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Complement Cascade (complement + cascade)
Selected AbstractsC-type lectin-independent interaction of complement opsonized HIV with monocyte-derived dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2005Monika Pruenster Abstract HIV directly activates the complement cascade and is, therefore, opsonized with C3-cleavage products in vivo. This cloud of C3 fragments on the viral surface may impair the interaction of the HIV envelope glycoproteins gp120/gp41 with C-type lectins expressed on immature dendritic cells (iDC). Therefore, we determined the accessibility of gp120 after opsonization and compared the interaction of DC with non-opsonized or complement-opsonized HIV. The recognition of native gp120 was drastically impaired when the virus was covered by complement. Independent of opsonization, similar amounts of HIV bound to DC. The interaction of iDC and the infection of DC-PBL co-cultures with non-opsonized virus was significantly reduced by mannan and antibodies which inhibit the ICAM-1-CR3 interaction. The binding of opsonized virus to iDC was reduced by an anti-CR3-antibody, which interferes with the binding of C3 fragments, but was not affected by mannan. Complement enhanced the HIV infection of DC and DC-PBL co-cultures significantly. Mannan did not inhibit the complement-dependent enhancement of infection. Thus, non-opsonized and opsonized HIV interacted with iDC, although the binding mechanisms seemed to differ. As HIV is opsonized in vivo, the C-type lectin-independent interaction of opsonized viruses with iDC has to be taken into account. [source] Complement and its implications in cardiac ischemia/reperfusion: strategies to inhibit complementFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2001Tiphaine Monsinjon Although reperfusion of the ischemic myocardium is an absolute necessity to salvage tissue from eventual death, it is also associated with pathologic changes that represent either an acceleration of processes initiated during ischemia or new pathophysiological changes that were initiated after reperfusion. This so-called ,reperfusion injury' is accompanied by a marked inflammatory reaction, which contributes to tissue injury. In addition to the well known role of oxygen free radicals and white blood cells, activation of the complement system probably represents one of the major contributors of the inflammatory reaction upon reperfusion. The complement may be activated through three different pathways: the classical, the alternative, and the lectin pathway. During reperfusion, complement may be activated by exposure to intracellular components such as mitochondrial membranes or intermediate filaments. Two elements of the activated complement contribute directly or indirectly to damages: anaphylatoxins (C3a and C5a) and the membrane attack complex (MAC). C5a, the most potent chemotactic anaphylatoxin, may attract neutrophils to the site of inflammation, leading to superoxide production, while MAC is deposited over endothelial cells and smooth vessel cells, leading to cell injury. Experimental evidence suggests that tissue salvage may be achieved by inhibition of the complement pathway. As the complement is composed of a cascade of proteins, it provides numerous sites for pharmacological interventions during acute myocardial infarction. Although various strategies aimed at modulating the complement system have been tested, the ideal approach probably consists of maintaining the activity of C3 (a central protein of the complement cascade) and inhibiting the later events implicated in ischemia/reperfusion and also in targeting inhibition in a tissue-specific manner. [source] Genetic study of the myelin oligodendrocyte glycoprotein (MOG) gene in schizophreniaGENES, BRAIN AND BEHAVIOR, Issue 1 2005G. Zai Schizophrenia (SCZ) is a neuropsychiatric disorder that affects approximately 1% of the general population. The human leukocyte antigen (HLA) system has been implicated in several genetic studies of SCZ. The myelin oligodendrocyte glycoprotein (MOG) gene, which is located close to the HLA region, is considered a candidate for SCZ due to its association with white matter abnormalities and its importance in mediating the complement cascade. Four polymorphisms in the MOG gene (CA)n (TAAA)n, and two intronic polymorphisms, C1334T and C10991T, were investigated for the possibility of association with SCZ using 111 SCZ proband and their families. We examined the transmission of the alleles of each of these polymorphisms with the transmission disequilibrium test. We did not observe significant evidence for biased transmission of alleles at the (CA)n (,2 = 2.430, 6 df, P = 0.876) (TAAA)n (,2 = 3.550, 5 df, P = 0.616), C1334T (,2 = 0.040, 1 df, P = 