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PubMed2000

Cytokines and cell surface molecules independently induce CXCR4 expression on CD4+ CCR7+ human memory T cells.

In the present study, we show that IL-2, IL-4, IL-7, and IL-15 are able to induce functional CXCR4 surface expression on resting in vitro-generated CD4+ CXCR4- CCR7+ memory T cells. Cytokine-mediated induction of CXCR4 expression was associated with an increase in CXCR4 transcription, enhanced stromal-derived factor-1-induced T cell migration in vitro, and increased susceptibility of these cells to infection with X4 strains of HIV-1. CXCR4 expression could also be induced through an alternative pathway, following coculture of these cells with CD40-activated, autologous, CD34+ progenitor-derived dendritic cells. Although these dendritic cells express transcripts for IL-7 and IL-15, addition of neutralizing anti-IL-7R and IL-15 mAbs did not block induction of CXCR4 expression. Indeed, dendritic cell-mediated up-regulation of CXCR4 expression was found to depend on CD40/CD154 and CD134/CD134L interactions. Whereas activated autologous dendritic cells induced the expression of both CXCR4 and CD25 on a portion of CCR7+ memory T cells, concomitant CD3-mediated activation of these cells further enhanced CD25 expression, but, in contrast, prevented induction of CXCR4 expression. This observation suggests that triggering of the CD134 and CD154 molecules, in contrast to TCR/CD3 complex-mediated stimulation, results in simultaneous T cell activation and CXCR4 expression. Taken together, these results show that common gamma-chain-interacting cytokines as well as signals mediated via noncognate interactions between activated dendritic cells and memory T cells are involved in the up-regulation of CXCR4 expression.

Animals↗
PubMed1985

Effectiveness of cyclosporin therapy for Behçet's disease.

Behcet's disease is a clinical entity with mouth and genital ulcers, skin lesions, and both anterior and posterior uveitis as its major criteria. It has been theorized that Behcet's disease is immune complex mediated, and is characterized by multiple attacks which often lead to severe visual handicap. Behcet's disease patients with severe ocular involvement and cytotoxic and/or systemic corticosteroid agent failures were treated with cyclosporin (CsA). CsA therapy effectively abrogated the acute phase of the ocular attack and either totally prevented, or markedly reduced, the recurrences of these attacks. Generally, patients tolerated the medication well; occasionally however, renal toxicity secondary to cyclosporin therapy prevented prescription of a maximally effective therapeutic dose of the drug. CsA levels in plasma were dose-dependent for each patient, but the dosage per kg of CsA needed to obtain a specific plasma level varied greatly from patient to patient. Circulating immune complex levels were not universally elevated during the acute ocular attack. However, increases in circulating immune complex concentrations were noted after treatment with CsA was begun and the disease became clinically inactive. These data, as well as the effectiveness of CsA, an agent with predominantly anti-T cell effects, raise a question as to whether circulating immune complexes are centrally relevant to the pathogenesis of this disorder, and if T cell mediation of this disease must be contemplated.

Adult↗
PubMed1986

Isolation and partial characterization of endothelial cell extracellular complexes.

Human endothelial cells release components into the growth medium that stimulate cell-substratum adhesion. Several macromolecular components were isolated by ultracentrifugation of the endothelial cell conditioned medium. The components were heterogeneous, consisting of several sizes when examined by sedimentation velocity and gel filtration. When the extracellular components were evaluated by electron microscopy, structurally discrete particles were observed. The extracellular components and the complexes mediated cell-substratum adhesion to both human umbilical and arterial endothelial cells. The majority of the extracellular components that promote endothelial cell adhesion were pelleted by ultracentrifugation. Although the complexes contained fibronectin, antibodies to fibronectin did not inhibit cell adhesion to the complexes. Significant inhibition of endothelial cell adhesion was observed in the presence of heparin and heparan sulfate. The supernatant fraction following ultracentrifugation of the growth medium contained a component that suppressed endothelial cell adhesion to culture dishes coated with fibronectin, type I collagen, and endothelial cell complexes. SDS-polyacrylamide gel electrophoresis indicated that the complexes contained several components, and the majority of the large-molecular-weight components were pelleted by ultracentrifugation. The conditioned medium from human endothelial cells contains specific complexes that promote cell-substratum adhesion and components that suppress cell-substratum adhesion.

Antigens, Surface↗
PubMed2000

Extracorporeal removal of circulating immune complexes: from non-selective to patient-specific.

