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LUAN, NGUYEN MINH. "PROTECTION OF ISLETS OF LANGERHANS FROM COMPLEMENT MEDIATED CYTOTOXICITY." 京都大学 (Kyoto University), 2011. http://hdl.handle.net/2433/151986.
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Pierre, Andrew F. "The effect of complement inhibition with soluble complement receptor 1 (sCR1) on pig allo-transplant lung function." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ29290.pdf.
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Crehan, H. "Complement receptor 1 in microglia : implications for Alzheimer's disease." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1425685/.
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Recent genome wide association studies in Alzheimer’s disease have highlighted the importance of the complement cascade in the pathogenesis of Alzheimer’s disease. However, the cellular and molecular roles of these complement proteins are not fully understood. Microglia express complement receptors and the activation of specific receptors may increase Aβ clearance and reduce/prevent neurodegeneration. The work presented in this thesis was aimed at investigating the contribution of Complement receptor 1 (CR1), the second most significant hit in GWAS studies, on microglia to neuronal damage. To explore the consequences of blocking CR1 to microglial-neuronal interactions, primary rat microglia were treated with a CR1 functional blocking antibody together with microglial activators for 24 h. It was found that microglia displaying an activated phenotype demonstrated an increase in CR1 expression. Activation of microglial CR1 was found to be detrimental to neurons and this correlated with an increase in microglial intracellular superoxide generation, nitric oxide (NO) production, tumor necrosis factor-α (TNFα) and interleukin-1 β (IL-1β) secretion. Amyloid-β 1-42 (Aβ1-42)-treated microglia displayed an increased ability to phagocytose dextran beads following antibody blockade of CR1 but a decreased capacity to phagocytose fluorescent-tagged Aβ1-42. CR1 immunoreactivity was investigated by immunohistochemistry in AD and control human post-mortem brain tissue. A higher level of CR1 immunoreactivity was found in areas of high Aβ plaque burden in AD brain tissue. A difference in CR1 expression on red blood cells between individuals was measured by flow cytometry. Together, these results indicate that microglial CR1 plays a role in the neuronal death observed in AD and investigating this further may provide a possible strategy to control neurotoxicity in the AD brain.
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Masilamani, Madhan. "Immunological investigation of human complement receptor type II (CR2/CD21) : serum soluble CD21 in health and disease /." Konstanz, 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=967076668.
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Imrie, Heather. "Studies on the reduction in expression of erythrocyte complement receptor 1." Thesis, University of Nottingham, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.363932.
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Clark, Nicola Suzanne. "Structural and functional studies on SCR domains from human complement receptor 1." Thesis, University of Southampton, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242559.
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McKeeman, G. C. "The measurement of circulation soluble vascular endothelial growth factor receptor-1 (sFlt-1)." Thesis, Queen's University Belfast, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273085.
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Murase, Takatoshi. "Identification of soluble forms of lectin-like oxidized LDL receptor-1." Kyoto University, 2004. http://hdl.handle.net/2433/148276.
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Mitsuoka, Hirokazu. "Interleukin 18 stimulates release of soluble lectin-like oxidized LDL receptor-1(sLOX-1)." Kyoto University, 2008. http://hdl.handle.net/2433/124235.
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Etheridge, W. "Production of soluble recombinant complement receptor (CR1) antigens to detect or inhibit antibodies to Knops (KN) blood group system antigens." Thesis, University of the West of England, Bristol, 2015. http://eprints.uwe.ac.uk/26375/.
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The purpose of this study was to produce a reagent to use in investigation of antibodies directed against the Knops blood group system antigens. A novel reagent based on sr-proteins was produced and used in a new test to inhibit these antibodies. Current investigation of patients with alloantibodies directed against Knops blood group system antigens can be a difficult, time-consuming process and the provision of blood for transfusion of these patients can often be delayed. This is because these antibodies are hard to identify and the most commonly found anti-Knops antibodies react with most reagent or donor cells that they are tested with because the corresponding Knops antigens are found at high frequency in most populations. The presence of Knops related antibodies can mask underlying antibodies that are clinically significant. The Knops antigens are carried on Complement Receptor 1 (CR1) located on the red blood cell membrane. Two DNA constructs encoding different parts of CR1 termed long homologous repeat (LHR) C and D were used to transfect human embryonic kidney (HEK293) cells. The cells were grown in different culture systems. Cell culture supernatant containing soluble recombinant (sr)-LHRC or sr-LHR-D was harvested and purified by affinity gel chromatography. The production and purification processes were optimised in terms of protein yield and cost. The resulting purified sr-LHR-C and sr-LHR-D proteins were used to create a novel reagent containing both proteins. This reagent was used in a new inhibition test based on an indirect antiglobulin technique using commercial gel cards. Using the reagent all examples of previously identified Knops antibodies were inhibited. In addition once these antibodies had been inhibited, underlying antibodies were then detected and identified in some samples. For the first time Knops specific antibodies can be detected and identified using one unique test. Any underlying clinically significant antibodies will be rapidly identified if present due to inhibition of the KN antibodies. Introduction of the inhibition test into nine NHSBT patient testing laboratories will reduce the time taken for investigation of these patients and make provision of blood for patients a safer, faster process.
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Mallin, Rosie L. "Structural study of the C3b-binding site of complement receptor type 1 (CD 35)." Thesis, University of Edinburgh, 2003. http://hdl.handle.net/1842/15256.
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Swann, Olivia Veronica Fowell. "Role of the Swain-Langley and McCoy polymorphisms in complement receptor 1 in cerebral malaria." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33280.
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Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor 1 (CR1) gene, named Swain-Langley (Sl2) and McCoy (McCb), occur at high frequencies, consistent with selection by malaria. This thesis investigates the association between these two polymorphisms and severe malaria. Previous studies into this area have produced conflicting findings. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, I found that the Sl2 polymorphism was associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism was associated with increased odds of cerebral malaria. I also identified an interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. Following these epidemiological findings, I explored potential biological hypotheses which might explain them. The first approach examined whether the Sl2 and McCb polymorphisms affected how CR1 forms clusters on erythrocyte membranes, a process which is key in the binding and transfer of immune complexes from erythrocytes to macrophages. Using erythrocytes from Kenyan children, I performed immunofluorescence assays (IFAs) with confocal microscopy to quantify CR1 cluster number and volume. I found no association between the Sl2 and McCb polymorphisms and either the number or volume of CR1 clusters formed. The second approach investigated whether the cerebral malaria-specific associations seen with Sl2 and McCb might be due to expression of CR1 by human brain endothelial cells (HBEC). The immortalised cell line HBEC-5i was investigated for expression of CR1 using IFA, flow cytometry, western blotting, functional C3b degradation assays, mass spectrometry, immunoprecipitation and siRNA knockdown experiments. A pool of α-CR1 monoclonal antibodies recognised an intracellular antigen in permeabilised HBEC-5i cells which was a similar molecular weight to CR1 on western blotting. However, when the α-CR1 monoclonal antibodies were tested individually, only E11 recognised an HBEC-5i antigen. Further investigative approaches did not support the presence of CR1 on HBEC-5i cells, instead suggesting that E11 was not specific for CR1 and was instead recognising a protein in the Golgi apparatus. The final approach was to examine whether the Sl2 and McCb polymorphisms might influence the binding of the complement components mannose binding lectin, C1q and L-ficolin to the LHR-D region of CR1. I aimed to generate recombinant proteins of the LHR-D region which included the polymorphisms. Site-directed mutagenesis of the region was successful and subcloning and expression of the mutant amplicons will be performed at a later date. In summary, I have identified opposing associations between the Sl2 and McCb polymorphisms and cerebral malaria, which do not appear to be due to differences in CR1 clustering or expression of CR1 by human brain endothelial cells. My investigation into whether the polymorphisms might influence complement component binding is ongoing.
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Black, Gordon M. "Studies of the structure and dynamics of the functional sites within complement receptor type 1." Thesis, University of Edinburgh, 2004. http://hdl.handle.net/1842/10824.
