA) was passively induced by lysozyme-antilysozyme complexes in Fc gamma RI-, Fc gamma RIII-, and Fc gamma RII-knockout mice and their wild-type controls. Total knee joints were isolated to study inflammation and cartilage destruction (loss of proteoglycans [PGs], chondrocyte death, matrix metalloproteinase [MMP]-mediated neoepitope [VDIPEN] expression, and erosion). The presence of an active phenotype of macrophages was studied by detection of myeloid-related proteins 8 and 14 (MRP8 and MRP14, respectively). RESULTS: Influx and activation of inflammatory cells (MRP expression) during ICA was decreased in Fc gamma RIII-deficient mice and enhanced in mice lacking Fc gamma RII. Mild cartilage destruction reflected by loss of PGs was consistent with the degree of inflammation. Mice lacking Fc gamma RIII showed almost no PG depletion, whereas in Fc gamma RII(-/-) mice, PG depletion was increased 3-7-fold in various cartilage areas. Initiation of erosive cartilage destruction, as reflected by MMP-mediated VDIPEN expression, was reduced in Fc gamma RIII(-/-) and Fc gamma RI(-/-) mice, directing the two different critical steps of cellular influx and subsequent activation. These aspects were enhanced in Fc gamma RII(-/-) mice. In Fc gamma RI(-/-) and Fc gamma RIII(-/-) mice, VDIPEN expression was 90-99% lower, whereas in Fc gamma RII(-/-) mice, VDIPEN expression was increased 4-fold. Chondrocyte death was reduced in Fc gamma RIII(-/-) mice (68% lower) and enhanced in Fc gamma RII(-/-) mice (6-12-fold higher). Progression of arthritis and erosion of the cartilage surface were markedly elevated in Fc gamma RII(-/-) arthritic joints. CONCLUSION: During ICA, Fc gamma RIII is the dominant activating receptor mediating joint inflammation, whereas both Fc gamma RI and Fc gamma RIII are involved in cartilage destruction. Fc gamma RII inhibits both joint inflammation and severe cartilage destruction during ICA.

Animals↗
PubMed2004

Correction of translational defects in patient-derived mutant mitochondria by complex-mediated import of a cytoplasmic tRNA.

A variety of clinical disorders result from mutations in mitochondrial tRNA genes, leading to translational defects. We show here that a protein complex from the kinetoplastid protozoon Leishmania induces specific, ATP-dependent import of human cytoplasmic tRNA(1)(Lys) into human mitochondria in vitro. The imported tRNA undergoes efficient aminoacylation within the organelle and supports organellar protein synthesis. Moreover, translation in mitochondria from patients with myclonic epilepsy with ragged red fibers (MERRF) and Kearns-Sayre syndrome (KSS), containing mutant tRNA(Lys) genes, is stimulated to near-wild-type levels and the formation of aberrant polypeptides suppressed by complex-mediated import. These results suggest a novel way to introduce RNAs for the modulation of mitochondrial gene expression.

Adenosine Triphosphate↗
PubMed1991

Clozapine attenuates N-methyl-D-aspartate receptor complex-mediated responses in vivo: tentative evidence for a functional modulation by a noradrenergic mechanism.

Recent studies revealed a role for dopamine and noradrenaline in the etiology of ischemia-induced neuronal cell death. In the present investigation, the modulation by clozapine, an atypical antipsychotic agent that interacts with adrenergic receptors, of N-methyl-D-aspartate (NMDA) receptor complex-mediated events were studied by examining its effects on levels of cGMP in the cerebellum. Clozapine decreased basal levels of cGMP in the cerebellum and antagonized harmaline-, methamphetamine-, pentylenetetrazol- and D-serine-induced increases in levels of cGMP with ED50 values of 3.9, 2.36, 2.13 and 2.1 mg/kg (i.p.). However, clozapine (1.25-25 mg/kg) did not attenuate the quisqualate-induced increases in levels of cGMP, indicating a specific modulation of events modulated by the NMDA receptor complex. Antagonists of dopamine (D2), serotonin (5-HT)-5-HT1, 5-HT2 and 5-HT3 [haloperidol, propranolol, ritanserin, ICS 205-930 [(3-tropanyl-indole-3-carboxylate methiodide)] respectively], did not reverse the response to harmaline. However, WB-4101 [(2,6-dimethoxy-phenoxyethyl)aminomethyl-1,4-benzodioxane HCl], and alpha 1-adrenergic antagonist, reversed harmaline-, D-serine-, PTZ- and MA-induced increases in levels of cGMP, indicating an adrenergic modulation of the events mediated by the NMDA receptor complex. Intracerebellar and intracerebroventricular administration of clozapine and intracerebellar administration of WB-4101 reversed the D-serine-induced response, indicating a central locus of action. These results indicated that clozapine modulates levels of cGMP predominantly through its interactions with central adrenergic receptors.

