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Cicardi M Zingale L Zanichelli A Pappalardo E Cicardi B 《Springer Seminars in Immunopathology》2005,27(3):286-298
C1 inhibitor (C1-INH) is a serine protease inhibitor (serpins) that inactivates several different proteases in the complement,
contact, coagulation, and fibrinolytic systems. By its C-terminal part (serpin domain), characterized by three β-sheets and
an exposed mobile reactive loop, C1-INH binds, and blocks the activity of its target proteases. The N-terminal end (nonserpin
domain) confers to C1-INH the capacity to bind lipopolysaccharides and E-selectin. Owing to this moiety, C1-INH intervenes
in regulation of the inflammatory reaction. The heterozygous deficiency of C1-INH results in hereditary angioedema (HAE).
The clinical picture of HAE is characterized by bouts of local increase in vascular permeability. Depending on the affected
site, patients suffer from disfiguring subcutaneous edema, abdominal pain, vomiting and/or diarrhoea for edema of the gastrointestinal
mucosa, dysphagia, and dysphonia up to asphyxia for edema of the pharynx and larynx. Apart from its genetic deficiency, there
are several pathological conditions such as ischemia–reperfusion, septic shock, capillary leak syndrome, and pancreatitis,
in which C1-INH has been reported to either play a pathogenic role or be a potential therapeutic tool. These potential applications
were identified long ago, but controlled studies have not been performed to confirm pilot experiences. Recombinant C1-INH,
produced in transgenic animals, has recently been produced for treatment of HAE, and clinical trials are in progress. We can
expect that the introduction of this new product, along with the existing plasma derivative, will renew interest in exploiting
C1-INH as a therapeutic agent. 相似文献
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The interactions that occur between viral proteins and host factors, such as cellular proteins and signal transduction machinery, have a significant influence on the replication, persistence, and pathogenesis of all viruses. This is exemplified by hepatitis C virus (HCV), which infects an estimated 3% of the world's population and is a significant cause of liver disease. HCV-host interactions also affect the outcome of interferon (IFN) antiviral therapy, which is effective only in certain patients. In this review, we focus on the HCV nonstructural 5A (NS5A) protein, a model for diverse virus-host interactions, and highlight the interaction of viruses, including HCV, with the chemokine system. 相似文献
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The activation of sodium/hydrogen exchanger (NHE) is associated with a variety of cell functions like cell adhesion, migration, proliferation, and apoptosis. Since its discovery, 9 NHE isoforms have been identified, but the most widely spread and the most important for the cellular functions is NHE-1. This ubiquitously expressed sodium/hydrogen exchanger (NHE-1) plays a central housekeeping role in all cells regulating cell volume and internal pH (pHi). At physiological pHi, NHE-1 is essentially inactive but it is extremely sensitive to pHi changes, being rapidly activated by small intracellular hydrogen concentration increases. NHE-1 activity can be stimulated via a series of cell surface receptors, including tyrosine kinase, G-protein-coupled, and integrin receptors. These signals converge, regulating the affinity of the internal hydrogen-binding site. NHE-1 also is a plasma membrane-anchoring protein for the cytoskeleton. Cytoskeleton anchoring of NHE-1 is important for cell adhesion to extracellular matrix proteins and cell migration. Moreover, NHE-1 plays the role of a "scaffold" for the building of various intracellular signaling molecule clusters. 相似文献
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Antibody-independent interactions of fibronectin, C1q, and human neutrophils with Treponema pallidum. 总被引:11,自引:5,他引:6
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R E Baughn 《Infection and immunity》1986,54(2):456-464
Although recent evidence suggests that fibronectin may be involved in the attachment of treponemes to mammalian cells, its possible role in promoting phagocytosis of Treponema pallidum has not been investigated. In the present study, we examined the antibody-independent interactions of fibronectin, C1q, and human polymorphonuclear leukocytes with T. pallidum. Binding of [125I]fibronectin was specific and saturable with an affinity constant of approximately 2 X 10(7) M-1. The number of binding sites per treponeme at 37 degrees C, irrespective of the mammalian source of fibronectin, was between 2,500 and 7,500, with a mean of approximately 4,700. Binding of [125I]C1q to T. pallidum, in the absence of antibodies to the organism, also was saturable and specific. Pretreatment of treponemes with C1q enhanced binding of soluble [125I]fibronectin two- to threefold and also increased attachment of 125I-surface-labeled treponemes to fibronectin-coated surfaces. Treatment of 125I-labeled T. pallidum with fibronectin alone, or together with C1q, however, did not enhance surface phagocytosis by neutrophils. 相似文献