0.841) and C10991T (,2 = 0.154, 1 df, P = 0.695) polymorphisms. Overall haplotype analysis using the TRANSMIT program was also not significant (,2 = 7.954, 9 df, P = 0.539). Furthermore, our results comparing mean age at onset in the genotype groups using the Kruskal,Wallis Test were not significant. Our case-control analyses (182 cases age-, sex- and ethnicity-matched with healthy controls) and combined z -score [(CA)n: z -score =,1.126, P = 0.130; (TAAA)n: z -score = ,0.233, P = 0.408; C1334T: z -score = 0.703, P = 0.241; C10991T: z -score = 0.551, P = 0.291] were also not significant. Although our data are negative, the intriguing hypothesis for MOG in SCZ may warrant further investigation of this gene. [source] The complement cascade: Yin,Yang in neuroinflammation , neuro-protection and -degenerationJOURNAL OF NEUROCHEMISTRY, Issue 5 2008Jessy John Alexander Abstract The complement cascade has long been recognized to play a key role in inflammatory and degenerative diseases. It is a ,double edged' sword as it is necessary to maintain health, yet can have adverse effects when unregulated, often exacerbating disease. The contrasting effects of complement, depending on whether in a setting of health or disease, is the price paid to achieve flexibility in scope and degree of a protective response for the host from infection and injury. Loss or even decreased efficiency of critical regulatory control mechanisms can result in aggravated inflammation and destruction of self-tissue. The role of the complement cascade is poorly understood in the nervous system and neurological disorders. Novel studies have demonstrated that the expression of complement proteins in brain varies in different cell types and the effects of complement activation in various disease settings appear to differ. Understanding the functioning of this cascade is essential, as it has therapeutic implications. In this review, we will attempt to provide insight into how this complex cascade functions and to identify potential strategic targets for therapeutic intervention in chronic diseases as well as acute injury in the CNS. [source] Complement component C1q inhibits ,-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanismsJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Karntipa Pisalyaput Abstract Alzheimer's disease is a neurodegenerative disorder characterized by neuronal loss, ,-amyloid (A,) plaques, and neurofibrillary tangles. Complement protein C1q has been found associated with fibrillar A, deposits, however the exact contributions of C1q to Alzheimer's disease is still unknown. There is evidence that C1q, as an initiator of the inflammatory complement cascade, may accelerate disease progression. However, neuronal C1q synthesis is induced after injury/infection suggesting that it may be a beneficial response to injury. In this study, we report that C1q enhances the viability of neurons in culture and protects neurons against A,- and serum amyloid P (SAP)-induced neurotoxicity. Investigation of potential signaling pathways indicates that caspase and calpain are activated by A,, but C1q had no effect on either of these pathways. Interestingly, SAP did not induce caspase and calpain activation, suggesting that C1q neuroprotection is in distinct from caspase and calpain pathways. In contrast to A,- and SAP-induced neurotoxicity, neurotoxicity induced by etoposide or FCCP was unaffected by the addition of C1q, indicating pathway selectivity for C1q neuroprotection. These data support a neuroprotective role for C1q which should be further investigated to uncover mechanisms which may be therapeutically targeted to slow neurodegeneration via direct inhibition of neuronal loss. [source] The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injuryLIVER TRANSPLANTATION, Issue 8 2008Constantino Fondevila Activation of the complement cascade represents an important event during ischemia/reperfusion injury (IRI). This work was designed to investigate the role of the membrane attack complex (MAC; C5b-9) in the pathogenesis of hepatic IRI. Livers from B&W/Stahl/rC6(+) and C6(,) rats were harvested, stored for 24 hours at 4°C, and then transplanted [orthotopic liver transplantation (OLT)] to syngeneic recipients. There were 4 experimental groups: (1) C6(+),C6(+), (2) C6(+),C6(,), (3) C6(,),C6(+), and (4) C6(,),C6(,). At day +1, C6(,) OLTs showed decreased vascular congestion/necrosis, contrasting with extensive necrosis in C6(+) livers, that was independent of the recipient C6 status (Suzuki score: 7.2 ± 0.9, 7.3 ± 1.3, 4.5 ± 0.6, and 4.8 ± 0.4 for groups 1-4, respectively, P < 0.05). The liver function improved in recipients of C6(,) grafts (serum glutamic oxaloacetic transaminase: 2573 ± 488, 1808 ± 302, 1170 ± 111, and 1188 ± 184 in groups 