The classical immune complex-mediated disease, termed serum sickness, developed a short time after the injection of horse anti-tetanus toxin. Antibodies against circulating horse plasma proteins lead to the formation of immune complexes within the blood circulation (CIC). The inflammatory response, including systemic complement activation and vasculitis, seriously affected the function of all organs, including the most susceptible kidney. Meanwhile CIC have been detected in almost every systemic disease, including autoimmune disorders and also cancer and infections. This brief review will focus on the rationale and the equipment for extracorporeal elimination of CIC.

Antigen-Antibody Complex↗
PubMed1986

Circadian and diurnal variation of circulating immune complexes, complement-mediated solubilization, and the complement split product C3d in rheumatoid arthritis.

Nine patients with active classical rheumatoid arthritis (ARA criteria) were studied with reference to circadian variation of immunological and clinical parameters. Complement-mediated solubilization (CMS) of immune complexes (IC) and the level of circulating IC were found to be inversely related with low CMS and increased IC levels in the morning, and vice versa in the afternoon. Bed rest and exercise did not influence these fluctuations. The C3d concentration in plasma was increased but showed no diurnal or circadian periodic fluctuations when the levels were corrected for fluctuations in plasma albumin concentration. Clinical assessment by means of pain score exhibited marked variations, with high scores in the morning, and lower in the daytime, whereas measurements of Ritchie's joint index showed no consistent pattern. The circadian variations in CMS, serum IC and clinical parameters indicate the need to collect blood specimens and perform clinical examinations of patients at a fixed time of day.

Adult↗
PubMed1979

Quantitation and characterization of soluble immune complexes precipitated from sera by polyethylene glycol (PEG).

Polyethylene glycol (PEG) was used to isolate immune complexes from sera. Complexes were then quantified and partially characterized by a variety of immunological techniques. Complexes were detected in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Felty's syndrome and vasculitis, but not in polymyositis, scleroderma or Behçets syndrome. The level of immune complexes correlated with disease activity in SLE and RA patients. Rheumatoid factors and anti-DNA antibodies were enriched by PEG precipitation of RA and SLE sera, respectively, thus these antibodies appeared to be present in the form of soluble immune complexes. Immune complexes usually contained all three immunoglobulin classes, IgG, IgM and IgA. Complexes from RA patients were generally larger and often contained Clq, while C3 was found almost exclusively in SLE complexes which also tended to be smaller. Such compositional differences may one day explain the differences in clinical manifestations of various immune complex-mediated diseases.

Antibodies, Antinuclear↗
PubMed1982

Glomerular accumulation of monocytes and macrophages in experimental glomerulonephritis associated with Trypanosoma rhodesiense infection.

Experimental infection in rabbits with a human isolate of Trypanosoma rhodesiense led to the formation of circulating immune complexes and glomerulonephritis. Granular deposits of C3 and lesser amounts of IgM and IgG were seen deposited in the glomeruli in a primarily mesangial pattern. The glomeruli became hypercellular beginning on day 7. This was associated with diffuse swelling and vacuolation of endothelial cells with focal loss of fenestrae, as well as vacuolation of mesangial cells processes protruding into the capillary lumina. The hypercellularity became maximal on day 21 and was accompanied by proteinuria and increased tubular hyaline droplets. The hypercellularity was in large part due to the accumulation of monocytes as demonstrated by nonspecific cytoplasmic esterase stains. Counts of the number of monocytic cellular profiles per glomerulus showed that maximal numbers were reached on the 21st day of the infection. Ultrastructural examination confirmed the presence of monocytes within capillary lumina and macrophages within mesangial regions. Electron-dense deposits were rarely seen by transmission electron microscopy, and the heavy granular deposits of IgM and C3 observed by immunofluorescence were attributed to ingested proteins within macrophages. This study implies an active role for monocytes and macrophages in immune complex-mediated glomerulonephritis.

Animals↗
PubMed1995

Adhesion molecules, sex steroids, and the pathogenesis of vasculitis syndromes.

The pathogenesis of the vasculitis syndromes slowly continues to yield its secrets. Over the past year, evidence has continued to accumulate, indicating that the endothelium exhibits a wide range of regulatory functions, mediated in large part through adhesion molecules. Several studies showed increased expression of such molecules in vasculitis. New appreciation of the Shwartzman reaction, which could explain non-immune complex-mediated vascular inflammation, continues to mount and to point toward potential future therapies. Soluble adhesion molecules were studied as potential diagnostic tools and/or markers of disease activity. Anti-endothelial cell antibodies (AECA) remain controversial as potential mediators of vasculitis. The results of recent studies suggest that AECA may be seen more frequently in ANCA-negative vasculitis and that AECA possess unique antigenic specificities in Wegener's granulomatosis and systemic lupus erythematosus. Sex steroids were shown to affect the expression of endothelial adhesion molecules, in addition to possessing well documented immunoregulatory properties. These findings may point to a critical role for sex steroids in the pathogenesis of vasculitis syndromes with female predominance, particularly Takayasu's arteritis.