Adrenergic alpha-Antagonists↗
PubMed2000

TFIIH is negatively regulated by cdk8-containing mediator complexes.

The mammalian cyclin-dependent kinase 8 (cdk8) gene has been linked with a subset of acute lymphoblastic leukaemias, and its corresponding protein has been functionally implicated in regulation of transcription. Mammalian cdk8 and cyclin C, and their respective yeast homologues, Srb10 and Srb11, are components of the RNA polymerase II holoenzyme complex where they function as a protein kinase that phosphorylates the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II (ref. 7). The yeast SRB10 and SRB11 genes have been implicated in the negative regulation of transcription. The cdk8/cyclin C protein complex is also found in a number of mammalian Mediator-like protein complexes, which repress activated transcription independently of the CTD in vitro. Here we show that cdk8/cyclin C can regulate transcription by targeting the cdk7/cyclin H subunits of the general transcription initiation factor IIH (TFIIH). cdk8 phosphorylates mammalian cyclin H in the vicinity of its functionally unique amino-terminal and carboxy-terminal alpha-helical domains. This phosphorylation represses both the ability of TFIIH to activate transcription and its CTD kinase activity. In addition, mimicking cdk8 phosphorylation of cyclin H in vivo has a dominant-negative effect on cell growth. Our results link the Mediator complex and the basal transcription machinery by a regulatory pathway involving two cyclin-dependent kinases. This pathway appears to be unique to higher organisms.

Amino Acids↗
PubMed1993

Cyclic amphipathic peptide-DNA complexes mediate high-efficiency transfection of adherent mammalian cells.

A DNA transfection protocol has been developed that makes use of the cyclic cationic amphipathic peptide gramicidin S and dioleoyl phosphatidylethanolamine. The DNA complex is formed by mixing gramicidin S with DNA at a 1:1 charge ratio and then adding phosphatidylethanolamine at a lipid/peptide molar ratio of 5:1. The complex mediates rapid association of DNA with cells and leads to transient expression levels of beta-galactosidase ranging from 1 to 30% of the transfected cells, with long-term expression being about an order of magnitude lower. The respective roles of peptide and phospholipid are not yet resolved but optimal transfection requires both the cyclic peptide and the hexagonal phase-competent phospholipid PtdEtn. Transfection in CV-1 cells is not affected by lysomotrophic agents, which suggests that DNA entry into the cell is via the plasma membrane. This technique that is simple, economical, and reproducible mediates transfection levels up to 20-fold higher than cationic liposomes in adherent mammalian cells.

Animals↗
PubMed1987

Amelioration of immune complex-mediated glomerulonephritis by synthetic protease inhibitors.

Proteases are involved in the pathogenesis of inflammatory diseases by participating in the activation of mediator systems and by producing proteolytic tissue injury. Homeostatic control of inflammation is accomplished in part by physiologic protease inhibitors. The authors investigated the effectiveness of a number of synthetic protease inhibitors in ameliorating the glomerular injury induced by immune complex-mediated glomerulonephritis in mice. Two amidine-type protease inhibitors, bis (5-amidino-2-benzimidazolyl)methane and 1,2-bis (5-amidino-2-benzimidazolyl)ethane, had the greatest effects. They caused a marked reduction in glomerular necrosis (P less than 0.001) but did not affect the amount or site of immune complex localization or leukocyte influx. The inhibition constants of the protease inhibitors against nine purified physiologic proteases were determined. These results were discussed in relation to the effectiveness of the protease inhibitors in reducing glomerular injury. This investigation indicates that the administration of synthetic protease inhibitors can have a beneficial effect on immune-mediated inflammatory injury.

Amidines↗
PubMed2002

Caenorhabditis elegans unc-37/groucho interacts genetically with components of the transcriptional mediator complex.

Groucho functions as a general corepressor by modulating chromatin structure and has a widespread role in many developmental processes. Here we show that Groucho may also interact with the basal transcriptional machinery. Mutations in Caenorhabditis elegans groucho interact with mutations in components of the transcriptional Mediator complex, resulting in synthetic lethality and loss of male sensory neurons.

Animals↗