1-4, respectively, P < 0.05). Intragraft macrophage infiltration (ED-1 immunostaining) and neutrophil infiltration (myeloperoxidase activity) were reduced in C6(,) grafts versus C6(+) grafts (P = 0.001); these data were confirmed by esterase staining (naphthol). The expression of proinflammatory interferon-,, interleukin-1,, and tumor necrosis factor messenger RNA/protein was also reduced in C6(,) OLTs in comparison with C6(+) OLTs. Western blot,assisted expression of proapoptotic caspase-3 was decreased in C6(,) OLTs versus C6(+) OLTs (P = 0.006), whereas antiapoptotic Bcl-2/Bag-1 was enhanced in C6(,) OLTs compared with C6(+) OLTs (P = 0.001). Terminal deoxynucleotidyl transferase,mediated dUTP nick end-labeling staining of apoptotic cells was enhanced (P < 0.05) in C6(+) OLTs compared with C6(,) OLTs. Thus, the terminal products of the complement system are essential in the mechanism of hepatic IRI. This is the first report using a clinically relevant liver cold ischemia model to show that local MAC inhibition attenuates IRI cascade in OLT recipients. Liver Transpl 14:1133,1141, 2008. © 2008 AASLD. [source] Plasma protein profiles in early asthmatic responses to inhalation allergen challengeALLERGY, Issue 1 2009T. Rhim Although mediators, such as lipids, cytokines, and chemokines, are related to the appearance of an IPR, there has been no reliable indicator to predict conditions for the appearance of an IPR. In this study, we adopted a proteomic approach to investigate the pathogenesis at the level of the plasma proteins and to develop plasma markers to predict the appearance of an IPR following an inhalation challenge with Dermatophagoides pteronyssinus (D.p.). Sixteen mild asthmatics were recruited. Plasma was obtained before challenge and when a decline in forced expiratory volume in 1 s (FEV1) values greater than 20% from the phosphate-buffered saline value was achieved during D.p. allergen challenge (positive responders), or at 60 min after the highest concentration of D.p. allergen was inhaled (negative responders). After comparing normalized volumes of the spots in the two groups, differentially expressed spots were identified using intra-gel digestion and mass spectrometric analysis. Before D.p. antigen challenge, four spots of gamma fibrinogen and its isoforms were significantly decreased and two spots of complement C3 fragments were significantly increased in the positive responders compared to the negative responders. After D.p. antigen challenge, complement C3 fragment was persistently higher, while gamma fibrinogen was lower in the positive responders than in the negative responders. A validation study using Western blotting showed that gamma fibrinogen expression in the IPR-positive asthmatics was significantly decreased compared to the average of the IPR-negative asthmatic control group. These results indicate that alterations in the complement cascade and fibrinogen may predispose patients to the appearance of an immediate response to D.p. allergen challenge and may provide plasma markers to predict the appearance of an IPR. [source] Correlation-associated peptide networks of human cerebrospinal fluidPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 11 2005Jens Lamerz Dr. Abstract Profiling of peptides and small proteins from either human body fluids or tissues by chromatography and subsequent mass spectrometry reveals several thousand individual peptide signals per sample. Any peptide is an intermediate in the course of biosynthesis, post-translational modification (PTM), proteolytic processing and degradation. Changes in the concentration of one peptide often affects the concentration of the other, hence a challenge consists in the development of suitable tools to turn this large amount of data into biologically relevant information. Comprehensive statistical analysis of the peptide profiling data allows associating peptides, which are closely related in terms of peptide biochemistry. Here, the bioinformatic concept of peptide networks, correlation-associated peptide networks (CANs), is introduced. Peptides with statistical similarity of their concentrations are grouped in form of networks, and these networks are interpreted in terms of peptide biochemistry. The spectrum of functional relationships found in cerebrospinal fluid CAN covers PTM and proteolytic degradation of peptides, clearance processing in the complement cascade, common secretion of peptides by neuroendocrine cells as well as ubiquitin-mediated degradation. Our results indicate that CAN is a powerful bioinformatic tool for the systematic analysis and interpretation of large peptidomics and proteomics data and helps to discover novel bioactive and diagnostic peptides. [source] Structure of human desArg-C5aACTA CRYSTALLOGRAPHICA SECTION