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PubMed1985

Membrane attack complex of complement in dermatitis herpetiformis.

The assembly of membrane attack complex (MAC) of complement implies activation of complement to the attachment of C9 and the presence of MAC on tissue suggests a possible pathogenic role for complement in disease since MAC is able to damage membranes. We examined normal skin of five patients with dermatitis herpetiformis for the presence of MAC using a monoclonal antibody (poly C9-MA) that recognizes a neoantigen of C9 that is not present on monomeric C9 but is common to both isolated MAC and to polymerized C9. Granular deposits of polymerized C9 were found at the sites of IgA deposition in the dermal papillae of normal skin from all patients. The pathologic importance of this finding is uncertain.

Antibodies, Monoclonal↗
PubMed1988

Immunohistochemical study of the membrane attack complex of complement in IgA nephropathy.

The localization of the membrane attack complex of complement (MAC) was examined in the normal human kidneys and in biopsy specimens from patients with primary IgA nephropathy by immunofluorescent and immunoelectron microscopies. Immunofluorescent staining for MAC was significantly more intense than in the normal kidneys, and was observed in the mesangium and occasionally along the glomerular capillary walls of 22 of 30 patients with IgA nephropathy. By dual-staining, the MAC deposits were generally concordant with the deposits of IgA, C3, C5 and C9, or of IgG, when present. C1q or C4 was infrequently observed in the glomeruli. Immunoelectron microscopy revealed various staining patterns of glomerular MAC deposition; homogeneous fine-granular staining beneath the glomerular basement membrane (GBM) in the paramesangial zone, patchy staining within the mesangial electron dense deposits (EDD), and ring-shaped or ribbon-like staining, associated with the striated membrane structures (SMS), in the matrix of the mesangium, GBM and tubular basement membrane (TBM). This study suggests that the terminal complement system is activated, mainly by an alternative complement pathway mechanism, in the mesangium of IgA nephropathy, and is associated with the paramesangial lesion and EDD. MAC deposition in glomerular SMS may also result from in situ activation rather than trapping from the circulation. There was little correlation between glomerular MAC deposition and proteinuria or renal histology of patients with IgA nephropathy.

Complement Membrane Attack Complex↗
PubMed1989

Mechanisms of tissue damage by the membrane attack complex of complement.

This article explores the role of the cytolytic membrane attack complex of complement in the pathogenesis of inflammatory diseases. Evidence of nucleated cell resistance to lysis by the membrane attack complex and the stimulation of secretion of pro-inflammatory factors in the absence of cell death in a variety of cell types in vitro are documented, and the possible significance of these non-lethal effects to the pathogenesis of inflammatory diseases highlighted.

Animals↗
PubMed1987

The membrane attack complex of complement induces permeability changes via thresholds in individual cells.

Flow cytometry was used to quantify the fluorescence of propidium iodide in rat polymorphonuclear leucocytes (PMN) attacked by the membrane attack complex (MAC) in order to establish the existence of permeability and lytic thresholds in individual cells, a 'threshold' being defined as a cellular event involving the rapid transition of cells from one state to another under physiological conditions. Activation of the complement pathway resulted in PMN being attacked by MAC within 5 min. Approximately 30-40% of the cell population subsequently became permeable to small molecules and macromolecules. Individual PMN passed through 'thresholds' of cell permeability and cell lysis, or recovered from complement attack at different times. In the flow cytometer, three distinct populations of PMN were identified: cells that had recovered before the permeability 'threshold', cells that had recovered after the permeability 'threshold' but before the lytic 'threshold', and cells that failed to recover from complement attack. Individual PMN attacked by MAC passed through permeability and lytic thresholds at different times after an initial lag of 7.5 +/- 2.5 min and 11.5 +/- 1.0 min, respectively. Adenosine, an activator of adenylate cyclase, inhibited removal of MAC from the cell surface. Consequently, more cells passed through the permeability and lytic 'thresholds', resulting in an increased percentage of lysed cells.

2-Chloroadenosine↗
PubMed1990

Comparison of channels formed by poly C9, C5b-8 and the membrane attack complex of complement.

The channels formed by poly C9, C5b-8 and C5b-9 were examined using the liposome swelling assay. By plotting the relative rate of swelling of C5b-8-containing liposomes vs the molecular weight of the sugar solute and by applying the Renkin equation, the size of the C5b-8 channel was estimated to be 1.5 mm radius. As increasing amounts of C9 were added during the formation of C5b-9, in C8:C9 ratios of 1:1, 1:2, 1:6 and 1:12, the size of the function channel increased. Poly C9 had a pore that was somewhat larger than C5b-9 at a C8:C9 ratio of 1:12. Using molecular sieving experiments with four different iodinated protein size markers, the channel diameter of poly C9 was estimated at between 90 and 100 A. Monoclonal antibodies to different complement proteins were added to the liposomes to see which might inhibit the channels. C5b-8 containing liposomes could be inhibited by antibodies to C8. Liposomes containing C5b-9 could be inhibited slightly by antibodies to C9 and most strongly by antibodies to the neoantigen of poly C9.

Antibodies, Monoclonal↗
PubMed1978

Leukocyte complement: assembly of the membrane attack complex of complement by human peripheral blood leukocytes in the presence and absence of serum.

