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At least 127 records · Page 7Linked to original sources
PubMed2002

Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell induced inflammation.

CD46 is a widely expressed transmembrane protein that was initially identified as binding and inactivating C3b and C4b complement products. We used mice that were transgenic for one of two human CD46 isoforms that differ in their cytoplasmic domains (termed CD46-1 and CD46-2) to analyze the effect of CD46 stimulation on the immune response. We show here that CD46 can regulate inflammatory responses, either by inhibiting (CD46-1) or increasing (CD46-2) the contact hypersensitivity reaction. We found that engagement of CD46-1 or CD46-2 differentially affected CD8(+) T cell cytotoxicity, CD4(+) T cell proliferation, interleukin 2 (IL-2) and IL-10 production as well as tyrosine phosphorylation of Vav in T lymphocytes. These results indicate that CD46 plays a role in regulating the T cell induced inflammatory reaction and in fine-tuning the cellular immune response by bridging innate and acquired immunity.

Animals↗
PubMed1990

Generation of the membrane attack complex during haemodialysis: impact of classical and alternative pathway components.

1. The generation of the plasma SC5b-9 complex (the soluble form of the membrane attack complex) during haemodialysis was studied in 29 patients together with markers of the classical (C4d fragment) and alternative (Bb fragment) pathways and the common iC3b fragment. 2. In the patients dialysed with Hemophan and Cuprophan membranes, a rapid increase in the plasma levels of SC5b-9 complex, Bb fragment and iC3b fragment occurred within 15 min of the initiation of the haemodialysis procedure. The SC5b-9 complex and the Bb fragment concentrations remained at a plateau until 120 min thereafter. The iC3b fragment level showed a continual decline. 3. The C4d fragment concentrations remained unchanged, indicating that generation of the membrane attack complex is most likely due only to activation of the alternative pathway. 4. The generation of the membrane attack complex occurred throughout the full haemodialysis period. In patients treated with Polysulfon membranes no statistically significant variation in these components was noted. 5. The study shows that the membrane attack complex may be generated during the full period of the haemodialysis session and is a stable index of biocompatibility. 6. Moreover, it seems be involved directly in haemodialysis-associated phenomena.

Complement Activation↗
PubMed2003

Pneumococcal immune adherence to human erythrocytes.

BACKGROUND: Human red blood cells bind various C3b-coated microorganisms via their C3b/CR1 receptor, a phenomenon referred to as immune adherence. The aim of the present study was to measure pneumococcal adherence to human red blood cells by flow cytometry and to study kinetic aspects of this binding. MATERIAL AND METHODS: We quantified pneumococcal adherence to human erythrocytes by FACS analysis and tested the involvement of antibodies and complement activation in this process. RESULTS: Pneumococci are able to bind to human red blood cells in the presence of human serum. Coating with C3b/C4b appeared obligatory for pneumococcal adherence to red blood cells. The ligand on erythrocytes was confirmed to be complement receptor 1. Kinetic studies showed that innate (mannose-binding lectin) and specific immune factors (IgG antibodies) contributed to the binding of C3b-coated pneumococci to human erythrocytes. After initial binding, serum-derived factor I was found to induce bacterial detachment from the erythrocyte. CONCLUSIONS: Pneumococci are able to adhere to red blood cells. Both the classical and lectin complement pathways are important for optimal C3b-coating of pneumococci for immune adherence. Bound pneumococci are detached from red blood cells by factor I. These findings are in line with the hypothesis of immune adherence in which human erythrocytes are able to bind pneumococci and target the bacteria to the reticulo-endothelial system in the spleen.

Bacterial Adhesion↗
PubMed2003

Activation of the complement system by different autologous transfusion devices: an in vitro study.