D, Issue 2 2010William J. Cook The anaphylatoxin C5a is derived from the complement component C5 during activation of the complement cascade. It is an important component in the pathogenesis of a number of inflammatory diseases. NMR structures of human and porcine C5a have been reported; these revealed a four-helix bundle stabilized by three disulfide bonds. The crystal structure of human desArg-C5a has now been determined in two crystal forms. Surprisingly, the protein crystallizes as a dimer and each monomer in the dimer has a three-helix core instead of the four-helix bundle noted in the NMR structure determinations. Furthermore, the N-terminal helices of the two monomers occupy different positions relative to the three-helix core and are completely different from the NMR structures. The physiological significance of these structural differences is unknown. [source] The role of complement testing in dermatologyCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 4 2005S. Jamal Summary An up-to-date knowledge of the molecular events involved in the activation and control of the complement cascade is essential to understand the pathogenesis of a number of conditions presenting to dermatologists. This knowledge underpins the pathogenesis of these conditions but allows the clinician to request the most useful tests in terms of diagnosis and monitoring. In this review we aim to discuss complement biology, the diseases in which complement testing is of particular relevance, the types of laboratory tests available, their utility and interpretation. Additionally it is of critical importance for clinicians not only to choose the most appropriate tests but also to choose to send these to an appropriately accredited laboratory. [source] Topography of a 2.0 Å structure of ,1 -antitrypsin reveals targets for rational drug design to prevent conformational diseasePROTEIN SCIENCE, Issue 7 2000Peter R. Elliott Abstract Members of the serpin family of serine proteinase inhibitors play important roles in the inflammatory, coagulation, fibrinolytic, and complement cascades. An inherent part of their function is the ability to undergo a structural rearrangement, the stressed (S) to relaxed (R) transition, in which an extra strand is inserted into the central A ,-sheet. In order for this transition to take place, the A sheet has to be unusually flexible. Malfunctions in this flexibility can lead to aberrant protein linkage, serpin inactivation, and diseases as diverse as cirrhosis, thrombosis, angioedema, emphysema, and dementia. The development of agents that control this conformational rearrangement requires a high resolution structure of an active serpin. We present here the topology of the archetypal serpin ,1 -antitrypsin to 2 Å resolution. This structure allows us to define five cavities that are potential targets for rational drug design to develop agents that will prevent conformational transitions and ameliorate the associated disease. [source] The role of bacteriolysis in the pathophysiology of inflammation, infection and post-infectious sequelaeAPMIS, Issue 11 2002Review article The literature dealing with the biochemical basis of bacteriolysis and its role in inflammation, infection and in post-infectious sequelae is reviewed and discussed. Bacteriolysis is an event that may occur when normal microbial multiplication is altered due to an uncontrolled activation of a series of autolytic cell-wall breaking enzymes (muramidases). While a low-level bacteriolysis sometimes occurs physiologically, due to "mistakes" in cell separation, a pronounced cell wall breakdown may occur following bacteriolysis induced either by beta-lactam antibiotics or by a large variety of bacteriolysis-inducing cationic peptides. These include spermine, spermidine, bactericidal peptides defensins, bacterial permeability increasing peptides from neutrophils, cationic proteins from eosinophils, lysozyme, myeloperoxidase, lactoferrin, the highly cationic proteinases elastase and cathepsins, PLA2, and certain synthetic polyamino acids. The cationic agents probably function by deregulating lipoteichoic acid (LTA) in Gram-positive bacteria and phospholipids in Gram-negative bacteria, the presumed regulators of the autolytic enzyme systems (muramidases). When bacteriolysis occurs in vivo, cell-wall- and -membrane-associated lipopolysaccharide (LPS (endotoxin)), lipoteichoic acid (LTA) and peptidoglycan (PPG), are released. These highly phlogistic agents can act on macrophages, either individually or in synergy, to induce the generation and release of reactive oxygen and nitrogen species, cytotoxic cytokines, hydrolases, proteinases, and also to activate the coagulation and complement cascades. All these agents and processes are involved in the pathophysiology