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PubMed1988

Induction of expression of cell-surface homologous restriction factor upon anti-CD3 stimulation of human peripheral lymphocytes.

Homologous restriction factor (HRF) is a 65-kDa membrane protein that inhibits transmembrane channel formation by the membrane-attack complex of complement and by the complement component C9-related cytolytic lymphocyte protein. Stimulation of resting peripheral human lymphocytes with the anti-CD3 monoclonal antibody OKT3 has been shown to induce cytotoxicity in the CD8+ subpopulation. As demonstrated here, OKT3 stimulation also induces expression of cell-surface HRF by CD4+ and CD8+ T lymphocytes. The small proportion of Leu 19+ natural killer lymphocytes present in peripheral blood mononuclear cells was found to express HRF prior to stimulation. Whereas unstimulated peripheral blood mononuclear cells were susceptible to lysis by the membrane-attack complex or by the C9-related protein, OKT3-stimulated peripheral blood mononuclear cells were relatively resistant to both the membrane-attack complex and C9-related protein. This acquired resistance was abrogated by blocking surface HRF with F(ab')2 anti-HRF, suggesting that resistance was due to lymphocyte-membrane HRF. By using solid-phase anti-HRF, a 65-kDa protein was isolated from the activated peripheral blood mononuclear cells and shown to be capable of conferring upon sheep erythrocytes the characteristic activity of human HRF.

Antibodies, Monoclonal↗
PubMed1989

Transfer of phospholipid and protein into the envelope of gram-negative bacteria by liposome fusion.

A liposome-bacterial fusion system was developed in order to introduce preformed terminal complement complexes, C5b-9, into the outer membrane of Gram-negative bacteria. Liposomes were prepared from a total phospholipid extract of Salmonella minnesota Re595. Fusion between liposomes and Salmonella sp. or Escherichia coli 17 was dependent on time, temperature, pH, and Ca2+ and PO4- concentration. Only Salmonella sp. with attenuated LPS core regions were able to fuse efficiently with liposomes. It was demonstrated that fusion of liposomes with S. minnesota Re595 or E. coli 17 under optimum conditions resulted in (i) quantitative transfer of the self-quenching fluorescent membrane probe octadecyl rhodamine B chloride from the liposomal bilayer to the bacterial envelope, (ii) transfer of radiolabeled liposomal phospholipid to the bacterial outer membrane and its subsequent translocation to the cytoplasmic membrane, demonstrated by isolation of the bacterial membranes following fusion, and (iii) delivery of liposome-entrapped horseradish peroxidase (HRP) to the periplasmic space, confirmed by a chemiluminescent assay. Following fusion of liposomes incorporating C5b-9 complexes with S. minnesota Re595 or E. coli 17, immunological analysis of the isolated membranes revealed C5b-9 complexes located exclusively in the outer membrane.

Biological Transport↗
PubMed2006

Inhibition of antimicrobial peptides by group A streptococci: SIC and DRS.

SIC (streptococcal inhibitor of complement) is a 31 kDa protein secreted by a few highly virulent strains of GAS (group A streptococci), predominantly by the M1 strain. Initially described as an inhibitor of the membrane attack complex of complement, it has turned out to be a polyfunctional inhibitor of the innate mucosal immune response. The SIC protein sequence contains three domains: an N-terminal SRR (short repeat region), followed by three longer tandem repeats [LRR (long repeat region)] and a C-terminal PRR (proline-rich region). SIC inhibits the antibacterial activity of a wide range of antimicrobial peptides and proteins: i.e. lysozyme, SLPI (secretory leucocyte proteinase inhibitor), LL-37, hNP-1 (human neutrophil peptide-1) and the human beta-defensins 1, 2 and 3. Analysis of the functional properties of recombinant domains of SIC shows that binding and inhibition of lysozyme and human beta-defensin-3 require the SRR+LRR, as does binding to SLPI. Complement inhibition is confined to the SRR. M12 GAS secrete a protein 'distantly related to SIC' (DRS). DRS contains a C-terminal PRR which is significantly similar to that of SIC, but it has no central LRR and the N-terminal SRR is very different. DRS inhibits human beta-defensin-3, but has no effect on lysozyme, SLPI or complement.