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The complement system is part of our innate immune response and is tightly regulated to prevent damage to host cells. Complement receptor type 1 (CR1) is one of the main regulators of complement activation and is also the immune adherance receptor on erythrocytes, important for clearance of immune complexes from the bloodstream. CR1s functions arise from its ability to bind complement proteins C3b and C4b. CR1 is a multimodular glycoprotein (220 kDa) that is too large to study in its intact form by NMR. Recently, the solution structure of functional site 2, which consists of three contiguous complement control protein (CCP) modules, has been solved. However, the structural information alone does not complete the story as dynamic motions within CR1 are likely to have implications for its functions. This thesis describes the assignment of 15N and 1H NMR data for the central CCP module (module 16) of functional site 2. The resonance assignments subsequently allowed the solution 3D structure to be determined and the Modelfree analysis of the module’s isotropic dynamics. The structure and dynamics of the lone module, when compared with previous work on larger fragments of functional site 2 allowed assessment of the importance, for their structure and flexibility, of the context of CCP modules. Following this, NMR 13C, 15N and 1H spectra for CR1 modules 2-3, which correspond to the C-terminal two thirds of functional site 1, were acquired. The resonance assignment of this double module was then performed to near completion. In parallel, a homology-based model of the structure of modules 2-3 was built using the structure of site 2 as a starting point. The isotropic dynamics were also analysed using Modelfree formalism.
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Tetteh-Quarcoo, Patience Borkor. "Investigations into polymorphisms within complement receptor type 1 (CD35) thought to protect against severe malaria." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6193.
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The human immune-regulatory protein, complement receptor type 1 (CR1, CD35), occurs on erythrocytes where it serves as the immune adherence receptor. It interacts with C3b, C4b, C1q and mannan-binding lectin (MBL). It additionally binds the Plasmodium falciparum protein, Rh4, in the non-sialic acid-dependent erythrocye-invasion pathway, and is also important for rosetting, via an interaction with P. falciparum erythrocyte membrane protein 1 (PfEMP1). A C3b/C4b, and PfEMP1 binding site lies in CCP modules 15-17 (out of 30 in CR1), while polymorphisms that afford advantage to some populations in dealing with severe malaria occur in CCPs 24-25, begging the question central to this thesis – do these polymorphism modulate function, and if so how? We hypothesized that the CR1 architecture apposes CCPs 15-17 and CCPs 24-25 using the exceptionally long linker between CCPs 21 and 22 as a hinge, thus polymorphic variants in CCPs 24-25 modulate functionality in CCPs 15-17. To test this, a panel of recombinant CR1 protein fragments (CCPs 21, 21-22, 20-23, 15-17, 17, 10-11, 17-25, 15-25 and 24-25) were produced in Pichia pastoris along with polymorphic forms of the relevant constructs. After purification, biophysical and biological methods were used to assess whether the linker does indeed act as a hinge, and the comparative abilities of the CCPs 15-25 variants (along with soluble CR1 (sCR1), CCPs 1-3 and the panel of CR1 fragments) to interact with a range of ligands were measured. We found no evidence from NMR for face-to-face contacts between CCPs 21 and 22 that would be consistent with the long linker permitting a 180-degree bend between them. Indeed, based on scattering and analytical ultracentrifugation data, CCPs 20-23 form an extended rather than a bent-back structure. All of the four Knops blood-group variants of the CCPs 15-25 proteins produced similar results according to dynamic light scattering and AUC indicating no structural difference or change in self-association state between variants. In addition, based on the data collected from surface plasmon resonance (SPR), ELISA and fluid-phase cofactor (for factor I) assays, there were no evidence of any difference between the polymorphic forms with respect to their interactions with C3b, C4b, C1q and MBL. Only weak interaction was observed for sCR1, and all CCPs 15-25 variants, with the relevant part of PfEMP1, and there was no measurable difference amongst the variants in disrupting rosettes. The sCR1-Rh4.9 interaction was confirmed by SPR; affinities measured between the binding domain of Rh4 and the panel of CR1 fragments identified CCPs 1-3 (site 1) as the main interaction site. It seemed unlikely therefore that CCPs 24 and 25 could modulate Rh4 binding; indeed none of the four CR1 15-25 variants bound Rh4.9 appreciably. Thus we concluded that allotypic variations in CCPs 24-25 have no measurable effect on the architecture as well as binding of CR1 to its host or parasite ligands The inferred selective pressure acting on these variants likely arise from some other (i.e. besides malaria) geographically localised infectious diseases.
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Watkins, Harriet A. "Characterisation of the soluble N terminal domain of the corticotropin releasing hormone receptor 1." Thesis, University of Warwick, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247650.
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Prokopec, Kajsa. "B cells in Autoimmunity : Studies of Complement Receptor 1 & 2 and FcγRIIb in Autoimmune Arthritis." Doctoral thesis, Uppsala universitet, Molekylär immunologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-109428.
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B cells are normally regulated to prevent activation against self-proteins through tolerance mechanisms. However, occasionally there is a break in tolerance and B cells can become self-reactive, which might lead to the development of autoimmune disease. The activation of self-reactive B cells is regulated by receptors on the B cell surface, such as Fc gamma receptor IIb (FcγRIIb), complement receptor type 1 (CR1), and CR type 2 (CR2). In this thesis I have studied the role of FcγRIIb, CR1 and CR2 on B cells in autoimmune arthritis. By using a model for rheumatoid arthritis, I discovered that the initial self-reactive B cell response in arthritis was associated with the splenic marginal zone B cell population. Marginal zone B cells express high levels of CR1/CR2 and FcγRIIb, suggesting that they normally require high regulation. Further, female mice deficient in CR1/CR2 displayed increased susceptibility to arthritis compared to CR1/CR2-sufficient female mice. When investigating whether sex hormones affected arthritis susceptibility, we found that ovariectomy, of the otherwise fairly resistant CR1/CR2-sufficient mice, reduced the expression of CR1 on B cells and rendered the mice more susceptible to arthritis. In humans, a significantly reduced CR1 and FcγRIIb expression was found on B cells in aging women, but not in men. This may contribute to the increased risk for women to develop autoimmune disease as reduced receptor expression may lead to the activation of self-reactive B cells. In agreement, lower CR1, CR2 and FcγRIIb expression was seen in patients with rheumatoid arthritis. Finally, a soluble form of FcγRIIb was used to investigate FcγRIIb’s ability to bind self-reactive IgG in an attempt to treat autoimmune arthritis. Treatment of mice with established arthritis was associated with less self-reactive IgG antibodies and consequently less disease, suggesting that soluble FcγRIIb may be used as a novel treatment in arthritis.
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Robinson, Joanne Claire. "Structure and functional studies of the short consensus repeats of the human complement receptor type 1." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342847.
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Kucukkilic, Ezgi. "Copy number variation and relevance to disease of the complement C3b/C4b receptor 1 (CR1) gene." Thesis, University of Leicester, 2017. http://hdl.handle.net/2381/40701.
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The complement 3b/4b receptor 1 (CR1) gene is located at chromosome 1q32.2 in a cluster of complement-related genes. CR1 regulates both classical and alternative pathways of the complement system. CR1 is a major receptor for Plasmodium falciparum, and variation within the gene has been associated with different malarial clinical phenotypes. CR1 shows intragenic copy number variation (CNV) resulting in variation in protein length and number of C3b/C4b binding domains. Previously, CR1 was related to Alzheimer’s disease (AD) via complement system regulation. Furthermore, CR1 variation is responsible for the alleles of the Knops blood group, including McCoy and Swain-Langley. In this thesis, Novel paralogue ratio test (PRT) assays were developed to robustly type CNV of the low-copy repeat (LCR) regions (which defines the common CR1-A and CR1-B alleles, but also rarer alleles) within the gene in large cohorts, and an allele-specific hybridisation assay to genotype alleles of the Knops blood group system. Variation was analysed across global populations, and in the Tori-Bossito cohort (563 infants) from Benin, followed since birth to observe malaria acquisition and treatment. This showed that the Swain-Langley Sl2 polymorphism is not in strong linkage disequilibrium (LD) with the CNV, nor with other Knops blood group alleles. It appears to provide protection against early acquisition of malaria and subsequent number of malarial infections in the Tori-Bossito cohort but these results were not confirmed in an independent cohort (n=276). The association between the CR1-B allele and AD (early-onset (EOAD) and late-onset (LOAD)) was explored, showing that the CR1 risk loci (rs3818361, rs6656401 (only for EOAD) and rs6701713) were in moderate LD with CR1-B, but revealing no association between CR1-B (p=0.755) and EOAD (n=633). However, the CR1-B allele (risk) appears to be associated with LOAD (n=2185) with (p=0.015) and without (p=0.048) use of a junction fragment PCR assay.