of septic shock and multiple organ failure resulting from severe microbial infections. Bacteriolysis induced in in vitro models, either by polycations or by beta-lactams, could be effectively inhibited by sulfated polysaccharides, by D-amino acids as well as by certain anti-bacteriolytic antibiotics. However, within phagocytic cells in inflammatory sites, bacteriolysis tends to be strongly inhibited presumably due to the inactivation by oxidants and proteinases of the bacterial muramidases. This might results in a long persistence of non-biodegradable cell-wall components causing granulomatous inflammation. However, persistence of microbial cell walls in vivo may also boost innate immunity against infections and against tumor-cell proliferation. Therapeutic strategies to cope with the deleterious effects of bacteriolysis in vivo include combinations of autolysin inhibitors with combinations of certain anti-inflammatory agents. These might inhibit the synergistic tissue- and- organ-damaging "cross talks" which lead to septic shock and to additional post-infectious sequelae. [source] Development of a New Pharmacophore Model That Discriminates Active Compstatin AnalogsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2008Ting-Lan Chiu Compstatin and its active peptide analogs can potentially be used for therapeutic purposes because their binding to the third component of complement prohibits its conversion into the proteolytically activated form of the third component of complement, thus inhibiting complement cascades in all three complement pathways. Mallik and Morikis built three quasi-dynamic pharmacophore models for compstatin peptide analogs before, but only nine compstatin peptide analogs were incorporated in their study and the most active compstatin analog had only medium inhibitory activity. Since then, many more compstatin analogs have been synthesized and their inhibitory activities tested. Furthermore, the X-ray structure of AcCompNH2-V4W-H9A bound to the third component of complement has become available (PDB ID: 2QKI). In this paper, we utilized all the new information and built a new pharmacophore model using a distinct approach. Our model demonstrated good performance in a separate test set of 82 compstatin analogs: it accurately identified 70% of the analogs of medium or high inhibitory activities and misclassified only 8.5% of the analogs of low or no inhibitory activities. The results proved our pharmacophore model to be a filter of great sensitivity and specificity. [source] C4d deposition on peritubular capillary (PTC) in the protocol biopsy of ABO-incompatible kidney transplantation under the treatment with anti-CD20 antibody and without splenectomyCLINICAL TRANSPLANTATION, Issue 2007Naofumi Imai Abstract:, For the desensitization of A/B antigens, we had developed and reported a new potent immunosuppressive treatment, which is the pre-prescription of anti-CD20 monoclonal antibody with mycophenolate mofetil and low-dose steroid. Using this kind of desensitization therapy, splenectomy is not required at the kidney transplantation. Complement C4d deposition on peritubular capillary (PTC) in graft biopsy has been reported as a relatively reliable marker for humoral rejection. However, the C4d deposition was often observed in the graft biopsy of ABO-incompatible kidney transplantation even with no rejection findings. The aim of this study was to examine the effect of this treatment on C4d deposition on PTC. Baseline and protocol graft biopsies obtained from 12 recipients of ABO incompatible kidney transplants were evaluated by light and immunofluorescence microscopy. To elucidate the involvement of classical and/or lectin pathway of complement cascades in C4d deposition, we examined the deposition of the initial activating proteins on PTC, IgG and IgM in the classical pathway and mannose-binding lectin (MBL), H-ficolin, L-ficolin, MBL-associated serine protease (MASP)-1 and MASP-2 in the lectin pathway. Three out of nine available baseline biopsy specimens showed diffuse C4d and IgM deposition on PTC. In the protocol biopsy, nine of 12 specimens revealed diffuse C4d deposition on PTC. Five of them had positive deposition of IgM and H-ficolin on PTC, whereas the other initial proteins were not detected in all specimens. Apart from one case, the histological findings of the protocol biopsies were normal or borderline changes. Our study suggested that although the new treatment with anti-CD20 antibody treatment and without splenectomy was clinically effective, it did not perfectly inhibit C4d deposition on PTC. It also confirmed the dual activation of both classical and lectin pathways in the process of C4d deposition on PTC in ABO-incompatible transplantation. [source] | |||||||||||||||||||||||||