Animals↗
PubMed1998

Role of complement in in vitro and in vivo lung inflammatory reactions.

Complement is one of the integral buttresses of the inflammatory response. In addition to host defense activities, proinflammatory properties of several complement components are described. This overview elucidates the role of complement in inflammatory reactions in vitro and in vivo, focusing on the complement activation products, C5a, and the membrane attack complex, C5b-9. Using several approaches, the impact of these complement components in mechanisms relevant to neutrophil recruitment is emphasized. In addition, the participation of complement in endothelial superoxide generation and its essential requirement for full expression of lung injury is demonstrated, as are the involved intracellular signal transduction pathways. Understanding the mechanisms of complement-induced proinflammatory effects may provide a basis for future therapeutic blockade of complement and/or its activation products.

Complement Activation↗
PubMed1984

Cell populations and membrane attack complex in glomeruli of patients with post-streptococcal glomerulonephritis: identification using monoclonal antibodies by indirect immunofluorescence.

Poststreptococcal glomerulonephritis (PSGN) had been thought to arise from renal deposition of immune complexes and as such is analogous to acute serum sickness. Recent studies of acute serum sickness in animals and PSGN in humans, however, have suggested a pathogenetic role for cellular immunity. To enlarge on these observations, cellular components of glomeruli were characterized by indirect immunofluorescence in 11 tissues from individuals with PSGN using monoclonal antibodies. These studies demonstrate infiltration of glomeruli by monocytes, granulocytes, and lymphoid cells. Focal accumulations of T lymphocytes were also observed adjacent to Bowman's capsule. Analysis of glomerular T-cell subpopulations revealed a predominance of cells reactive with OKT4 early and with OKT8 later in the course of disease. Proliferation of parietal and visceral epithelial cells was associated with increased binding of BA-1 and J5, respectively. The presence of the membrane attack complex of complement was demonstrated by glomerular reactivity with a monoclonal antibody (poly-C9 MA) which recognizes a neoantigen present in poly-C9. Fluorescence was present along the glomerular basement membrane early and within the mesangium late in the course of disease, a distribution similar to that observed for C3 and C5. These observations suggest that immune cells as well as terminal components of complement either provoke or mark tissue injury in PSGN.

Adolescent↗
PubMed1996

Anti-inflammatory drugs in the fight against Alzheimer's disease.

Lesions in Alzheimer disease are characterized by the assembly of a variety of cells and proteins associated with the immune system. Activated microglia express high levels of MHC glycoproteins and receptors for complement. Small numbers of T-lymphocytes infiltrate tissue. Proteins of the classical complement pathway are closely connected with beta-amyloid deposits. Several materials associated with senile plaques, including beta-amyloid protein itself, bind C1q in vitro and activate the pathway. The membrane attack complex of complement, as well as proteins which defend against that complex, colocalize with dystrophic neurites. These data imply that an autodestructive process is occurring in Alzheimer's disease, and that anti-inflammatory drugs might be an effective form of therapy. Some epidemiological evidence and results of a pilot clinical trial support this hypothesis.

Alzheimer Disease↗
PubMed1990

Structural homologies of component C5 of human complement with components C3 and C4 by neutron scattering.

The complement component C5 is one of a family of structurally related plasma proteins that includes components C3 and C4. Activation of C5 is the initial step in the formation of the membrane attack complex of complement. Analysis of the solution structure of C5 and comparisons with similar analyses of the structures of C3 and C4 are reported here. Neutron solution scattering gave an Mr for C5 of 201,000, which demonstrates that C5 is monomeric in solution. The radius of gyration RG of C5 at infinite contrast is 4.87 nm and corresponds to an elongated structure. The longest length of C5 was determined to be at least 15-16 nm from three calculations on the basis of the RG, the scattering intensity at zero angle I(0), and the indirect transformation of the scattering curve into real space. Comparison of the RG and contrast variation data and indirect transformations of the scattering curves for C3, C4, and C5 show that these have very similar structures. Comparisons of the C5 scattering curve with Debye small-sphere models previously employed for C4 and C3 show that good curve fits could be obtained. Unlike previous studies that have suggested significant differences, these experiments indicate that, while C5 differs from C3 and C4 in its activation and inactivation pathways, significant structural homology exists between the native proteins, as might be predicted from their high (and similar) sequence homology.