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Machado, de Oliveira Stephan Alberto [Verfasser]. "Complement receptor 1 mediated control of Leishmania infection in inflammatory human macrophages / Stephan Alberto Machado de Oliveira." Mainz : Universitätsbibliothek Mainz, 2016. http://d-nb.info/1104522063/34.
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Zhou, Xueyuan. "Follicular Dendritic Cells, Human Immunodeficency Virus Type 1, and Alpha 1 Antitrypsin." BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/3407.
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HIV/AIDS is raging and causing millions of deaths around the world. The major challenge in treating HIV/AIDS is the establishment of HIV reservoirs where the viruse escapes both drug and immune system attempts at eradication. Throughout the course of HIV/AIDS, productive HIV infection occurs primarily in the lymphoid follicles or germinal centers (GC) surrounding follicular dendritic cells (FDC). In the GCs, FDCs trap and maintain infectious HIV for years and provide these infectious viruses to the host cells. FDCs also attract B and T cells into the GCs and increase the ability of CD4+ T cells to be infected. Additionally, FDCs also mediate the increase of HIV replication in HIV-infected CD4+ T cells. Recently, several clinical cases and in vitro studies suggest that alpha-1-antitrypsin (AAT) might inhibit HIV infection and replication. Therefore, I hypothesized that AAT inhibited both the infection and replication of HIV in primary CD4+ T cells. I also postulated that AAT inhibited the FDC-mediated contributions that potentiate HIV infection and replication. To test whether AAT inhibited HIV infection in lymphocytes, CD4+ T cells were pretreated with AAT and then incubated with HIV to detect HIV infection. To exam whether AAT inhibited HIV replication, infected CD4+ T cells were cultured with AAT to detect the replication of HIV. To determine whether AAT blocked the FDC-mediated contributions to HIV pathogenesis, activated or resting FDCs were treated with AAT to detect the trapping and maintenance of HIV. The results suggested that AAT inhibited HIV entry into CD4+ T cells by directly interacting with gp41 and thereby inhibiting the interaction between HIV and CD4+ T cells. AAT also inhibited HIV replication in infected CD4+ T cells. Further study revealed that AAT interacted with low-density lipoprotein-receptor related protein to mediate the internalization of AAT through a clathrin-dependent endocytic process in CD4+ T cells. Subsequently, internalized AAT was transported from the endosome to the lysosome and then released into the cytosol. In the cytosol, AAT directly interacted with IκBα to block its polyubiquitinylation at lysine residue 48, which resulted in the accumulation of phosphorylated/ubiqutinylated IκBα in the cytosol. In turn, the dissociation of IκBα from NF-κB was blocked, which thereby inhibited the nuclear translocation and activation of NF-κB. Additionally, AAT also down-regulated FDC-CD32 and FDC-CD21 expression, which are regulated by NF-kB, thereby inhibiting the trapping and maintenance of HIV on FDCs. Hence, AAT not only suppresses HIV replication, but also blocks HIV replication in CD4+ T cells. Moreover, AAT also inhibits the activation of FDCs thereby affecting the trapping and maintenance of HIV.
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Oran, Alp E. "Defining sites of interaction in the Ã-chain of C3 for factor H, membrane cofactor protein (MCP), and complement receptor 1 (CR1)." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ29260.pdf.
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Torres, Vitor Félix. "Receptor desencadeador expresso nas células mielóides Tipo 1 (TREM-1) no diagnóstico e prognóstico na meningite bacteriana em crianças." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/129631.
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Base teórica: A meningite bacteriana é uma causa importante de morbidade e mortalidade na infância. Análise do líquido cefalorraquidiano (LCR) continua a ser a ferramenta de diagnóstico padrão ouro, porém novos biomarcadores para o diagnóstico e prognóstico ainda são necessários. Receptor Desencadeador Expresso nas Células Mielóides Tipo 1 (TREM-1) é um receptor transmembrana expresso em neutrófilos e monócitos, que desempenha um papel importante na modulação da resposta inflamatória. A sua fração solúvel (sTREM-1) também é aumentada na infecção, inflamação ou doenças imunológicas. Neste estudo nós avaliamos, prospectivamente, o valor do TREM-1 como um biomarcador de meningite bacteriana aguda em pacientes pediátricos e sua possível utilização como uma ferramenta de prognóstico neste cenário. Objetivos: O objetivo primário do presente estudo é caracterizar os níveis líquóricos solúveis de TREM-1 (sTREM-1) em pacientes admitidos por suspeita clínica de meningite. Analisamos também os níveis de sTREM-1 nos casos de meningite bacteriana e viral, além de medir a sensibilidade e especificidade deste biomarcador no LCR e estudar se esse biomarcador pode ser um fator associado ao prognóstico em meningite bacteriana aguda. Métodos: Sessenta e um pacientes pediátricos, de 0 a 10 anos foram avaliados quanto à meningite e foram prospectivamente incluídos neste estudo. Na admissão, após a suspeita clínica de meningite foram submetidos à análise do LCR para o diagnóstico e uma amostra do LCR inicial foi utilizado também para análise do sTREM-1. Os pacientes foram acompanhados durante a sua internação com o registro de seu tratamento e desfecho clínico para posterior análise dos dados. Resultados: Dentre os 61 pacientes, 38 (62%) foram negativos para a meningite, 7 (11%) pacientes foram diagnosticados com meningite viral e 16 (27%) pacientes foram diagnosticados com meningite bacteriana aguda e recebeu tratamento direcionado. Sexo (p = 0,15), presença de fatores de risco identificados (p = 0,17), presença de convulsões (p = 0,31), outras complicações clínicas (p = 0,11) e mortalidade (p = 0,66) não diferiram entre os grupos. Anormalidades sensoriais (p <0,0001) e presença de cefaléia (p = 0,003) foram mais prevalentes em pacientes com meningite. Como esperado, a contagem de leucócitos, glicose e proteína no LCR foram significativamente diferentes entre pacientes com meningite e pacientes sem meningite. As concentrações de sTREM-1 no LCR de pacientes com meningite bacteriana foi superior quando comparada com pacientes com meningite viral e com controles (1204,67 pg/ml, 39,34 pg/ml e 12,09 pg/ml, respectivamente; p <0,0001). Quando sTREM-1 foi usado como um determinante de diferenciação entre pacientes com ou sem meningite bacteriana, a análise da área sob a curva ROC foi de 0,95 (IC de 95% = 0,89-1,00; p <0,0001). A presença de fatores de risco para a meningite bacteriana (p = 0,04), anormalidades sensoriais (p <0,0001), contagem de leucócitos no LCR (p = 0,01), níveis de glicose no LCR (p = 0,002), níveis de proteína no LCR (p = 0,032) e os níveis de sTREM-1 no LCR (p = 0,004) foram associados com meningite bacteriana, incluindo os níveis sTREM-1 acima do ponto de corte estabelecido de 68,0 pg/ml (p <0,0001). A meningite bacteriana (p = 0,02) e os valores de sTREM-1 maior do que o ponto de corte (68,0 pg/ml) (p = 0,04) foram associados com sequelas neurológicas graves e morte neste grupo de pacientes. Conclusão: Avaliamos os níveis sTREM-1 de crianças com suspeita clínica de meningite. Os níveis de s-TREM-1 foram aumentados nos casos de meningite bacteriana e correlacionados com o prognóstico. Os nossos resultados sugerem que níveis elevados de sTREM-1 no LCR podem ser utilizados como um biomarcador para o diagnóstico de meningite bacteriana aguda em crianças e que pode ser útil na determinação do prognóstico do paciente nesse cenário.Background: Bacterial meningitis is an important cause of morbidity and mortality in infancy. Cerebrospinal fluid (CSF) analysis remains the gold standard diagnostic tool, however new biomarkers for diagnosis and prognosis are still required. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a transmembrane receptor expressed on neutrophils and monocytes that plays an important role on the immune response. Its soluble fraction (sTREM-1) is also increased in infection, inflammation or immune diseases. In this study we evaluate the value of sTREM-1 as a biomarker of acute bacterial meningitis in pediatric patients and its possible use as a prognostic tool prospectively. Methods: Sixty-one pediatric patients, from 0 to 10 years of age were evaluated for meningitis and were prospectively included in this study. At admission, following clinical hypothesis of meningitis patients were submitted to CSF analysis for diagnosis and a sample of initial CSF was also used for TREM-1 analysis. Patients were followed during hospitalization and clinical evaluation and treatment outcome were recorded for posterior analysis. Results: Thirty-eight (62%) out of 61 patients were negative for meningitis, 7 (11%) patients were diagnosed with viral meningitis and 16 (27%) patients were diagnosed with and received treatment for acute bacterial meningitis. Sex (p = 0.15), presence of identified risk factors (p = 0.17), presence of seizures (p = 0.31), other clinical complications (p = 0.11), and mortality (p = 0.66) did not differ among groups. Sensorial abnormalities (p<0.0001) and presence of headache (p= 0.003) were more prevalent in patients with meningitis. As expected, leukocyte count, glucose, and protein levels were significantly different between patients with meningitis and patients without meningitis. Concentrations of sTREM-1 in CSF from patients with bacterial meningitis was higher when compared to patients with viral meningitis and with controls (1204.67 pg/ml, 39.34 pg/ml and 12.09 pg/ml, respectively; p<0.0001). When sTREM-1 was used as a determinant to differentiate between patients with or without bacterial meningitis, the analysis of the area under the ROC curve (AUC) was 0.95 (95% CI=0.89-1.00; p<0.0001). Presence of risk factors for bacterial meningitis (p = 0.04), sensorial abnormalities (p<0.0001), CSF leukocyte count (p = 0.01), CSF glucose levels (p = 0.002), CSF protein levels (p = 0.032) and CSF sTREM-1 levels (p = 0.004) were all associated with bacterial meningitis, including sTREM-1 levels above the established cut-off point of 68.0 pg/ml (p<0.0001). Bacterial meningitis (p = 0.02) and values of sTREM-1 higher than the cut-off point (68.0 pg/ml) (p = 0.04) were associated with death and severe neurological disabilities in this patient cohort. Conclusion: We evaluated sTREM-1 levels in CSF of children with clinical hypothesis of meningitis. The sTREM-1 levels were increased in bacterial meningitis and correlated with prognosis. Our results suggest that CSF sTREM- 1 levels can be used as a biomarker for diagnosis of acute bacterial meningitis in children and it might be useful in determining patient’s prognosis in this scenario.
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Price, Philip John Ritchie [Verfasser], and Gerd [Akademischer Betreuer] Sutter. "Leukocyte trafficking during infection with modified vaccinia virus Ankara : the role of chemokine receptor 1 and complement activation / Philip John Ritchie Price. Betreuer: Gerd Sutter." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1058077538/34.
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Costa, Rafaela Alkmin da. "Dosagem seriada dos fatores reguladores de angiogênese soluble fms-like tyrosine kinase-1 (sFlt-1) e placental growth factor (PIGF) para predição de pré-eclâmpsia e pré-eclâmpsia superajuntada." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-12012015-144329/.
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Apesar de sua importância clínica e epidemiológica, a fisiopatologia da préeclâmpsia ainda não foi completamente compreendida. Sabe-se que a doença constitui-se de uma fase pré-clínica e um estágio clínico. Durante a última década muito esforço tem se concentrado na identificação precoce da doença, ainda em sua fase pré-clínica. A literatura científica tem demonstrado claramente um desequilíbrio na regulação da angiogênese das gestantes com pré-eclâmpsia, marcado por níveis elevados do fator antiangiogênico soluble fms-like tyrosine kinase-1 (sFlt-1) e níveis diminuídos do fator pró-angiogênico placental growth fator (PlGF). Embora um número crescente de estudos em populações de alto risco tenha avaliado o papel desses biomarcadores no diagnóstico de pré-eclâmpsia, dados sobre sua utilização para a predição de pré-eclâmpsia superajuntada, cujo diagnóstico pode ser particularmente difícil, permanecem relativamente escassos e controversos. Com o presente estudo pretendemos avaliar o desempenho de medidas seriadas dos níveis maternos circulantes dos fatores sFlt-1 e PlGF, bem como da razão sFlt-1/PlGF, para predição de pré-eclâmpsia superajuntada e compará-lo ao seu desempenho na predição de pré-eclâmpsia em sua forma \"pura\", não superajuntada. Para este propósito, estudamos uma coorte prospectiva composta de dois braços, um de gestantes com hipertensão arterial crônica e outro de gestantes normotensas, e avaliamos os níveis séricos de sFlt-1 e de PlGF e a razão sFlt-1/PlGF nas idades gestacionais de 20, 26, 32 e 36 semanas, tendo como desfecho principal o diagnóstico de pré-eclâmpsia. Um total de 97 gestantes foram acompanhadas, 37 normotensas e 60 com hipertensão arterial crônica. Entre elas, 4 (10,8%) desenvolveram pré-eclâmpsia e 14 (23,3%) desenvolveram pré-eclâmpsia superajuntada. Para predição de pré-eclâmpsia, a análise ROC (Receiver Operating Characteristics) apresentou área sob a curva (AUC - area under curve) de 0,83 (IC 95% = 0,68-0,99, P = 0,035) para dosagem de PlGF com 20 semanas e AUC = 0,92 (IC 95% = 0,81 - 1,00, P = 0,007) para a razão sFlt-1/PlGF com 26 semanas de gestação. A variação percentual dos níveis de PlGF entre 26 e 32 semanas de gestação apresentou AUC = 0,96 (IC de 95% = 0,89-1,00, P = 0,003). Para a predição de pré-eclâmpsia superajuntada, a razão sFlt-1/PIGF na idade gestacional de 32 semanas apresentou AUC = 0,69 (IC de 95% = 0,53-0,85, P = 0,039). Entre 20 e 26 semanas de gestação, a variação percentual do PIGF e da razão sFlt-1/PlGF apresentaram, respectivamente, AUC = 0,74 (IC de 95% = 0,58-0,90, P = 0,018) e AUC = 0,71 (IC 95% = 0,52-0,91, P = 0,034). Por nossos resultados podemos concluir que, embora os níveis de PlGF e a razão sFlt-1/ PlGF tenham apresentado bons desempenhos na predição de pré-eclâmpsia, é preciso ter cuidado ao usá-los para a predição de pré-eclâmpsia superajuntada. Nessas gestantes, a dosagem dos fatores angiogênicos apresenta capacidade de predição menor e mais tardia. Avaliações seriadas dos fatores podem melhorar o desempenho dos testes para predição de pré-eclâmpsia superajuntada em idades gestacionais mais precocesDespite being a major public health problem, the pathophysiology of preeclampsia is incompletely understood. Preeclampsia progression comprises a pre-clinical stage and a clinical stage. During the last decade much work has focused on identifying the pre-clinical stage of preeclampsia. Many researchers have clearly demonstrated an anti-angiogenic imbalance that is marked by higher levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and lower levels of placental growth factor (PlGF) in the subjects who develop preeclampsia compared with those who do not. Although a growing number of studies in the high-risk population have shown the role of these biomarkers in diagnosing preeclampsia, superimposed preeclampsia, which can be a challenging diagnosis, remains partially understudied and the literature regarding this subject continues to be relatively scarce as well as controversial. By this study, we aimed to evaluate the performance of serial measurements of maternal circulating sFlt-1 and PlGF levels for the prediction of superimposed preeclampsia in chronic hypertensive subjects and to compare it to the prediction of preeclampsia in normotensive control subjects. For this purpose, we evaluated a two-armed prospective cohort of women with normotensive and chronic hypertensive pregnancies and assessed the serum levels of sFlt-1 and PlGF and the sFlt-1/PlGF ratio at gestational ages of 20, 26, 32 and 36 weeks, having preeclampsia as the primary outcome to be predicted. A total of 97 women were followed-up, 37 in the normotensive group and 60 in the chronic hypertensive group. Among them, 4 (10.8%) women developed preeclampsia and 14 (23.3%) developed superimposed preeclampsia. For predicting preeclampsia, PlGF at 20 gestational weeks presented an AUC=0.83 (CI 95% = 0.68 - 0.99, P=0.035) and the sFlt-1/PlGF ratio at 26 gestational weeks presented an AUC=0.92 (CI95% = 0.81 - 1.00, P=0.007). The percent change of the PlGF levels between 26 and 32 gestational weeks presented an AUC=0.96 (CI 95% = 0.89 - 1.00, P=0.003). For predicting superimposed preeclampsia, the sFlt-1/PlGF ratio at 32 gestational weeks presented an AUC=0.69 (CI 95% = 0.53 - 0.85, P=0.039). Between 20 and 26 gestational weeks, the percent change of PlGF and the sFlt-1/PlGF ratio presented, respectively, an AUC=0.74 (CI 95% = 0.58 - 0.90, P=0.018) and an AUC=0.71 (CI 95% = 0.52 - 0.91, P=0.034). By our results, we concluded that, although the PlGF level and the sFlt-1/PlGF ratio present good performances in the prediction of preeclampsia, caution is required when using them for the prediction of superimposed preeclampsia. Sequential assessments slightly improve the test performances for predicting superimposed preeclampsia at earlier gestational ages
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Grimsley, Philip George Medical Sciences Faculty of Medicine UNSW. "Receptor mediated catabolism of plasminogen activators." Awarded By:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/44489.