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Summary: Natural killer (NK) cells express families of homologous receptors, members of which either activate or inhibit NK cells. We demonstrate that mouse Ly-49D is an activating receptor for the MHC antigen H2-Dd , which is also a ligand for the related inhibitory receptor Ly-49A. To compare and contrast their interactions with class I MHC ligand, we studied each of these receptors expressed in a rat NK-cell line, RNK-16, for their capacity to recognize wild-type or mutated H2-Dd . Our studies with Ly-49A reveal that functional interaction with H2-Dd depends on residues in the floor of the H2-Dd peptide-binding groove. The recent co-crystal of Ly-49A with H2-Dd indicates that these are not contact residues, thus they may contribute to allelic specificity through conformational changes in H2-Dd . We found that structural requirements for functional recognition of H2-Dd by Ly-49D differ markedly from those for recognition by Ly-49A. We note that H2-Dd expression on certain target cells is not sufficient to activate lysis mediated by Ly-49D, though the additional requirements for functional interaction are not yet identified. Here we review recent studies of Ly-49 receptor ligand specificities and their molecular basis. The functions of these related receptors with opposing functions and shared allospecificity remains unclear.
This work was supported by the Veterans Administration. M.C.N. is also supported by the Arthritis Foundation and the American Cancer Society. W.E.S. received NIH grant RO1 CA69299. We thank J.C. Ryan for communication of unpublished results. We thank H. Houtkooper and T. Ferrin for the molecular graphics image in Fig. 3 , which was created with the MidasPlus modeling system, supported by the NIH grant P41-RR-01081. 相似文献
This work was supported by the Veterans Administration. M.C.N. is also supported by the Arthritis Foundation and the American Cancer Society. W.E.S. received NIH grant RO1 CA69299. We thank J.C. Ryan for communication of unpublished results. We thank H. Houtkooper and T. Ferrin for the molecular graphics image in Fig. 3 , which was created with the MidasPlus modeling system, supported by the NIH grant P41-RR-01081. 相似文献
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Macrophages, centrally involved in both the innate and adaptive arms of the immune system are not only the chief target of the human immunodeficiency virus (HIV), but also its main reservoir and vehicle of transmission. Macrophage-tropic (M-tropic) viruses are responsible for the initial infection, predominate in the asymptomatic phase, and persist throughout infection, even after the emergence of preferential T cell- and/or dual-tropic HIV-1 variants. Functional impairment of HIV-infected macrophages plays a role in the immune dysregulation characteristic of acquired immunodeficiency syndrome (AIDS). Efforts directed at understanding the cellular and molecular mechanisms underlying HIV-macrophage interactions remain the basis for devising novel and efficacious therapeutic strategies against HIV ant the AIDS epidemic. 相似文献
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Gérard J. Arlaud Christine Gaboriaud Nicole M. Thielens Véronique Rossi Beate Bersch Jean-François Hernandez Juan C. Fontecilla-Camps 《Immunological reviews》2001,180(1):136-145
The classical pathway of complement is initiated by the C1 complex, a multimolecular protease comprising a recognition subunit (C1q) and two modular serine proteases (C1r and C1s) associated as a Ca2+‐dependent tetramer (C1s‐C1r‐C1r‐C1s). Early studies have allowed identification of specialized functional domains in these proteins and have led to low‐resolution models of the C1 complex. The objective of current studies is to gain deeper insights into the structure of C1, and the strategy used for this purpose mainly consists of dissecting the C1 components into modular fragments, in order to solve their three‐dimensional structure and establish the structural correlates of their function. The aim of this article is to provide an overview of the structural and functional information generated by this approach, with particular emphasis on the domains involved in the assembly, the recognition function, and the highly specific proteolytic properties of C1. The original work cited in this review was supported in part by the Commissariat à l’Energie Atomique (CEA), the Centre National de la Recherche Scientifique, and the European Union Biotechnology programme. 相似文献