Complement C3↗
PubMed1992

Generation of terminal complement complexes in psoriatic lesional skin.

The complement system is thought to play an important role in the recruitment of neutrophils within the epidermis. In the present study we examined whether or not complement activation in psoriatic lesional skin results in the deposition of terminal complement complexes within the epidermis by measuring levels of SC5b-9 in the plasma and horny tissues of psoriatic patients. The levels of SC5b-9 in psoriatic plasma were significantly higher than those of controls or those of patients with atopic dermatitis. However, when the levels of SC5b-9 in the psoriatic plasma were compared before and after successful treatment of psoriasis, a significant reduction was observed after treatment. Studies of total protein extracts from lesional skin showed that, while no SC5b-9 was detected in the noninflammatory horny tissues, there were high levels of SC5b-9 in lesional horny tissues of psoriasis. By immunofluorescence using a monoclonal antibody to the C5b-9 neoantigen, deposition of C5b-9 was observed only in the stratum corneum of psoriatic skin. Thus the results of the present study suggests that in psoriatic lesional skin, the complement system is activated and that this complement activation proceeds all the way to the terminal step, generating membrane attack complex.

Adolescent↗
PubMed1994

Low levels of vitronectin and clusterin in acute meningococcal disease are closely associated with formation of the terminal-complement complex and the vitronectin-thrombin-antithrombin complex.

Patients with terminal complement deficiencies and thus impaired lytic efficiency have a highly increased likelihood of contracting invasive meningococcal infections but generally experience a mild disease course. Deficiencies of lysis inhibitors might therefore be associated with severe disease. We have quantified the complement lysis inhibitors vitronectin and clusterin, as well as complexes containing the proteins, in plasma from patients with acute meningococcal disease. At hospital admission, the median vitronectin concentrations were 0.10 (range, 0.04 to 0.17) g/liter in 10 septic patients and 0.19 (0.09 to 0.47) g/liter in 14 nonseptic patients (P = 0.001). The corresponding clusterin concentrations were 0.09 (0.01 to 0.13) and 0.14 (0.06 to 0.29) g/liter (P = 0.005). The vitronectin-thrombin-antithrombin complex concentration was 1.8 (0.22 to 35.6) arbitrary units (AU)/ml in septic patients, but the complex was not detectable in most nonseptic patients (< 0.10 to 0.16 AU/ml) (P < 0.0001). The corresponding levels of the terminal complement complex (contains vitronectin and clusterin) were 4.4 (3.6 to 20.1) and 2.6 (1.6 to 4.7) AU/ml (P = 0.0005). We found no evidence of constitutively low levels of vitronectin or clusterin in patients contracting meningococcal disease. The low levels of the proteins may partly be explained by hemodilution, extravasation, and increased consumption due to incorporation into complexes which are quickly removed from circulation.

Adolescent↗
PubMed1995

The role of a complement regulatory protein in rat mesangial glomerulonephritis.

The host cells are protected from the indiscriminate attack of homologous complement by the membrane-associated complement regulatory proteins. A mouse monoclonal antibody (mAb) 512 (immunoglobulin G1 subclass) has recently been described that recognizes and inhibits the function of a rat complement regulatory protein, a rat homologue of mouse Crry/p65. The aim of this work is to assess the role of a complement regulatory protein (512Ag) recognized by mAb 512 in the complement-dependent glomerular injury induced by mAb OX7 against rat Thy-1.1. For the induction of mesangial injury, the left kidney of a rat was perfused with a combination of OX7 and 512 and the perfusate was discarded from the renal vein (Group I). After the renal artery and vein were restored, the left kidney was connected to the systemic circulation. Rats were euthanized 3 h, 2 days, and 14 days later. Rats perfused either with OX7 (Group II) or with 512 (Group III) or with vehicle only (Group IV) were used as controls. At 3 h, rats of Group I showed more prominent cellular infiltration and mesangial lysis and more C3 deposition in the glomeruli than rats of Group II. Rats of Groups III and IV showed no significant changes. At Day 2, there was still significant mesangial lysis and leukocyte infiltration in Group I rats, whereas rats in other groups showed an almost normal appearance. Glomerular injury in Group I rats returned to normal by Day 14.