Animals↗
PubMed1994

The histopathologic spectrum of palisaded neutrophilic and granulomatous dermatitis in patients with collagen vascular disease.

BACKGROUND AND DESIGN: Patients with lupus erythematosus, rheumatoid arthritis, and other diseases in which circulating immune complexes occur can develop a papular eruption on the extremities. Terms including Churg-Strauss granuloma, cutaneous extravascular necrotizing granuloma, rheumatoid papules, superficial ulcerating rheumatoid necrobiosis, and interstitial granulomatous dermatitis with arthritis have been given to this entity. We evaluated the clinical and histopathologic features of six patients with systemic lupus erythematosus, two patients with rheumatoid arthritis, and one patient with an incompletely characterized collagen vascular disease who developed cutaneous papules. RESULTS: The lesions were located largely on the extremities and were symmetrically distributed in most of the patients. They ranged from a few to many and from skin colored to erythematous, and they had smooth, ulcerated, or umbilicated surfaces. Histopathologic examination showed a spectrum of changes that, we believe, reflect the evolution of lesions, ie, leukocytoclastic vasculitis with dense neutrophilic infiltrates and degenerated collagen in early lesions; palisaded granulomas surrounding leukocytoclastic debris, fibrin, and altered collagen in fully developed lesions; and, as the process wanes, palisaded granulomas with dermal fibrosis and scant neutrophilic debris. Each stage of development elicits a different differential diagnosis, which can be resolved by the application of histopathologic criteria. CONCLUSION: The histopathologic findings are consonant with the evolution of an immune complex-mediated disease. The diverse histopathologic, and sometimes clinical, appearances account for the variety of names given to this condition. We propose the name palisaded neutrophilic and granulomatous dermatitis of immune complex disease to reflect the histopathologic evolution and clinical aspects of this condition.

Adult↗
PubMed1992

A protein kinase C-activating phorbol ester accelerates the T cell antigen receptor-stimulated phosphatidylinositol cycle in normal human CD4+ T cells.

Ligation of the TCR on Jurkat T lymphoblastoid cells causes an 1,4,5-inositol trisphosphate-dependent rise in intracellular cytoplasmic calcium that is inhibited by PMA, a potent activator of protein kinase C. Consequently, protein kinase C is widely believed to mediate feedback inhibition of TCR-activated phospholipase C. We have now extended these studies to normal unblasted human CD4+ T lymphocytes, examining the PMA sensitivity of both the TCR complex-mediated release of total inositol-phosphates and the resynthesis of the parent phosphoinositides. In contrast to Jurkat, in which PMA inhibited release of 1,4,5-inositol trisphosphate by 60% and total inositolphosphates by 40% (50% inhibitory concentration, 5.6 nM), normal cells displayed a marked increase in anti-CD3-induced phosphatidylinositol (PI) cycling in the presence of PMA. Both total inositolphosphate release and PI resynthesis were maximally elevated (88% and 342%, respectively) by a PMA concentration that also optimally supported a subsequent proliferative response; the ED50 was at least 11.7-fold lower than that for the inhibitory effect of PMA on breakdown of total Jurkat PI. A PKC nonactivating phorbol ester had no effect. If anti-CD3 was replaced by the mitogenic lectin PHA, PI resynthesis was similarly up-regulated by PMA in these highly purified cells. The PMA up-regulatory phenomenon was not a simple consequence of cell blastogenesis, inasmuch as there was no early effect on the non-signaling-associated phosphatidylethanolamine compartment after CD3 stimulation. Thus, PKC activation appears to accelerate TCR-linked PI metabolism in normal Th cells, in contrast to the feedback inhibitor paradigm observed in Jurkat and other tumor cell systems.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1994

Nucleosome disruption and enhancement of activator binding by a human SW1/SNF complex.

CHROMATIN structure can affect the transcriptional activity of eukaryotic structural genes by blocking access of sequence-specific activator proteins (activators) to their promoter-binding sites. For example, the DNA-binding domain of the yeast GAL4 protein interacts very poorly with nucleosome cores compared with naked DNA2 (and see below), and binding of other activators is even more strongly inhibited. The way in which activators bind to nucleosomal DNA is therefore a critical aspect of transcriptional activation. Genetic studies have suggested that the multi-component SWI/SNF complex of Saccharomyces cerevisiae facilitates transcription by altering the structure of the chromatin. Here we identify and partially purify a human homologue of the yeast SWI/SNF complex (hSWI/SNF complex). We show that a partially purified hSWI/SNF complex mediates the ATP-dependent disruption of a nucleosome, thereby enabling the activators, GAL4-VP16 and GAL4-AH, to bind within a nucleosome core. We conclude that the hSWI/SNF complex acts directly to reorganize chromatin structure so as to facilitate binding of transcription factors.