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Complement C3: a molecular mosaic of binding sites. 总被引:2,自引:1,他引:2
Z Fishelson 《Molecular immunology》1991,28(4-5):545-552
Many of the biological activities of the complement system are mediated by C3, the third complement component, and its proteolytic fragments. At the same time, several of the molecules which regulate complement activation target their action at the C3 molecule. Accordingly, the C3 molecule is equipped with multiple binding sites for at least 14 other complement or complement-related proteins. As described in this review, major progress has been made recently in the identification of the C3 binding sites and the residues involved. Yet this has exposed only the "tip of the iceberg". A novel technique which may facilitate the elucidation of the active sites in C3 is presented. Finally, based on the current knowledge on the C3 molecule, a hypothetical model of the molecular organization of this molecule and its binding sites is presented. 相似文献
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Hüseyin Uysal Kutty Selva Nandakumar Christoph Kessel Sabrina Haag Stefan Carlsen Harald Burkhardt Rikard Holmdahl 《Immunological reviews》2010,233(1):9-33
Summary: The discovery of antibodies specific for citrullinated protein epitopes [anti-citrullinated protein antibodies (ACPAs)] is a hallmark for the diagnosis and prognosis of rheumatoid arthritis (RA) and will also be a useful tool for understanding the fundamental pathologic processes. There are several essential questions pertaining to ACPA that remain to be explored, such as understanding the early specificity of the underlying T-cell recognition, whether the production of ACPA is a primary or secondary process, and in the event of such antibodies being arthritogenic, whether they could possibly regulate the disease development. To answer these questions, animal models are needed, but unfortunately ACPA is not a prominent feature of any of the classical animal models of RA. However, we showed recently that ACPA can be isolated from animals susceptible to collagen-induced arthritis that are specific for citrullinated type II collagen (CII). The citrulline specificity could be visualized, and the specificity is determined primarily by a direct interaction with citrulline. We also demonstrated that these antibodies are specific for the citrullinated epitopes and are pathogenic in vivo. A new hypothesis to explain how inflammation in RA can be directed to cartilaginous joints and be self-perpetuating is suggested, which involves recognition of post-translational modifications (glycosylation and citrullination) on CII by T and B cells that can have both arthritogenic and regulatory consequences. 相似文献
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Previous studies identified specific receptors for C1q on human blood platelets in purified systems using monomeric C1q. To assess the physiologic potential of platelet C1q receptors, C1q binding was evaluated in whole blood and in the presence of immune complexes or aggregated IgG. Blood was obtained from healthy volunteers and collected directly into EDTA (1 vol 100mM EDTA:9 vol whole blood) and purified, 125I-labeled C1q or 125I-C1q associated with albumin-anti-albumin immune complexes. Samples were incubated at 22 or 37 degrees C for 60 min, and total cell bound C1q and platelet associated C1q were quantified. Platelet-bound, monomeric C1q or immune complex-associated C1q represented 40-50% of total peripheral blood cell-associated C1q. C1q binding was unaffected by the incubation temperature, but the preincubation of 125I-C1q with immune complexes enhanced binding two- to threefold. This binding was partially inhibited by preincubating platelets with either the collagen-like amino-terminal fragments of C1q (c-C1q) or a monoclonal antibody Fab fragment recognizing platelet Fc receptors. A more complete inhibition was achieved if platelets were preincubated with both agents. Similar observations were made using washed platelets and 125I-C1q associated with aggregated IgG. The role of C1q and platelet C1q receptors in enhancing aggregated-IgG binding to platelets was further supported by experiments demonstrating increased 125I-aggregated IgG binding to platelets not only after preincubation of 125I-aggregated IgG with C1q but also following platelet preincubation with C1q. These data suggest that C1q receptors may participate in the localization and presentation of C1q-associated immune complexes on the platelet surface and demonstrate that platelets contribute significantly to the C1q binding activity of peripheral blood. 相似文献