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Humans have two plasminogen activators (PAs), tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), which generate plasmin to breakdown fibrin and other barriers to cell migration. Both PAs are used as pharmaceuticals but their efficacies are limited by their rapid clearance from the circulation, predominantly by parenchymal cells of the liver. At the commencement of the work presented here, the hepatic receptors responsible for mediating the catabolism of the PAs were little understood. tPA degradation by hepatic cell lines was known to depend on the formation of binary complexes with the major PA inhibitor, plasminogen activator inhibitor type-1 (PAI-1). Initial studies presented here established that uPA was catabolised in a fashion similar to tPA by the hepatoma cell line, HepG2. Other laboratories around this time found that the major receptor mediating the binding and endocytosis of the PAs is Low Density Lipoprotein Receptor-related Protein (LRP1). LRP1 is a giant 600 kDa protein that binds a range of structurally and functionally diverse ligands including, activated α2 macroglobulin, apolipoproteins, β amyloid precursor protein, and a number of serpin-enzymes complexes, including PA??PAI-1 complexes. Further studies for the work presented here centred on this receptor. By using radiolabelled binding assays, ligand blots, and Western blots on cultured cells, the major findings are that: (1) basal LRP1 expression on HepG2 is low compared to a clone termed, HepG2a16, but appears to increase in long term culture; (2) a soluble form of LRP1, which retains ligand-binding capacity, is present in human circulation; (3) soluble LRP1 is also present in cerebral spinal fluid where its role in neurological disorders such as Alzheimer??s disease is a developing area of interest; and (4) the release of LRP1 is a mechanism conserved in evolution, possibly as distantly as molluscs. The discovery, identification, and characterisation of soluble LRP1 introduces this protein in the human circulation, and presents a possible further level of regulation for its associated receptor system.
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Guedes, Sandra Daniela Silva. "Testing a dementia risk group for polymorphisms in inflammation-related genes." Master's thesis, Universidade de Aveiro, 2016. http://hdl.handle.net/10773/18512.
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Mestrado em Biomedicina MolecularA doença de Alzheimer (AD) é uma perturbação degenerativa multifatorial associada com a idade que ocorre no sistema nervoso central. Após a sua descrição inicial em 1907, numerosas teorias foram propostas para elucidar quais as principais causas associadas. A hipótese da inflamação tem sido recentemente reconhecida pela comunidade científica, uma vez que muitos estudos em modelos e doentes de Alzheimer propuseram fortes evidências da ativação do sistema imunológico e de processos inflamatórios durante o curso da doença. De facto, a acumulação de β-amilóide (Aβ) e proteína tau provocam uma resposta inflamatória cerebral como resultado do desenvolvimento patológico da AD. Atualmente, os estudos de associação genómica genética (GWAS) proporcionaram a identificação de diversas variantes genéticas que influenciam por exemplo processos inflamatórios e as vias do sistema imunitário na AD, estando as regiões polimórficas CLU rs11136000 e CR1 rs3818361 entre elas. Além disso, ambos os polimorfismos de um único nucleótido (SNPs) parecem ter um papel colaborativo relativamente à eliminação de Aβ e à ativação do sistema imunitário através da estimulação do complemento. No trabalho aqui descrito, foram realizadas análises bioinformáticas de genes de risco para a AD, principalmente o CLU e o CR1. As informações obtidas foram usadas para criar uma rede de interação proteína-proteína, bem como para realizar análises de enriquecimento de Ontologia Genética. A nossa análise bioinformática indica que ambos os genes CLU e CR1 estão envolvidos numa variedade de vias de sinalização que compreendem a regulação do processo inflamatório e ativação do sistema imunológico. A expressão genética de cada alelo de risco das SNPs CLU rs11136000 e CR1 rs3818361 foi ainda avaliada em amostras de doentes “Putativos AD” e Controlos por testes de PCR e análises de sequenciação de Sanger. Adicionalmente, as frequências genotípicas e alélicas também foram determinadas com o intuito de criar um perfil genético dos grupos estudados. Os nossos resultados demostraram que no grupo de doentes “Putativos AD” analisado para a variante CLU rs11136000, o alelo de risco C apresentou maior frequência (64%) quando comparado com o grupo Controlos (40%). O grupo de Controlos apresentou uma frequência de 60% para o alelo de não-risco. Para a variante CR1 rs3818361, o alelo de risco A apresentou frequências semelhantes entre grupos, apesar do aumento da percentagem de homozigóticos de risco (6%) no grupo de doentes “Putativos AD”. Este trabalho auxilia na compreensão da relação entre estes polimorfismos genéticos e demência. Estudos adicionais devem avaliar o uso destas SNPs como ferramentas potencialmente úteis no diagnóstico da AD.
Alzheimer’s disease (AD) is a multifactorial age associated degenerative disorder that occurs in the central nervous system. After its initial report in 1907, numerous theories have been proposed to elucidate on what are the related main causes. The inflammation hypothesis has been recently acknowledged by the scientific community since several studies in AD models and patients strongly supported the activation of the immune system and of inflammatory processes during disease development. In fact, the accumulation of amyloid-β (Aβ) and tau-neurofibrillary tangles provokes a brain inflammatory response as a consequence of the pathological development of AD. Currently, genome-wide association studies (GWAS) have provided several genetic variants that impact inflammation and immune system pathways in AD, being the polymorphic regions CLU rs11136000 and CR1 rs3818361 among them. Furthermore, both single-nucleotide polymorphisms (SNPs) appear to have a collaborative role regarding Aβ clearance and immune system activation via complement stimulation. In the work here described, bioinformatics analyses of AD risk-related genes, focusing on CLU and CR1 were performed and the retrieved information used to rise a protein-protein interaction network, as well as to perform Gene Ontology enrichment analyses. Our bioinformatics analysis indicates that CLU and CR1 are involved in a variety of signaling pathways that comprise activation and regulation of immune system process. CLU rs11136000 and CR1 rs3818361 genetic expression of each SNP risk allele was further evaluated in whole blood samples from “Putative AD” and Controls groups by PCR assays and Sanger sequencing analyses. Additionally, the genotyping and allelic frequencies were also determined in order to create a genetic profile of the studied groups. Our results showed that on the “Putative AD” group analyzed for CLU rs11136000 variant, the C-risk allele presented a higher frequency (64%) when compared to Controls (40%). The Controls group displayed a 60% frequency for the non-risk allele. For the CR1 rs3818361 variant, the A-risk allele showed similar frequencies among groups, although an increase in the percentage of homozygous risk carriers (6%) was observed in the “Putative AD” group. This work aids into the understanding of the relation between these genetic polymorphisms and dementia. Additional studies should address the use of these SNPs as potential tools in AD diagnostics.