Adenosine Triphosphatases↗
PubMed2001

IGF-II induces rapid beta-catenin relocation to the nucleus during epithelium to mesenchyme transition.

The epithelium to mesenchyme transition is thought to play a fundamental role during embryonic development and tumor progression. Loss of cell-cell adhesion and modification of both cell morphology and gene expression are the main events associated with this transition. There is a large amount of evidence suggesting that growth factors can initiate these events. Yet, the connection from growth factor induction to changes in cell adhesion and morphology is largely unknown. To elucidate this connection, we have investigated the action of IGF-II on E-cadherin/beta-catenin complex-mediated cell-cell adhesion and on beta-catenin/TCF-3 mediated gene expression. We can show that (1) IGF-II induces a rapid epithelium to mesenchymal transition; (2) IGF1R, the receptor for IGF-II, belongs to the same membrane complex as E-cadherin and beta-catenin; (3) IGF-II induces a redistribution of beta-catenin from the plasma membrane to the nucleus and an intracellular sequestration and degradation of E-cadherin; (4) IGF-II induces the transcription of beta-catenin/TCF-3 target genes. Based on the given case of IGF-II and E-cadherin/beta-catenin complex, this study reveals the backbone of a cascade connecting growth factor signaling with cell-cell adhesion during EMT.

3T3 Cells↗
PubMed1995

Langerhans cells and vasculitis.

Langerhans cells are members of the dendritic cell system, which reside in the skin. These cells have many immunohistochemical and ultrastructural markers (for example, they are CD1a+ and possess Birbeck granules), which consent to identify them in an infiltrate. Langerhans cells have the specific role to present the antigens to T lymphocytes and to induce the cell-mediated immune reaction. Cutaneous necrotizing vasculitis (CNV) can be divided in two major forms: a leukocytoclastic type and a lymphocytic type. The pathogenesis of the first one is presumably immune complex-mediated, while for the second one a cell-mediated immunity has been proposed. Our group investigated on the cell infiltrate of some cases of CNV, both leukocytoclastic and lymphocytic type; and for leukocytoclastic CNV two phases were studied: an early one (at the onset of the lesion) and a later one (more than 24 hours). Special attention was paid to the presence of dendritic cells in the infiltrate and to their relationship to lymphocytes, if present. By immunohistochemistry and electron microscopy we could find many Langerhans cells and T lymphocytes in lymphocytic and in the late phase of leukocytoclastic CNV. The observed pattern of the cell infiltrate suggests that a cell mediated immune response play a major role in the pathogenesis of lymphocytic vasculitis and that dendritic cells and lymphocytes contribute to self-perpetuate leukocytoclastic vasculitis, which cannot be anymore considered as simply due to infiltration of neutrophils.

Animals↗
PubMed1978

Decrease in circulating immune complexes during hemodialysis.

Raji cell radioimmunoassay and Clq solid phase radioimmunoassay were used to determine serially circulating immune complexes in a patient with rapidly progressive glomerulonephritis who was receiving hemodialysis therapy. Initiation of hemodialysis was associated with a significant decrease in detectable immune complexes which, in turn, was associated with improvement and stabilization of renal function. We suggest that hemodialysis may remove immune complexes from the circulation and that it could be of therapeutic benefit in selected patients with presumed immune complex-mediated glomerulonephritis.

Adolescent↗
PubMed2026

Phosphatase-mediated mitigation of rare earth element toxicity to Pseudomonas putida.

Anthropogenic activities are driving an increasing flux of rare earth elements (REE) into environmental compartments, raising concerns about their biological impact, particularly on microorganisms that sustain ecosystem functioning. Here, we provide a systematic assessment of the toxicity of all 16 REE toward Pseudomonas putida KT2440, a soil bacterium that can use these metals as enzyme cofactors. Dose-response growth inhibition assays revealed high sensitivity to light REE. Toxicity correlated strongly with ionic radius, with IC50 values ranging from 0.3 µM for lanthanum to 10 µM for scandium. Serial propagation of P. putida under gradually increasing REE stress yielded resistant populations, from which two stably resistant strains were isolated. Genome resequencing showed that both strains carried a single mutation in uxpB, encoding an alkaline phosphatase. Gene deletion and overexpression experiments, together with phosphatase activity measurements, confirmed the involvement of uxpB in REE resistance. Our findings reveal a previously unrecognized mechanism of tolerance to REE, suggesting that mutations enhancing phosphatase activity promote phosphate release from organic phosphorus compounds, thereby reducing REE bioavailability through phosphate-mediated complexation and/or immobilization.