BACKGROUND: The aim of the present investigation was to study whether autologous transfusion devices activate the complement system and whether complement-activated blood is more vulnerable to further activation during processing. STUDY DESIGN AND METHODS: Forty-eight blood units were randomized to be processed by one of three different salvage systems: Group 1 underwent whole blood filtration (hemofiltration) (n=16); Group 2 underwent continuous processing, saline washing, and centrifugation (CATS, Fresenius AG ) (n=16); and Group 3 underwent saline washing and centrifugation (Cell-Saver, Haemonetics Corp.) (n=16). Eight blood units for each system were activated with cobra venom factor (CVF) at a concentration of 0.2 U per mL whole blood before processing. C activation was studied by determinations of C4d, Bb, C3a, and SC5b-9. Samples were drawn from whole blood, processed blood, and the waste bags. RESULTS: The concentrations of Bb, C3a, and SC5b-9 in whole blood after activation with CVF were significantly elevated compared to blood that was not activated (p < 0.01). Processed blood from hemofiltration contained significantly higher levels of complement-split products than techniques that use washing and centrifugation. The concentrations of SC5b-9 in blood processed by hemofiltration were higher in the experiments with CVF activation (p < 0.05). CONCLUSION: The tested autologous transfusion systems did not themselves activate the complement system, and complement-activated blood was not more vulnerable to further activation during processing. A blood-salvaging technique that used washing and centrifugation reduced elevated concentrations of complement-split products, whereas hemofiltration did not.

Blood Transfusion, Autologous↗
PubMed2005

A case of renal sarcoidosis with complement activation via the lectin pathway.

A 57-year-old woman with pulmonary sarcoidosis was admitted to the hospital because of an elevation of serum creatinine and blood urea nitrogen. On admission, the laboratory data suggested interstitial nephritis without proteinuria and hematuria, whereas a renal biopsy showed granulomatous interstitial nephritis and mild mesangial proliferative glomerulonephritis. Immunoglobulin and C1q deposits were negative, but mannose-binding lectin, C3, C4d, and C5b-9 deposits were marked in the glomerular mesangial areas. The lectin pathway of complement activation may have contributed to the development of glomerular injury in this patient. DNA of Propionibacterium acnes , which is now strongly suspected as the pathogen of sarcoidosis, was detected in the patient's glomerular mesangial cells; tubular epithelial cells, which were involved in granulomatous inflammation; and mononuclear cells in epithelioid granulomas by in situ hybridization. These findings may add new insights to the pathogenesis of renal sarcoidosis, including its relation to infection, because mannose-binding lectin plays a crucial role in the host defense against various pathogens. From this case of renal sarcoidosis, it is hypothesized that P acnes may be involved in pathogenesis of granulomatous interstitial nephritis and that it plays a role in glomerular complement activation via the lectin pathway.

Anti-Inflammatory Agents↗
PubMed2002

Complement activation in chromosome 13 dementias. Similarities with Alzheimer's disease.

Chromosome 13 dementias, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with neurodegeneration and cerebrovascular amyloidosis, with striking neuropathological similarities to Alzheimer's disease (AD). Despite the structural differences among the amyloid subunits (ABri in FBD, ADan in FDD, and Abeta in AD), these disorders are all characterized by the presence of neurofibrillary tangles and parenchymal and vascular amyloid deposits co-localizing with markers of glial activation, suggestive of local inflammation. Proteins of the complement system and their pro-inflammatory activation products are among the inflammation markers associated with AD lesions. Immunohistochemistry of FBD and FDD brain sections demonstrated the presence of complement activation components of the classical and alternative pathways as well as the neo-epitope of the membrane attack complex. Hemolytic experiments and enzyme-linked immunosorbent assays specific for the activation products iC3b, C4d, Bb, and C5b-9 indicated that ABri and ADan are able to fully activate the complement cascade at levels comparable to those generated by Abeta1-42. ABri and ADan specifically bound C1q with high affinity and formed stable complexes in physiological conditions. Activation proceeds approximately 70-75% through the classical pathway while only approximately 25-30% seems to occur through the alternative pathway. The data suggest that the chronic inflammatory response generated by the amyloid peptides in vivo might be a contributing factor for the pathogenesis of FBD and FDD and, in more general terms, to other neurodegenerative conditions.

Alzheimer Disease↗
PubMed2004

Cellular membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves C3b, an essential component of the complement system.