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The hemolytic activity of C5 in the serum treated with zymosan, immune precipitate, or C1s was measured, and the C5 precipitin line on immunoelectrophoresis and the protein concentration of C5 in these serum specimens were also analyzed. A marked decrease in the hemolytic activity of C5 and a complete conversion of C5 precipitin line from beta- to alpha-globulin region were observed in teh serum treated with more than 1 mg/ml of zymosan. The elongation of C5 precipitin line from beta- to alpha-globulin region and the decrease in C5 hemolytic activity were observed in the serum treated with the immune precipitate. But neither change in C5 precipitin line, nor a decrease in hemolytic activity of C5 was observed in C1s treated serum. C5 protein concentrations in these serum preparations were essentially the same as those of control. From these results, it was concluded that the immunoelectrophoretic change of C5 precipitin line might express the grade of the decrease in C5 hemolytic activity in the serum treated with the activating substances of the complement system. 相似文献
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Tissue expression of four troponin I genes and their molecular interactions with two troponin C isoforms in Caenorhabditis elegans 总被引:1,自引:0,他引:1
Ruksana R Kuroda K Terami H Bando T Kitaoka S Takaya T Sakube Y Kagawa H 《Genes to cells : devoted to molecular & cellular mechanisms》2005,10(3):261-276
Gene duplication is a major genetic event that can produce multiple protein isoforms. Comparative sequence and functional analysis of related gene products can provide insights into protein family evolution. To characterize the Caenorhabditis elegans troponin I family, we analyzed gene structures, tissue expression patterns and RNAi phenotypes of four troponin I isoforms. Tissue expression patterns were determined using lacZ/gfp/rfp reporter gene assays. The tni-1, tni-2/unc-27 and tni-3 genes, each encoding a troponin I isoform, are uniquely expressed in body wall, vulval and anal muscles but at different levels; tni-4 was expressed solely in the pharynx. Expressing tni-1 and -2 gene RNAi caused motility defects similar to unc-27 (e155) mutant, a tni-2 null allele. The tni-3 RNAi expression produced egg laying defects while the tni-4 RNAi caused arrest at gastrulation. Overlay analyses were used to assay interactions between the troponin I and two troponin C isoforms. The three body wall troponin I isoforms interacted with body wall and pharyngeal troponin C isoforms; TNI-4 interacted only with pharyngeal troponin C. Our results suggest the body wall genes have evolved following duplication of the pharynx gene and provide important data about gene duplication and functional differentiation of nematode troponin I isoforms. 相似文献
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Silvia Moncini Maria Teresa Bonati Ilaria Morella Luca Ferrari Riccardo Brambilla Paola Riva 《European journal of human genetics : EJHG》2015,23(11):1531-1537
Noonan syndrome (NS) is a genetic condition characterized by congenital heart defects, short stature and characteristic facial features. We here present the case of a girl with moderate learning disabilities, delayed language development, craniofacial features and skin anomalies reminiscent of NS. After a mutation screening of the known NS genes PTPN11, SOS1, RAF1, KRAS, GRB2, BRAF and SHOC2 we found the heterozygous c.755T>C variant in SOS1 causing the p.I252T amino-acid substitution, which was considered possibly pathogenetic by bioinformatic predictions. The same variant was present in the proband''s mother, displaying some NS features, and maternal grandfather showing no NS traits, but also by a healthy subject in 1000 genomes project database without phenotype informations. The functional analysis revealed that SOS1 c.755C activated the RAS-ERK intracellular pathway, whereas no effects on RAC-JNK cascade have been detected. After a comparison between the sequence of SOS1 cDNA from peripheral blood and SOS1 genomic DNA, we showed for the first time a differential allelic expression of the SOS1 gene in healthy individuals, thus occurring as a physiologic condition. Interestingly, we found that the mutated allele C was 50% more expressed than the wild-type allele T in all familial carriers. The comparable amount of SOS1 mRNA between mutated individuals and the controls indicates that the variant does not affect SOS1 expression. The present study provides a first evidence of allelic imbalance of SOS1 and pinpoints this condition as a possible mechanism underlying a different penetrance of some SOS1-mutated alleles in unrelated carriers. 相似文献
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