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Wendt, Astrid [Verfasser]. "Korrelation von placental growth factor, vascular endothelial growth factor und soluble vascular endothelial growth factor receptor-1 im Serum mit Tumorstadien und Prognose des hepatozellulären Karzinoms / Astrid Wendt." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1212435109/34.
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Bensusan, Christiane de Oliveira. "Avaliação dos níveis de formas solúveis do receptor de produtos finais de glicação avançada em pacientes com diabetes mellitus tipo 2." Niterói, 2017. https://app.uff.br/riuff/handle/1/5461.
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UNIMED - Rio Empreendimentos Médicos e Hospitalares
Introdução: O Diabetes Mellitus tipo 2 (DM2) representa um importante problema de saúde pública, considerando sua grande morbi/mortalidade, decorrente das complicações crônicas da doença. A formação de produtos finais de glicação avançada (AGE) representa um dos diversos mecanismos fisiopatológicos implicados na gênese das complicações do DM2. Através da ligação dos AGE com os seus receptores teciduais (RAGE) vias intracelulares são ativadas, levando ao aumento da resposta inflamatória e à indução de estresse oxidativo, que culminam com as complicações micro e macrovasculares do DM2. Por outro lado, há um pool de RAGE solúveis (sRAGE), constituído por variantes do RAGE (esRAGE e cRAGE), com capacidade de interagir com os mesmos ligantes do RAGE tecidual, sem, entretanto, desencadear a transdução do sinal intracelular após a sua ligação. Dessa forma, o sRAGE funcionaria como um fator protetor para o desenvolvimento das complicações crônicas do DM2. No entanto, a associação entre os níveis de sRAGE com a presença de complicações micro e acrovasculares do DM2, assim como a associação entre os níveis de sRAGE com o grau de controle glicêmico, não está bem estabelecida, já que os trabalhos existentes na literatura mostram resultados divergentes. Objetivos: O presente estudo visou compreender melhor as correlações entre os níveis de sRAGE, as complicações crônicas do DM2 e o controle glicêmico, através da avaliação de pacientes DM2 acompanhados no Hospital Universitário Antônio Pedro. Métodos: Foram incluídos 89 pacientes DM2, 43 com complicações e 46 sem complicações. Cada um desses dois grupos pacientes foi subdividido, de acordo com o controle glicêmico, em outros 3 subgrupos. Os pacientes foram submetidos a uma avaliação clínica e laboratorial, com dosagem de sRAGE e hemoglobina glicada. O sRAGE foi mensurado no soro dos pacientes utilizando-se o teste imunoenzimático ELISA. Resultados: Não foi encontrada diferença estatisticamente significativa nos níveis de sRAGE plasmático entre os pacientes DM2 com e sem complicações microvasculares do DM2, bem como não foi constatada correlação do sRAGE com o controle glicêmico. Conclusão: Novos estudos são necessários para melhor elucidar os mecanismos envolvidos na produção e regulação da concentração das formas solúveis do RAGE e esclarecer a relação de causa-efeito entre os níveis séricos do sRAGE e as complicações crônicas do DM2
Background: Type 2 diabetes mellitus (T2DM) is a major public health problem, considering its high morbidity and mortality due to chronic complications. The formation of advanced glycation end products (AGE) is one of several pathophysiological mechanisms involved in the development of complications of T2DM. By binding of AGE with its tissue receptors (RAGE), intracellular pathways are activated, leading to increased inflammatory response and the induction of oxidative stress, which culminate in the micro and macrovascular complications of T2DM. Moreover, there is a pool of soluble RAGE (sRAGE) consisting of variants of RAGE (esRAGE and cRAGE), with ability to interact with the same tissue RAGE ligands, without, however, trigger the intracellular signal transduction after binding. Thus, sRAGE would behave as a protective factor for the development of chronic complications of T2DM. Nevertheless, the association between sRAGE levels with the presence of micro and macrovascular complications of T2DM, as well as the association between sRAGE levels with the degree of glycemic control, is not well established, since the studies in the literature show divergent results. Objectives: This study aimed to better understand the correlations between the levels of sRAGE, the chronic complications of T2DM and glycemic control, through the evaluation of T2DM patients treated at University Hospital Antônio Pedro. Methods: A total of 89 T2DM patients were included, 43 with complications and 46 without complications. Each of these two groups was divided according to glycemic control, in other 3 groups. The patients underwent a clinical evaluation and laboratory, dosing sRAGE and glycated hemoglobin. sRAGE was measured in serum of patients by ELISA. Results: No statistically significant difference was found in plasma sRAGE levels between T2DM patients with and without microvascular complications, as well as no correlation between sRAGE and glycemic control. Conclusion: Further studies are needed to better elucidate the mechanisms involved in producing and regulating the concentration of soluble forms of RAGE and to clarify the cause-effect relationship between serum levels of sRAGE and the chronic complications of T2DM
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Palm, Anna-Karin E. "Function and Regulation of B-cell Subsets in Experimental Autoimmune Arthritis." Doctoral thesis, Uppsala universitet, Kemisk biologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-265024.
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B lymphocytes play a significant role in autoimmune arthritis, with their function stretching beyond autoantibody production to cytokine secretion and presentation of autoantigen. However, the involvement and activation of different B-cell subset in the autoimmune response is not fully clear. The main focus of this thesis has been to understand the contribution of marginal zone (MZ) B cells in the induction of collagen-induced arthritis (CIA), a mouse model for rheumatoid arthritis (RA). We show that MZ B cells in the spleen of naïve mice display a natural self-reactivity to collagen type II (CII), the autoantigen used for immunization of CIA. The CII-reactive MZ B cells expand rapidly following immunization with CII, and produce IgM and IgG antibodies to CII. They also very efficiently present CII to cognate T cells in vitro and in vivo. Moreover, absence of regulatory receptors such as CR1/2 or FcγRIIb on the MZ B cells increases their proliferation and cytokine production in response to toll-like receptor, but not B-cell receptor, activation. Further, FcγRIIb-deficient MZ B cells present CII to T cells more efficiently than wild-type MZ B cells. We additionally demonstrate for the first time the existence of a small population of nodal MZ B cells in mouse lymph nodes. Similar to splenic MZ B cells, the nodal MZ B cells expand after CIA induction, secrete IgM anti-CII antibodies and can present CII to cognate T cells. Finally, we show that mast cells, associated with ectopic B cell follicles in inflamed RA joints, in coculture with B cells promote their expansion, production of IgM and IgG antibodies as well as upregulation of CD19 and L-selectin. Coculture with mast cells further causes the B cells to upregulate costimulators and class II MHC, important molecules for antigen-presenting function. In summary, my findings suggest that splenic and nodal self-reactive MZ B cells participate in breaking T-cell tolerance to CII in CIA. B-cell intrinsic regulation is needed to keep such autoreactive B cells quiescent. Mast cells can potentiate B-cell responses locally in the arthritic joint, thus feeding the autoimmune reaction.
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Grattone, Marisa Lidia. "Étude du rôle des récepteurs du complément de type 1 (CR1/CD35) et de type 2 (CR2/CD21) dans l'internalisation et la localisation intracellulaire des ligands." Grenoble 1, 1998. http://www.theses.fr/1998GRE10075.