Animals↗
PubMed1993

Renal tubular antiproteinase (alpha-1-antitrypsin and alpha-1-antichymotrypsin) response in tubulo-interstitial damage.

We studied the role of proteinase inhibitors (Pls) alpha 1-antitrypsin and alpha 1-antichymotrypsin in relation to lysozyme (LZM), and membrane attack complex (C5b-9) in renal tubular damage by immunohistochemical techniques. Fifty-five cases, including 45 patients with glomerular diseases, and 10 controls were studied. The patients were divided into two groups; one with tubulo-interstitial lesions (TILs; 30 cases), and the other without (15 cases). Significant antiproteinase response was observed in the proximal tubules in both disease groups, indicating that they were subjected to proteolytic attack. This response correlated with proteinuria and occurred in tubules which showed protein reabsorption as demonstrated by the presence of LZM staining in consecutive serial sections. Increased deposition of membrane attack complex (C5b-9) was observed in the disease group with TILs, indicating direct damage to cell membranes. C5b-9 may also generate oxygen species, potent inhibitors of Pls, which allow the proteases to cause tubular damage.

Basement Membrane↗
PubMed1991

Complement activation in relation to development of preeclampsia.

Six hundred eighty-five primigravidas followed as a series had complement activation evaluated by the formation of anaphylatoxins (C3a and C5a) and terminal C5b-9 complement complexes in venous blood. Samples for complement determinations were obtained four times during pregnancy, in pregnancy weeks 12-16, 20-24, 28-32, and 34-36. Seven of the women developed preeclampsia and one of them the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome). Eleven others with uncomplicated pregnancies were selected as a control group. Plasma samples were taken from these 18 women at delivery and 1 and 7 days after delivery. At delivery, plasma C5a levels were significantly greater in the preeclamptics than in controls, and four of the seven preeclamptics had elevated plasma C3a values compared with controls. One week after delivery, these plasma anaphylatoxins had returned to normal. Elevations of the anaphylatoxins could not be detected before the women developed clinical signs of preeclampsia. No alterations in terminal C5b-9 complement complexes could be observed in the women with preeclampsia. However, the women who developed HELLP syndrome had elevated plasma concentrations of C3a, C5a, and terminal C5b-9 complement complex at delivery. These values returned to the normal range 1 week after delivery. We conclude that complement activation in the systemic circulation does not occur early in pregnancy and that plasma concentrations of C3a, C5a, or terminal C5b-9 complement complex cannot be used as predictors of preeclampsia.

Adult↗
PubMed1992

Expression and function of membrane attack complex inhibitory proteins on thyroid follicular cells.

Human thyroid cells are resistant to lysis by the homologous membrane attack complex. By immunohistochemical staining we here show that normal thyroid cells and those in Graves' disease and Hashimoto's thyroiditis express two membrane attack complex-inhibiting proteins, CD59 antigen and membrane attack complex-inhibiting protein/homologous restriction factor (MIP/HRF). In vitro, the expression of both molecules was enhanced by interleukin-1 (IL-1), tumour necrosis factor (TNF) and interferon-gamma (IFN-gamma) and cytokine-treated thyroid cells were more resistant to lysis by homologous complement. Blocking experiments with monoclonal antibodies against CD59 antigen and MIP/HRF showed that both molecules contributed but CD59 antigen was the more important in mediating resistance to complement attack. Expression of these proteins may be an important determinant of the severity of tissue injury produced by complement-fixing thyroid peroxidase antibodies in autoimmune thyroid disease.

Antigens, CD↗
PubMed2005

IL-4 and IL-13 induce protection of porcine endothelial cells from killing by human complement and from apoptosis through activation of a phosphatidylinositide 3-kinase/Akt pathway.