Alkaline phosphatase↗
PubMed2005

Differential regulation of cortactin and N-WASP-mediated actin polymerization by missing in metastasis (MIM) protein.

Missing in metastasis (MIM) gene encodes an actin binding protein that is expressed at low levels in a subset of malignant cell lines. MIM protein tagged by green fluorescent protein (GFP) colocalizes with cortactin, an Arp2/3 complex activator, and interacts directly with the SH3 domain of cortactin. Recombinant full-length MIM promotes markedly cortactin and Arp2/3 complex-mediated actin polymerization in an SH3 dependent manner. In contrast, MIM-CT, a short splicing variant of MIM, binds poorly to cortactin in vitro and is unable to enhance actin polymerization. Full-length MIM binds to G-actin with a similar affinity as N-WASP-VCA, a constitutively active form of N-WASP, and inhibits N-WASP-VCA-mediated actin polymerization as analysed in vitro. The significance of the association of MIM with cortactin and G-actin was evaluated in NIH3T3 cells expressing several MIM constructs. Overexpression of full-length wild-type MIM-GFP inhibited markedly the motility of NIH3T3 cells induced by PDGF and that of human vein umbilical endothelial cells induced by sphingosine 1 phosphate. However, an MIM mutant with deletion of the WH2 domain, which is responsible for G-actin binding, enhanced cell motility. The motility inhibition imposed by MIM was compromised in the cells overexpressing N-WASP. In contrast, deletion of an MIM proline-rich domain, which is required for an optimal binding to cortactin, substantiated the MIM-mediated inhibition of cell motility. These data imply that MIM regulates cell motility by modulating different Arp2/3 activators in a distinguished manner.

3T3 Cells↗
PubMed1981

Detection and composition of immune complexes in experimental African trypanosomiasis.

Humoral immune responses in experimental African trypanosomiasis were assessed in rabbits infected with Trypanosoma rhodesiense. Immune complexes as measured by a Clq binding assay or a Clq solid-phase assay were detected by day 10 and increased progressively through day 28. Immune complexes analyzed by double diffusion in agar or enzyme immunoassay contained immunoglobulin M (IgM) and IgG consistently, and usually C3. In one serum, immune complexes contained trypanosomal antigens in addition to C3, IgG, and IgM. By sucrose density gradient ultracentrifugation Clq-binding immune complex-like materials were shown to contain IgG, IgM, and C3, sedimentating as intermediate (between 7S and 19S) or as higher-molecular-weight (greater than 19S) aggregates. Serum IgM and IgG antibodies to trypanosomes were measured by enzyme immunoassay. IgM antibodies were detected by day 7, rose to peak by day 14, and declined slowly thereafter. IgG antibodies were detected by day 14 and continued to rise through day 32. Total IgM and IgG measured by radial immunodiffusion paralleled the corresponding changes in antibody levels. Host immune responses, in part directed to trypanosomal antigens, produced circulating immune complexes containing bound C3; these may be deposited in tissue or may serve as a serological marker of immune complex-mediated tissue injury.

Animals↗
PubMed1984

Neutrophil activation by immune complexes and the role of rheumatoid factor.

Membrane activation of human neutrophils by preformed immune complexes and heat aggregated human gammaglobulins was studied by chemiluminescence. Strong neutrophil activation was found with human-albumin rabbit-antialbumin complexes prepared at equivalence, with maximal activation occurring in slight antigen excess. Furthermore different preparations of heat aggregated gammaglobulin which were of large size also showed similar activity. In contrast, heat aggregates of small size were inactive and blocked the chemiluminescent response found with larger active aggregates. A purified monoclonal rheumatoid factor with specificity for IgG modulated these responses when preincubated with preformed complexes or aggregates. Both enhancement of the neutrophil chemiluminescence response with inactive preparations and suppression of the response with highly active preparations were observed. Kinetic studies of the neutrophil chemiluminescent response varied with respect to the activating preparation, but were generally biphasic. This observation suggested an initial direct membrane activation followed by a more delayed response reflecting phagocytosis of complexes. We have demonstrated the direct activation of neutrophil chemiluminescence by laboratory preparations of immune complexes. The chemiluminescent responses observed were influenced by both the size and immunochemical properties of the activating complexes and by the presence of rheumatoid factor. These observations may have important implications in the immunopathogenesis of immune-complex-mediated diseases.

Animals↗