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Le systeme du complement a un role critique dans le developpement de la reponse immune specifique : la deficience acquise ou genetique de la proteine c3 affecte la production des anticorps contre des antigenes (ag) t-dependant. Cette proteine se lie covalemment aux ag lors de l'activation du systeme du complement et est progressivement proteolysee donnant des differents fragments : ic3b, c3dg, c3d qui restent lies a l'ag. Cr1 et cr2 sont deux recepteurs exprimes sur les lymphocytes b, t et les cellules dendritiques folliculaires. Cr1 fixe le fragment c3b et ic3b tandis que cr2 lie ic3b, c3dg et c3d. L'importance de cr1 et cr2 est soulignee par le fait que la production des ac specifiques des ag t-dependant peut etre inhibee par le blocage fonctionnel de ces recepteurs. Il semblerait que c'est au niveau des lymphocytes b que leur expression est essentielle, pour le controle de la reponse immune. Le role respectif de ces recepteurs dans l'internalisation est difficile a determiner du fait qu'ils sont toujours exprimes ensemble sur les lymphocytes b. Pour mieux definir leur role nous avons developpe un modele d'etude base sur la transfection des fibroblastes murins permettant l'expression de cr1, cr2 ou cr1 plus cr2. Nous avons etudie la capacite de ces recepteurs a fixer leurs ligands et a les internaliser. Nous montrons que cr1 et cr2 cooperent dans l'endocytose de c3b, c3b-c3b ou ic3b mais non dans l'endocytose de c3de ou j3d3, un anticorps specifiques de cr1. Pour expliquer cette cooperation, deux hypotheses ont ete emises : 1) apres fixation a cr1, le ligand pourrait etre endocyte ou proteolyse en ic3b ou c3dg, capte par cr2 et endocyte ; 2) un pontage de cr1 et cr2 induit par le ligand declencherait d'une maniere plus efficace les phenomenes d'internalisation, tels que la formation des puits a clathrine. Cette hypothese est particulierement favorisee par notre modele. Par ailleurs, nous avons etudie le role de cr1 dans la localisation intracellulaire des ag lies a c3b. Nous montrons que cet ag localise dans la peripherie cellulaire, en contraste avec l'ag libre qui se distribue dans toute la cellule. Cela pourrait impliquer un transit intracellulaire de l'ag different pouvant affecter sa proteolyse et/ou sa presentation aux lymphocytes t.
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Kang, David E. "Genetic and functional characterization of the low density lipoprotein receptor-related protein (LRP) in clearance of soluble amyloid [beta] protein in late-onset Alzheimer's disease : and functional characterization of presenilin 1 in modulation of [beta]-catenin signaling pathway and downstream effects on amyloid [beta] protein /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1999. http://wwwlib.umi.com/cr/ucsd/fullcit?p9943953.
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Reinagel, Michele Lynn. "Transfer of model immune complexes from erythrocyte complement receptor 1 to murine macrophages /." 2001. http://wwwlib.umi.com/dissertations/fullcit/3022093.
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Masilamani, Madhan [Verfasser]. "Immunological investigation of human complement receptor type II (CR2/CD21) : serum soluble CD21 in health and disease / vorgelegt von Madhan Masilamani." 2003. http://d-nb.info/967076668/34.
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Yasruel, Zivart. "Expression of membrane-anchored and soluble isoforms of interleukin-5 receptor Ü mRNA in bronchial asthma." Thesis, 1996. http://spectrum.library.concordia.ca/6253/1/MM18457.pdf.
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Rana, Amardeep. "Assessment of the Functional Role of the NTR Domain of Complement Component C3 using a Homologous Dmain Exchange Approach." Thesis, 2010. http://hdl.handle.net/1807/25901.
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The complement system plays an important role in innate and adaptive immunity. Central to all complement activities is the function of complement component 3 (C3). C3 contains a C-terminal extension of ~150 residues known as the NTR (or C345C) domain. To address the role of the NTR domain in binding and functional activities of C3, a C3/C5 chimera was engineered, in which the NTR domain of C3 was replaced by the homologous domain of the closely related
protein C5. Functionally, the C3(C5NTR) was devoid of classical pathway-dependent hemolytic activity and deficient in factor H- and CR1-dependent factor I cleavability. Direct binding SPR assays, using chip bound methylamine treated His6-tagged C3(C5NTR), showed a complete loss of C5 binding while retaining wild type binding with CR1, factor H and factor B. These results present the first evidence for a major C5 binding site within C3 NTR.
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Chia-Hui, Wang, and 王嘉慧. "The predictive value of soluble triggering receptor expressed on myeloid cells (sTREM-1) in pulmonary disorder patients." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/47175798810095415118.
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碩士國立中興大學
生命科學院碩士在職專班
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Community-acquired pneumonia (CAP) is a common illness with an incidence rate of approximately 4 to 12 per 1000 adults per year. Because the incidence of CAP increases with age, and with the currently aging population , CAP remains as an important public health problem. Early and appropriate treatment of CAP patients is therefore becoming one of the most important factors to reduce morbidity and mortality. The triggering receptor expressed on myeloid cells (TREM-1) is a member of immunoglobulin superfamily, and its expression on phagocytes is specifically up-regulated by microbial products. The presence of soluble TREM-1 (sTREM-1) in bronchoalveolar-lavage fluid from patients receiving mechanical ventilation may be an indicator of pneumonia. sTREM-1 has been reported as the strongest independent predictor of pneumonia. However, the level of sTREM-1 in plasma and pleural effusion to predict the treatment response is yet to be defined. The aim of this study was to investigate predictive value of PSI score and sTREM-1 on day 1 and day 3 following the clinical treatment. The study would evaluate the cause of treatment failure and the perspective indicator(s), which could help a clinical physician to determine whether to keep on or to discontinue antibiotic treatment and to reduce medical cost. The study was carried out from October, 2004 to June, 2005. Study population included: (1) serum group: patients who had lower respiratory tract infections; (2) pleural effusion group: CAP, TB and lung cancer patients who had recently developed pleural effusion. All patients were treated in the general medical wards. Serum and pleural effusion were centrifuged and the supernatant was frozen at -70C until assay. Duo Set ELISA Development kit (R&D) was used to assay sTREM-1 level in those samples. Following statistical analysis , a significant difference in sTREM-1 level was detected between response and non-response group patients. Also ,a significant difference was found among sTREM-1 levels in normal control, CAP (response and non-response), TB and sever CAP patients (p＜0.001). Moreover, level of sTREM-1 in pleural effusion was higher than that of serum. In particular, in lung cancer patients sTREM-1 level was much higher than that in CAP and TB groups. Since most of pleural effusions was non-inflammatory in lung cancer patients. Therefore, we suspected that lung cancer cell might contain factor(s), which could trigger sTREM-1 Expression in addition to microbial infection, and sTREM-1 may play a different role in disease progression of lung cancer.
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Chen, Hsiu-Lin, and 陳秀玲. "Soluble form of the triggering receptor expressed on myeloid cells-1 (sTREM-1) and CXC chemokine IP-10 as diagnostic markers of serious bacterial infection in infants younger than 4 months of age." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/86046193513893686321.
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碩士高雄醫學大學
醫學研究所碩士班
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英文摘要 Background: Early diagnosis of serious bacterial infection (SBI) in young infants is a difficult problem by using clinical symptoms and signs. The goal of this study is to evaluate to diagnostic value of newly discovered inflammatory mediators: soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) or CXC chemokine IP-10 level for early diagnosis of SBI in infants younger than 4 months of age. Methods: We enrolled pediatric patients who were less than 4 months of age with a suspicion to have SBI and admitted in neonatal intensive care unit or complete nursing unit of pediatric department of Kaohsiung Medical University hospital. Peripheral blood was drawn for measurement of complete blood count, CRP, sTREM-1 or IP-10 levels at admission. Positive blood, CSF, or urine culture was considered to have SBI. Soluble TREM-1 and IP-10 were detected by commercial ELISA kits. Results: There were 118 patients to have sTREM-1 measurement. The SBI group (n=39) have higher plasma sTREM-1 level than non-SBI group (n=79) (299.8±555.4 v.s. 15.4±19.7，p=0.003 after adjusting age by ANCOVA analysis). Plasma sTREM-1 level higher than 55.2 ng/mL was more accurate than WBC count, absolute neutrophils counts, IT ratio, and CRP for indicating SBI in infants.[sensitivity 64.1% (95% CI, 55%-73%); specificity 97% (95% CI, 94%-100%); positive likelihood ratio 21.3; negative likelihood ratio 0.37; diagnostic odds ratio 57.5]。Sixty patients were collected to have measurement of IP-10. Plasma IP-10 level had significantly increase in SBI group [320.1±497.9 v.s. 11.6±23.7, p=0.016, after adjusting age by ANCOVA analysis] 。Plasma IP-10 level higher than 48.2 ng/mL had best diagnostic accuracy for indicating SBI. [sensitivity 81% (95% CI, 71%-90%); specificity 95% (95% CI 89%-100%); positive likelihood ratio 15.9，negative likelihood ratio 0.2; diagnostic odds ratio 79.3]。 Conclusion: In infants who were less than 4 months old, plasma sTREM-1 or IP-10 level might play a potential role in early identification of serious bacterial infection.
