Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor-beta2-treated Ag-pulsed APC mimic APC from the immune privileged eye, and provide signals that generate regulatory T (Tr) cells and mediate peripheral tolerance. We postulated that TGF-beta2-treated Ag-pulsed APC (tolerogenic APC (tol-APC)) might also orchestrate regulation of immune mediated pathogenesis in nonimmune privileged tissues such as the lung. We used an adoptive transfer model of autoimmune pulmonary interstitial fibrosis called hapten immune pulmonary interstitial fibrosis (ADT-HIPIF) in this study. Mice that received 2,4,6-trinitrobenzene sulfonic acid-sensitized cells and challenged (intratracheally) with the hapten developed pulmonary interstitial fibrosis. However, transfer (i.v.) of TGF-beta2-treated 2,4,6-trinitrobenzene sulfonic acid-pulsed bone marrow-derived APC (tol-APC) to experimental mice 1 day after intratracheal challenge reduced the collagen deposition in the interstitium of the lung that usually follows challenge. Furthermore, ADT-HIPIF mice that received tol-APC developed Ag-specific efferent CD8+ Tr cells. Adoptive transfer of the Tr cells to another set of presensitized mice mediated suppression of the efferent phase of Th1 immune response and the subsequent immune dependent pulmonary interstitial fibrosis. Thus, tol-APC induced efferent CD8+ Tr cells in immune mice, and the regulation of the immune response limited the development of autoimmune pulmonary fibrosis in sensitized and pulmonary-challenged mice. Because ADT-HIPIF shares etiological and pathological characteristics with a variety of human immune inflammatory conditions in the lung that eventuate into interstitial fibrosis, these studies provide insight into potential therapy to alter the course of pulmonary fibrosis in humans.
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PMID:Tolerogenic APC generate CD8+ T regulatory cells that modulate pulmonary interstitial fibrosis. 1468 24

Over a 5-year period, we investigated 77 consecutive patients (36 males, 41 females, mean age 40.9 years) referred to our hospital with the diagnosis of CNS vasculitis. Extensive workup including MRI, echocardiography, laboratory tests, angiography ( n=53), and biopsies at appropriate sites ( n=26) was performed based on individual history and symptoms. Prominent symptoms were stroke ( n=61), encephalopathy ( n=14), and headaches ( n=2). Vasculitis was finally diagnosed in 13 patients (17%) including isolated angiitis of the CNS ( n=3), giant cell arteritis ( n=4), and septic arteritis ( n=3). Thirty-two patients (42%) presented noninflammatory vasculopathies including moyamoya ( n=6), Sneddon's syndrome ( n=5), dissection ( n=4), CADASIL ( n=2), and collagen vascular disease ( n=9). Coagulopathy was found in 14 cases (18%) including antiphospholipid syndrome ( n=8) and APC resistance ( n=4). Other causes were cardiogenic embolism ( n=8), multiple sclerosis ( n=5), and migraine stroke ( n=3). Only a minority of patients referred for evaluation of suspected CNS vasculitis actually present with inflammatory vascular disease. Main differential diagnosis includes noninflammatory vasculopathies, coagulopathies, and cardiac disease. Since septic processes may be responsible for the symptoms, "blind" treatment with immunosuppressive agents should be strictly avoided.
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PMID:[Diagnosis and differential cerebral vasculitis diagnosis]. 1477 Feb 79

Recent studies have implicated the protein C pathway in the mechanism of lung and airway remodeling. The effector enzyme of this pathway is activated protein C (APC). Clinical studies have shown that APC generation is decreased in patients with lung injury and airway inflammation and that this decrease is associated with increased collagen deposition in the lung. In line with these findings, low APC activity has been observed in the bronchoalveolar lavage fluid in animal models of lung injury and airway inflammation. Treatment with APC significantly inhibits the development of lung fibrosis in bleomycin-induced lung injury and the development of airway hyperresponsiveness and allergic inflammation in ovalbumin-induced bronchial asthma. APC may protect the lung from fibrosis and airway remodeling by suppressing activation of coagulation, decreasing the secretion of inflammatory cytokines and platelet-derived growth factor, and promoting fibrinolysis. APC inhibits the expression of cytokines by decreasing the nuclear translocation of signal transducer and activator of transcription 6 and the nuclear factor-kappaB family of transcription factors. In view of its multiple functions, APC constitutes a potential therapeutic agent for inflammatory disorders of the lung and airways.
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PMID:Protective role of activated protein C in lung and airway remodeling. 1511 28