Neoplasms have developed numerous strategies to protect themselves against the host immune system. Membrane type-1 matrix metalloproteinase (MT1-MMP) is strongly associated with many cancer types and is up-regulated in the aggressive, metastatic neoplasms. During the past few years, there has been an increasing appreciation of the important, albeit incompletely understood, role of MT1-MMP in cancer. We have discovered, using cell-free and cell-based assays in vitro, that MT1-MMP proteolysis specifically targets C3b, an essential component of the complement propagation pathway. MT1-MMP proteolysis liberates the deposited C3 activation fragments from the cell surface. The shedding of these cell-deposited opsonins by MT1-MMP inhibits the complement cascade and protects breast carcinoma MCF7 cells from direct complement-mediated injury in the in vitro tests. The functional link associating MT1-MMP with the host immune system, heretofore unrecognized, may empower tumors with an escape mechanism that contributes to the protection against the host anti-tumor immunity as well as to the survival of invading and metastatic malignant cells in the bloodstream.

Blotting, Western↗
PubMedDate not supplied

Study on a nonhealing fracture from a patient with systemic lupus erythematosus and its pathogenetic mechanisms.

Arthritis and osteonecrosis affect a large number of patients with systemic lupus erythematosus (SLE). A patient with history of SLE suffered a traumatic fracture of the left foot. Despite a long period of immobilization and internal fixation, the fracture failed to heal and required arthrodeses with removal of the phalanx. Histopathological investigation revealed destruction of cartilage, subchondral cystic degeneration, vasculitis, deposition of fibrinogen, type III collagen and fibronectin, absence of bone remolding, and detectable F-actin. The nonhealing was therefore due to lack of progression of healing process beyond the initial stage. There was deposition of immunoglobulins and complement C4b, possibly forming immune complex by autoantibodies and cellular components. The authors found that MSE55 protein, required for polymerization of actin and initiation of cellular process organization, had a similar cellular deposition as that of immunoglobulins. Autoantibodies thus may inhibit differentiation of the bone cells, and resulted in nonunion in the patient.

Adaptor Proteins, Signal Transducing↗
PubMed1989

Analysis of mutations causing steroid 21-hydroxylase deficiency.

Steroid 21-hydroxylase deficiency is the most frequent cause of congenital adrenal hyperplasia, an inherited inability to synthesize cortisol. Mutations causing this disorder have been characterized by hybridization analysis of patient DNA samples using cDNA and oligonucleotide probes, and by cloning and sequencing of mutant 21-hydroxylase (CYP21B) genes. About 20% of mutant alleles carry a 30 kilobasepair deletion that includes the 3' end of the CYP21A pseudogene, the C4B complement gene, and the 5' end of CYP21B, leaving behind a single CYP21A-like gene that is not functional. Non-deletional mutations include a nonsense mutation at codon 318 that is associated with severe disease and missense mutations at codons 172 (isoleucine to asparagine) and 281 (valine to leucine) that are respectively associated with intermediate and mild deficiency states. All of these alleles have apparently resulted from gene conversion events that have transferred deleterious mutations from the CYP21A pseudogene to CYP21B. Thus, recombinations between CYP21A and CYP21B probably account for the majority of 21-hydroxylase deficiency alleles.

Adrenal Hyperplasia, Congenital↗
PubMed1985

Human genes for three complement components that regulate the activation of C3 are tightly linked.

A new cluster of complement component genes, including C4BP, C3bR, and FH, is described. Family segregation data indicate that FH is linked to the genes for C4-bp and C4bR, previously reported to be linked and to maintain linkage disequilibrium. This cluster is not linked to the major histocompatibility complex, which contains the genes for the complement components, C4, C2, and factor B, or to the C3 locus. These data further suggest that the organization of genes for functionally related proteins in clusters may be a rule for the complement system.

Carrier Proteins↗
PubMed1985

Connective tissue proteins and phagocytic cell function. Laminin enhances complement and Fc-mediated phagocytosis by cultured human macrophages.