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Pullmann, Barbara [Verfasser]. "Soluble triggering receptor expressed on myeloid cells (sTREM-1) in der bronchoalveolären Lavage : diagnostischer Wert bei polytraumatisierten Patienten auf der Intensivstation ; eine prospektive Studie / vorgelegt von Barbara Pullmann." 2010. http://d-nb.info/1006115749/34.
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Δεττοράκη, Αθηνά. "Η συσχέτιση των τελικών προϊόντων προχωρημένης γλυκοζυλίωσης (AGEs), του υποδοχέα τους (RAGE) και του διαλυτού τμήματός του (sRAGE) σε παιδιά, εφήβους και νεαρούς ενήλικες με σακχαρώδη διαβήτη τύπου 1 (ΣΔ1)." Thesis, 2011. http://hdl.handle.net/10889/5275.
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Τα τελικά προϊόντα προχωρημένης γλυκοζυλίωσης (AGEs: Advanced Glycation Endproducts) παίζουν σημαντικό ρόλο στην παθογένεια των διαβητικών αγγειακών επιπλοκών. Το καλύτερα χαρακτηριζόμενο είναι η N-καρβοξυμεθυλ-λυσίνη (CML). Τα AGEs προκαλούν σημαντικές επιδράσεις στα αγγεία με την πρόσδεσή τους σε ειδικούς υποδοχείς της κυτταρικής επιφάνειας, όπως τον RAGE (Receptor for Advanced Glycation Endproducts). Διαλυτές μορφές του RAGE (sRAGE) εμφανίζονται στο ανθρώπινο αίμα και δρουν ως παγίδα αιχμαλωτίζοντας τους φλεγμονώδεις προσδέτες του RAGE εξωκυττάρια, προστατεύοντας με αυτό τον τρόπο τα κύτταρα από τη βλάβη που προάγεται από τα AGEs.
Σκοπός αυτής της εργασίας ήταν να μελετηθούν τα επίπεδα του sRAGE, η πρωτεϊνική έκφραση του RAGE, καθώς και τα επίπεδα CML σε σχέση με διάφορες κλινικές και βιοχημικές παραμέτρους σε παιδιά, εφήβους και νεαρούς ενήλικες με ΣΔ1. Τα επίπεδα sRAGE και CML προσδιορίστηκαν με ELISA και η πρωτεϊνική έκφραση του RAGE στα μονοπύρηνα του περιφερικού αίματος με ανοσοαποτύπωση κατά Western σε 74 παιδιά, εφήβους και νεαρούς ενήλικες με ΣΔ1 (13± 4 χρονών) και 43 μάρτυρες αντίστοιχης ηλικίας, φύλου και σταδίου Tanner.
Σ’ αυτή την εργασία τα αυξημένα επίπεδα sRAGE στα παιδιά με ΣΔ1 και πιο ειδικά, σ’ αυτά ηλικίας κάτω από 13 ετών και με διάρκεια διαβήτη κάτω από 5 έτη, μπορεί να είναι ένα προσωρινό προστατευτικό μέτρο ενάντια στην κυτταρική βλάβη και πιθανόν να είναι επαρκές για να εξουδετερώσει επαρκώς τα κυκλοφορούντα CML, εμποδίζοντας έτσι τις διαβητικές αγγειακές επιπλοκές. Επίσης, μια ήπια αύξηση της LDL θα μπορούσε να είναι ένα ερέθισμα για την αύξηση του sRAGE, οδηγώντας στη δέσμευση του CML και τελικά τη μείωση των επιπέδων CML στην κυκλοφορία. Τα μειωμένα επίπεδα της πρωτεϊνικής έκφρασης του RAGE 55 kd (υποδοχέα πλήρους μήκους) μπορεί να αντανακλούν την αυξημένη έκφραση του sRAGE στους ασθενείς με ΣΔ1 συνολικά λόγω της αποκοπής του RAGE με μεταλλοπρωτεϊνάσες. Με την παρουσία κάποιου παράγοντα κινδύνου, όπως αύξηση ηλικίας, περιμέτρου κοιλίας, BMI, συστολικής ή διαστολικής αρτηριακής πίεσης ή επιδείνωση λιπιδαιμικού προφίλ αυξάνεται η πρωτεϊνική έκφραση της ισομορφής αυτής, ενώ φαίνεται αντίστοιχα να μειώνονται τα επίπεδα του sRAGE. Φαίνεται τελικά ότι συνολικά στα παιδιά, τους εφήβους και τους νεαρούς ενήλικες με ΣΔ1 υπάρχει μια υποκλινική διαταραχή του άξονα sRAGE-RAGE-CML, η οποία δύναται να μετατραπεί σε κλινικά εμφανείς αγγειακές βλάβες, αν προστεθούν περαιτέρω επιβαρυντικοί παράγοντες.The binding of Advanced Glycation Endproducts (AGEs) to their receptor (RAGE) plays a major role in the development of diabetic vascular complications. This work is based on the relation between circulating soluble RAGE (sRAGE) levels in children, adolescents and young adults with IDDM and RAGE protein expression in association with N-(carboxymethyl)lysine (CML), a major antigenic AGEs component. Circulating sRAGE and CML levels were determined by ELISA and RAGE protein expression was evaluated in peripheral blood mononuclear cells by western immunoblotting in 74 children, adolescents and young adults with IDDM (134 years old) and 43 age, sex and Tanner stage-matched controls. Serum sRAGE levels were significantly higher in IDDM than in controls, inversely correlated to diabetes duration and directly correlated to LDL levels. Furthermore, circulating CML levels were not significantly different between IDDM and controls. Also, the protein expression of the RAGE isoforms 55 kd (full-length), 64 kd and 100 kd, measured by western immunoblotting, was significantly lower in IDDM than in controls, whereas RAGE 37 kd levels were not significantly different between IDDM and controls. Finally, when there was a risk factor, such as increased age, poor lipid profile, increased BMI or waist circumference or increased systolic or diastolic pressure, then it seemed that isoforms RAGE 55, 64 and 100 kd were increased. Isoform RAGE 64 kd could be RAGE-v5, a splice variant which resulted in a change of amino acid sequence in the extracellular ligand-binding domain of RAGE. Isoform RAGE 37 kd seemed to be Δ8-RAGE, a soluble splice variant with probably protective function, which had been found increased in patients with increased HDL. Finally, isoform RAGE 100 kd seemed to be some other splice variant in peripheral mononuclear cells. In conclusion, increased serum levels of sRAGE seen in IDDM children may be a temporary protective measure against cell damage and may be sufficient to efficiently eliminate excessive circulating CML. Moreover, the lower protein expression of the full-length RAGE in IDDM may also reflect the increased sRAGE expression in patients due to RAGE cleavage by metalloproteases. Consequently, in IDDM children, adolescents and young adults there may be a subclinical perturbation of the sRAGE-RAGE-CML axis, which could lead to future clinical vascular damage if additional risk factors are added over time.
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Zakiyanov, Oskar. "Nové biomarkery u pacientů s onemocněním ledvin." Doctoral thesis, 2014. http://www.nusl.cz/ntk/nusl-338466.
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Chronic kidney disease (CKD) and acute kidney injury (AKI) are major public health problems. It is important to be able to identify those at high risk of adverse outcome, CKD progression and associated cardiovascular disease. The aim of the thesis was to study novel promising biomarkers, their relationship to kidney function, chronic inflammation and/or cardiovascular risk - placental growth factor (PlGF), pregnancy associated plasma protein A (PAPP-A), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), soluble receptor for advanced glycation end products (sRAGE), calcium binding protein S100A12 or extracellular newly identified RAGE binding protein (EN-RAGE), and high mobility group box protein-1 (HMGB-1) in patients with renal diseases including CKD, haemodialysis (HD), AKI patients, and healthy controls for comparison. First study revealed that PlGF is elevated in patients with decreased renal function. Second study demonstrated the association of MMP-2 and PAPP-A with proteinuria in patients with CKD. Moreover, serum MMP-2, MMP-9 and PAPP-A levels significantly differed in patients with various nephropathies. EN-RAGE levels are not elevated in patients with CKD, but are related to inflammatory status. PAPP-A, EN-RAGE and HMGB-1 levels are significantly elevated, but sRAGE and PlGF...