Vascular endothelial cells (EC) perform critical functions that require a balance of cell survival and cell death. EC death by apoptosis and EC activation and injury by the membrane attack complex of complement are important mechanisms in atherosclerosis and organ graft rejection. Although the effects of various cytokines on EC apoptosis have been studied, little is known about their effects on complement-mediated EC injury. Therefore, we studied the abilities of various cytokines to induce protection of porcine aortic EC against apoptosis and killing by human complement, a model of pig-to-human xenotransplantation. We found that porcine EC incubated with IL-4 or IL-13, but not with IL-10 or IL-11, became protected from killing by complement and apoptosis induced by TNF-alpha plus cycloheximide. Maximal protection required 10 ng/ml IL-4 or IL-13, developed progressively from 12 to 72 h of incubation, and lasted 48-72 h after cytokine removal. Protection from complement was not associated with reduced complement activation, C9 binding, or changes in CD59 expression. Inhibition of PI3K prevented development of protection; however, inhibition of p38 MAPK or p42/44 MAPK had no effect. IL-4 and IL-13 induced rapid phosphorylation of Akt. Although protection was inhibited by an Akt inhibitor and a dominant negative Akt mutant transduced into EC, it was induced by transduction of EC with the constitutively active Akt variant, myristylated Akt. We conclude that IL-4 and IL-13 can induce protection of porcine EC against killing by apoptosis and human complement through activation of the PI3K/Akt signaling pathway.

Animals↗
PubMed1993

Immunohistochemical localization of C3d fragment of complement and S-protein (vitronectin) in normal and diseased human kidneys: association with the C5b-9 complex and vitronectin receptor.

The localization of C3d, a fragment produced by C3 activation and S-protein (vitronectin), a regulatory factor of C5b-9, was studied immunohistochemically in normal human kidney and renal biopsies from patients with several types of glomerulonephritis. Immunofluorescent staining of the normal kidneys showed that C3d was present along the glomerular basement membrane (GBM), tubular basement membrane (TBM) and arterioles, and that S-protein was present in the GBM, mesangium, TBM, and arterioles. Immunoelectron microscopy of isolated basement membranes showed that C3d was localized exclusively on the epithelial side of the GBM, and that S-protein was present along both the epithelial and endothelial sides. In nephritic tissues, glomerular staining of C3d, C5b-9, and S-protein was increased when compared with that in normal tissues. S-protein, frequently co-localized with C3d and C5b-9 neoantigen, was intensely positive in the immune deposits of glomerular capillaries and the mesangial area, overlapping the background staining of GBM and mesangial matrix. S-protein and its receptor were occasionally co-localized in the glomeruli. These findings indicate that C3d and S-protein are normally present in the glomeruli. Co-staining of C3d, C5b-9 neoantigen, and S-protein within the immune deposits of nephritic kidneys suggests in situ binding of S-protein to locally-formed C5b-9 complex, or merely co-distribution of S-protein with the complex, rather than trapping of large molecular SC5b-9 complex from the circulation.

Complement C3d↗
PubMed1996

Analysis of the gene that encodes the complement regulatory protein, membrane inhibitor of reactive lysis (CD59). Identification of an alternatively spliced exon and characterization of the transcriptional regulatory regions of the promoter.

Membrane inhibitor of reactive lysis (MIRL, CD59) is an 18-kDa glycosylphosphatidylinositol-anchored protein that regulates formation of the membrane attack complex of complement. The purpose of these studies was to characterize the gene that encodes CD59. Our experiments redefined the structural organization of the gene by identifying a previously unrecognized alternatively spliced exon. Analysis by PCR of cDNA derived from a variety of cultured human cell lines and from PBMC showed that transcripts containing the alternatively spliced exon sequence were expressed concordantly with transcripts lacking that sequence. Primer extension studies demonstrated that the transcriptional start site of alternatively spliced CD59 mRNA is the same as that of transcripts without the alternatively spliced exon sequence, suggesting that expression of both forms of CD59 mRNA is regulated similarly. Analysis of the promoter region showed that the first 70 nucleotides immediately 5' of the transcriptional start site of the CD59 gene are essential for both constitutive and PMA-responsive transcription; however, responsiveness to PMA is cell line specific. Together, these studies have redefined the organization of the CD59 gene and identified regions of the promoter involved in constitutive and PMA-inducible transcription.

Antigens, Neoplasm↗