Brief exposure of culture-derived human macrophages to laminin, a glycoprotein component of all mammalian basement membranes that has a molecular weight of 1,000,000, led to enhancement of subsequent macrophage phagocytosis of EAC4b, EAC3bi, and EAIgG (sheep erythrocytes sensitized with IgG anti-Forssman antibody). This effect on macrophage phagocytosis occurred with both substrate-adherent and fluid phase laminin. Preincubation of macrophages, but not of EAC4b, with laminin led to augmentation of phagocytosis, suggesting that interaction with the phagocytic cell, but not with the opsonized particle, was required for laminin's effect. Laminin-stimulated phagocytosis of EAC4b was blocked entirely by a monoclonal antibody to CR1. Direct comparison of the phagocytic ability of macrophages adherent to laminin- and fibronectin-coated glass slides showed that fibronectin had a somewhat greater enhancing effect on phagocytosis. Nonetheless, the phagocytosis-enhancing effect of laminin was not due to contamination of the purified laminin preparation by fibronectin, since the laminin preparation was free of fibronectin, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and enzyme-linked immunosorbent assay; in addition, laminin-enhanced phagocytosis was decreased in the presence of laminin-specific antibodies. Laminin inhibited macrophage adherence and spreading, but selection of a laminin-binding macrophage subpopulation could not account for the laminin-induced increases in phagocytosis. We hypothesize that interaction with extracellular matrix proteins may represent an important activation stimulus both to the macrophages normally present in the extravascular compartment and to the phagocytic cells that have emigrated from the blood-stream into areas of inflammation.

Adjuvants, Immunologic↗
PubMed1981

Rocket immunoelectrophoresis of C4 and C4d. A simple sensitive method for detecting complement activation in plasma.

Activation of complement component C4 has recently been measured by the quantitation of C4 and C4d (a cleavage fragment of C4) by electroimmunodiffusion in gels containing specific precipitating antibodies for C4 and C4d (Rocket immunoelectrophoresis, RIE). Quantitative measurements of the complement component C4 and its fragment C4d were determined in rocket immunoelectrophoresis (RIE) and compared with measurements of total hemolytic complement activity (CH50) or concentrations of C4 as determined by single radial immunodiffusion (RID). This newly developed RIE assay shows activation of the classical complement pathway and involves electroimmunodiffusion in gels containing specific precipitating antibodies for C4 and its cleavage fragment, C4d. In 37 plasma samples, excellent correlation was demonstrated between the C4 in RIE and CH50 (r = .70) and C4 by RID (r = .87). In vivo activation of C4 was determined by measuring the ratio of C4d to C4; 21 of the plasma samples assayed had ratios greater than 1.1 indicating activation of C4. In 13 of the plasma samples there were correspondingly low CH50 values, whereas 8 had normal CH50 levels. Therefore, activation can be detected in those instances when other measurements (CH50 and C4 quantitation) are normal. Thus the RIE assay for plasma C4 activation appears to be the most sensitive method available for assessing in vivo activation of the classical pathway of complement.

Animals↗
PubMed1987

Multiple sclerosis in north-east Scotland. An association with HLA-DQw1.

This study reports the frequencies of HLA antigens and the polymorphic variants of C4, C2, and Bf for 200 patients with multiple sclerosis (MS) living in the Grampian region of Scotland, an area of high disease prevalence. A group of 128 normal subjects from the same region were typed for comparison. Although the frequencies of HLA-B7 and DR2 in the patient group (43.3% and 49.4%, respectively) were found to be similar to those reported for other Northern European HLA studies on patients with MS, high frequencies of these antigens were also observed in the group of normal Grampian subjects (38.3% and 40.6%) the differences were not statistically significant. However, a significant association was found between the recently defined Class II HLA antigen, DQw1, and MS (P less than 0.006) when compared with controls. There were no significant differences in frequency of the polymorphisms of C4, C2, and Bf when the group of patients with MS was compared with the control group of normal subjects. The patients were subdivided according to disease severity, remittent versus progressive clinical course, age of onset of the disease and initial symptoms. The frequencies of the HLA and complement polymorphisms (C4, C2, and Bf) were analysed in these subdivisions. DQw1 was found with similar frequency in severe and benign disease (78% and 80%, respectively) but DR2 was most frequent in the group of patients with remittent disease (54%). There were no significant differences in frequency of the polymorphisms of C4, C2, and Bf between the above subgroups of patients and overall no significant HLA associations were found with age of onset of disease or initial symptoms. The findings suggest that in an area of high prevalence of MS, the disease is more closely associated with DQw1 than DR2. Furthermore, there was no evidence to support the hypothesis that the HLA region complement gene polymorphisms show significant association with a putative HLA-linked MS susceptibility gene.