The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis also termed primary, secondary and tertiary hemostasis. From the platelet transcriptome 6000 mRNA species and represent receptors, ion channels, signalling molecules, kinases, phosphatases, and structural, metabolic and regulatory proteins. This abundance of regulatory proteins points towards the importance of signal transduction in platelet function. First platelets adhere to collagen, this induces activation signals such as TXA(2) that induces further Ca(2+) increase. Consecutively, fibrinogen binds to the integrin alpha(IIb)beta(3) resulting in aggregation.This self-amplifying process is controlled by signals, from endothelial cells, to restrict the platelet plug to the site of vessel injury. Secondary hemostasis (coagulation) consists of an extrinsic and intrinsic pathway. Thrombin is generated via Factor Xa resulting from the extrinsic tenase reaction that is turned of by tissue factor pathway inhibitor. While thrombin generation is maintained via positive feedback mechanisms activating factors V, VIII and XI. Excess thrombin is inhibited by antithrombin or by autodownregulation via activation of protein C. Since minor injuries are common, platelets and plasma clotting factors constantly produce clots to stop bleeding. If clots remained after the tissue healing, the vascular bed would become obstructed with clots therefore this is regulated by fibrinolysis, tertiary hemostasis. Tissue-type plasminogen activator synthesised by the endothelium, converts plasminogen to plasmin, the clot lysis enzyme. Plasmin clears the blood vessels by degrading fibrin. Fibrinolysis is controlled by plasminogen activators inhibitor (PAI-1), alpha2-antiplasmin and alpha2-macroglobulin, and thrombin-activatable fibrinolysis inhibitor (TAFI).
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PMID:The hemostatic system. 1537 10

Inflammation contributions to the thrombotic response involve both cellular and humoral modulation. Inflammation impacts the initiation, propagation and the inhibitory phases of blood coagulation. Inflammatory mediators like endotoxin and tumor necrosis factor alpha (TNF alpha) elicit the expression of tissue factor on blood cells. Under normal circumstance, negatively charged membrane surfaces are limiting so that, even if some activated coagulation factors are generated, propagation of the coagulant stimulus is minimal. Complement activation, however, or exposure of collagen in combination with thrombin, provides a potent stimulus eliciting the exposure of negatively charged phospholipid membrane surfaces. Natural anticoagulant mechanisms limit the thrombotic response, but these pathways are depressed by inflammatory mediators. The protein C pathway is one of the major targets. Thrombomodulin and the endothelial cell protein C receptor are both required for optimal protein C activation, but both are down regulated by inflammatory mediators. Furthermore, free protein S levels often decrease resulting in impaired anticoagulant function of the activated protein C that is generated. In addition, anti-phospholipid antibodies severely impair the protein C pathway further inhibiting this pathway in inflammatory states associated with auto-immunity. In addition to shifting the hemostatic system in favor of clot formation, inflammation elevates the levels of plasminogen activator inhibitor thereby decreasing fibrinolytic activity. The procoagulant impact of inflammation can also be seen at the cellular level. Inflammatory mediators like interleukin 6 can increase both platelet count and their responsiveness to agonists like thrombin. All of these events tend to shift the hemostatic balance in favor of clot formation.
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PMID:The impact of the inflammatory response on coagulation. 1550 61

Lysyl oxidase is the enzyme that is essential for collagen and elastin cross-linking. Previous investigations showed that lysyl oxidase is down-regulated in many human tumors and ras-transformed cells. Recently, we proved that antisense down-regulation of lysyl oxidase in NRK-49F cells induced phenotypic changes and oncogenic transformation, characterized by p21(ras) activation and beta-catenin/cyclin D1 up-regulation. In the present paper, we examined beta-catenin intracellular distribution and its association with E-cadherin. We observed an increased association between E-cadherin and beta-catenin in the lysyl-oxidase down-regulated cells during serum starvation. Moreover, we found that beta-catenin cytoplasmic and nuclear levels were increased, suggesting a failure of its down-regulation by the APC-GSK-3beta system, in particular the GSK-3beta phosphorylation of ser-33/37 and thr-41 of beta-catenin. Finally, we investigated the mechanisms leading to the observed cyclin D1 up-regulation. We showed that in the antisense lysyl oxidase cells the cyclin D1 promoter was activated through the LEF and the ATF/CRE sites in the proximal promoter. While the promoter activation through LEF is compatible with beta-catenin signaling, we investigated the possibility that the CRE-dependent activation might be linked to the down-regulation of lysyl oxidase. In fact, up-regulation of lysyl oxidase in a COS-7 cell model showed a significant diminution of the CREB protein binding to the cyclin D1 promoter, leading to a dramatic inhibition of its activity and a significant down-regulation of cyclin D1 protein level in vivo. Finally, our study describes some major anomalies occurring in lysyl oxidase down-regulated fibroblasts, related to beta-catenin signaling and cyclin D1 expression.
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PMID:beta-catenin signaling and regulation of cyclin D1 promoter in NRK-49F cells transformed by down-regulation of the tumor suppressor lysyl oxidase. 1594 52