Complement C4↗
PubMed1990

Activation of the complement system in human immunodeficiency virus infection: relevance of the classical pathway to pathogenesis and disease severity.

In vitro studies implicate classical and alternative complement pathway activation in the pathogenesis of human immunodeficiency virus (HIV) infection. To ascertain their importance in vivo, activation fragments of the classical (C4d), alternative (Ba), and common (C3d) pathways were measured and fragment to parent molecule ratios derived in 74 HIV-infected individuals and related to circulating immune complex (CIC) levels, Centers for Disease Control (CDC) stage, and beta 2-microglobulin, neopterin, and CD4-positive (CD4+) lymphocyte levels. All fragments and ratios were significantly higher in patients (P less than .01) than controls. C4 conversion indices (C4d and C4d to C4) increased linearly with increasing CDC stage (P less than .001), while CD4+ lymphocytes decreased linearly (P less than .001). C4d, C3d, C4d to C4, and C3d to C3 correlated with increasing CIC and beta 2-microglobulin, and C4d and C4d to C4 correlated with decreasing CD4+ lymphocytes (P less than .05). The relationship of classical complement pathway activation to disease progression and CD4+ lymphocytes suggests its involvement in the pathogenesis of HIV infection.

Adult↗
PubMed1993

Human anti-endotoxin antibody HA-1A mediates complement-dependent binding of Escherichia coli J5 lipopolysaccharide to complement receptor type 1 of human erythrocytes and neutrophils.

HA-1A has been shown clinically to decrease mortality in septic patients with gram-negative bacteremia. In this study, the ability of HA-1A to augment the serum complement-dependent immune adherence of 125I-labeled Escherichia coli J5 lipopolysaccharide (LPS) to human erythrocytes (RBC) and polymorphonuclear leukocytes (PMNL) was evaluated. In vitro studies indicated three things: HA-1A mediates immune adherence of 125I-J5 LPS to human RBC and PMNL in a dose-dependent manner; under these conditions, high concentrations of LPS (400 ng/mL) could be specifically bound. Immune adherence occurs via the classical complement pathway as demonstrated by its calcium dependence; HA-1A-J5 LPS-C' immune complexes bound to CR1 on human RBC and PMNL. PMNL binding and internalization of immune complexes was demonstrated by trypsin stripping of externally bound immune complexes. These studies support the proposal that HA-1A can lower the bioavailability of endotoxin by mediating binding and potential clearance of LPS via human RBC through the reticuloendothelial system or via direct internalization by peripheral blood PMNL.

Antibodies, Monoclonal↗
PubMed2005

The pathology of multiple sclerosis is location-dependent: no significant complement activation is detected in purely cortical lesions.

Complement activation is known to occur in white matter multiple sclerosis (MS) lesions. It is thought to mediate oligodendrocyte/myelin damage and to be a marker of pathologic heterogeneity among individuals. Less is known about complement deposition in the gray matter in MS. The aim of this study was to characterize the presence and distribution of complement activation products in cortical MS lesions. Immunohistochemical staining was performed on cryostat sections from the brains of 22 MS patients and 5 nonneurologic control patients obtained at autopsy. Deposition of the complement activation products C1q, C3d, and C5b-9 (membrane attack complex) was detected on and within macrophages/microglia and astrocytes and in blood vessel walls in white matter MS lesions. C3d and C4d were detected along myelin sheaths at the edge of the lesions. In the gray matter part of combined gray matter/white matter lesions complement activation was less frequent, but increased immunopositivity was detected for C3d on blood vessels, and for C3d and C4d on myelin at the border of lesions, when compared with control areas. In contrast, in the purely cortical lesions, the extent of complement deposition in general was low. In conclusion, the role of complement in MS pathogenesis seems lesion location-dependent.

Adult↗