To evaluate the role of the innate immune system during schistosomiasis in vivo, we infected myeloid differentiation factor 88 (MyD88)-deficient mice with Schistosoma mansoni and analyzed their pathognomonic formation of hepatic granulomas and T cell responses. Even though the differences between knockout and wild-type mice in terms of mortality, liver damage, serum IgE and parasite burden were insignificant, the liver granulomas in the MyD88-deficient mice were significantly smaller, less cellular and contained a reduced percentage of eosinophils. Histologically, these granulomas revealed stronger fibrosis, confirmed also by increased levels of soluble collagen and IL-13, implying a Th2 bias. Spleen cells from infected MyD88-deficient mice also produced significantly less IFN-gamma than their wild-type controls upon restimulation with Schistosoma-egg-antigen (SEA). Furthermore, SEA-loaded APC from naive wild-type or MyD88-deficient mice induced equal amounts of proliferation and cytokine secretion by T cells from wild-type infected mice. In contrast, Ag-specific T cells from infected MyD88-deficient mice produced hardly any IFN-gamma but considerably more IL-10, again regardless of the APC type. These findings indicate that the loss of IFN-gamma production is not due to impaired antigen presentation but may perhaps is due to suppression by IL-10-producing T cells. Thus, MyD88 plays an important role in cellular infiltration, granuloma composition and T cell responses during schistosomiasis.
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PMID:Lack of antigen-specific Th1 response alters granuloma formation and composition in Schistosoma mansoni-infected MyD88-/- mice. 1627 83

Kidney graft loss because arterial thrombosis is not common and is related to risk factors such as recurrent vascular hemodialysis access thrombosis, collagen-vascular disease, repeated miscarriage, diabetes mellitus and thrombophilia. Patients having this last disorder have an increased risk of repeated thrombosis in successive transplants unless they receive anticoagulation therapy. We report a 51 year-old diabetic woman who had a history of recurrent vascular hemodialysis access thrombosis (both native and prosthetic) while on dialysis and received a cadaveric donor kidney. One month after transplantation she had axillary vein thrombosis complicated with pulmonary embolism and received anticoagulants for six months. Just days after stopping the anticoagulation, she became suddenly anuric due to renal artery thrombosis and complete graft infarction. The coagulation study showed moderate hyperhomocysteinemia and a significant protein C deficiency (39%). Days after nephrectomy she suffered a femoral vein thrombosis and anticoagulation was prescribed for life.
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PMID:[Renal artery thrombosis after withdrawal from anticoagulation therapy in a kidney transplant recipient with thrombophilia: report of one case]. 1736 90

Regular multilaboratory surveys of laboratories by the Royal College of Pathologists of Australasia Quality Assurance Program (QAP) have been conducted to assess proficiency in tests of hemostasis for the last 40 years. This article focuses primarily on specialized assays of hemostasis, for which surveys have been conducted for some 10 years. For von Willebrand disease (vWD) evaluations, a total of 47 plasma samples have been dispatched to survey participants, including representative samples from normal individuals plus all of the major vWD subtypes (i.e., types 1, 2A, 2B, 2M, 2N, and 3). These surveys have focused partly on the issue of diagnostic interpretive error rates associated with different assays and test panels. In this context, considerable improvement is seen when laboratories incorporate the vWF:collagen-binding assay into the test panel. Thrombophilia-associated tests assessed by the program and discussed in this review include activated protein c resistance, lupus anticoagulant, and deficiencies of protein C, protein S, and antithrombin. Other tests briefly reviewed here include factor assays and inhibitors, D-dimer, and heparin/anti-Xa assays. Anticardiolipin antibody and anti-beta(2)-glycoprotein I antibody (aB(2)GPI) testing, assessed by the Immunology QAP, is also reviewed briefly, as are genetic tests associated with thrombophilic markers such as factor V Leiden and the prothrombin gene.
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PMID:Emerging technologies and quality assurance in hemostasis: a review of findings from the Royal College of Pathologists of Australasia Quality Assurance Program. 1742 57

In this study, we demonstrate that genetically modified bone marrow-derived dendritic cells (DC) and exosomes derived from the DC, expressing either secreted IL-4 or membrane-bound IL-4, can reduce the severity and the incidence of established collagen-induced arthritis and inhibit inflammation of delayed-type hypersensitivity (DTH) in mice. The ability of the DC and DC-derived exosomes to suppress the DTH response was MHC class II and, in part, Fas ligand/Fas dependent. The DC-derived exosomes were internalized by CD11c(+) DC in the dermis at the site of injection and in the draining lymph node as well as by CD11c(+) DC and F4/80(+) macrophages in the spleen. Moreover, adoptive transfer of CD11c(+) or CD3(+) splenic cells from mice treated with exosomes showed significant reduction of footpad swelling in the DTH model. These results demonstrate that administration of DC/IL-4 or exosomes derived from DC/IL-4 are able to modulate the activity of APC and T cells in vivo through a MHC class II and partly Fas ligand/Fas-dependent mechanism, resulting in effective treatment of established collagen-induced arthritis and suppression of the DTH inflammatory response. Thus, APC-derived exosomes could be used therapeutically for the treatment of autoimmune disease and inflammatory disorders.
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PMID:Effective treatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4. 1767 85


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