The specific neoantigenic determinants (neoAg) that are indicative of the assembled C5b-9 C complex are generated on the surface of peripheral blood leukocytes (PBL) during collection and processing of blood. Formation of neoAg on PBL could be prevented by collecting blood directly into 20 mM EDTA and, could be induced in vitro by adding autologous serum to isolated PBL that lacked neoAg. When neoAg was induced by the addition of serum containing 125I-labeled C8, the C8 was incorporated into a 23S complex which could be eluted from PBL. A mechanism for neoAg formation on PBL independent of exogenous serum factors was detected when PBL were placed into culture in serum-free medium. Results with metabolic inhibitors and 14C-leucine suggest that PBL can synthesize C5 and assemble the C5b-9 complex. The possible relevance of these findings to the understanding of mechanisms of cell-mediated cytotoxicity is discussed.

Antigens↗
PubMed1988

In vivo and in vitro evidence of cell recovery from complement attack in rheumatoid synovium.

In the previous article we have demonstrated, by quantifying terminal complement complexes in synovial fluid, that membrane attack complex activation occurs in the joint in rheumatoid arthritis. Here we describe evidence of synoviocyte resistance to complement attack in vivo and in vitro. Gel filtration of terminal complement complex positive synovial fluid on Sepharose 2B revealed two forms of terminal complement complex: one form, eluting coincident with the column void, did not react with antibody to the fluid-phase inhibitor of complement membrane attack, the S-protein, suggesting that it was composed of membrane attack complexes, the other form, eluting in the included volume, did react with the anti-S-protein antibody, suggesting that it was composed of functionally inactive SC5b-9 complexes. The high molecular weight membrane attack complex peak was demonstrated by electron microscopy to be composed of membrane vesicles bearing many lesions having the typical appearance of complement membrane attack complexes. No discernible structures were present in the lower molecular weight peak. The effects of non-lethal complement membrane attack on human synoviocytes in culture were also investigated. Synoviocytes were relatively resistant to killing by autologous complement, end-point lysis of optimally antibody-sensitized cells never exceeding 60% even at a serum dilution of 1:2. At serum dilutions of 1:20 or less, no significant cell killing occurred despite a high degree of membrane attack pathway activation, suggesting the existence of resistance and recovery mechanisms. Non-lethal complement membrane attack stimulated the release of toxic reactive oxygen metabolites from synoviocytes. These, and other reactive species released during non-lethal complement attack in vivo, may play a significant role in the pathogenesis of rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed1985

Characterization of human S protein, an inhibitor of the membrane attack complex of complement. Demonstration of a free reactive thiol group.

S protein, an inhibitor to the membrane attack complex of complement, was purified from human plasma. The procedure involved barium citrate adsorption and fractionation by poly(ethylene glycol) 4000 precipitation, followed by chromatography on DEAE-Sephacel, Blue Sepharose, Sephacryl S-200, and finally anti-albumin-Sepharose. Reduced glutathione was added throughout to inhibit spontaneous formation of disulfide-linked S-protein dimers. The recovery was 7%, resulting in approximately 10 mg of pure S protein from 1 L of starting plasma. S protein is a single-chain molecule; sedimentation equilibrium ultracentrifugation yielded a molecular weight of 83 000; the s020,W value was estimated to be 4.0 S. The purified protein contained a free, reactive thiol group causing spontaneous formation of disulfide-linked S-protein dimers. Alkylated and nonalkylated S proteins were equally active in inhibiting C9 polymerization, catalyzed by the C5b-8 complex. In parallel with the inhibition of C9 polymerization, nonalkylated S protein catalyzed the formation of disulfide-linked C9 dimers, presumably through disulfide interchanges.

Amino Acid Sequence↗
PubMed1989

Deposition of the membrane attack complex of complement in pemphigus vulgaris and pemphigus foliaceus skin.

The present study was performed to determine whether complement activation in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) results in the assembly of the terminal complement sequence or membrane attack complex (MAC) in skin lesions. Biopsy specimens of skin lesions from five patients with PV and three patients with PF contained C5, C7, C9, and the MAC related neoantigen (C5b-9 neoantigen) in intercellular substance areas (ICS), as well as IgG and the early complement components Clq, C4, and C3. The presence of these late complement components and the C5b-9 neoantigens in ICS sites of the skin lesions is indicative of complement activation by the pemphigus antibody, with subsequent assembly of the MAC. The binding of IgG and early complement components to ICS was observed in both non-lesional (normal appearing) skin and in skin lesions. However, no MAC could be detected in the normal appearing skin of our pemphigus patients. It was also noted that the MAC could be generated in vitro on cryostat sectioned normal human skin by pemphigus antibody in the presence of complement. Results of these studies suggest that complement activation may be related to membrane damage of epidermal cells in both PV and PF.

Complement Membrane Attack Complex↗
PubMed1989

Inhibition of the formation of the complement membrane-attack complex by a monoclonal antibody to the complement component C8 alpha subunit.

The effect of nine monoclonal antibodies to complement component C8 on the interaction of C9 with preformed cell-surface C5b-8 complexes and on the functional insertion of C8 into the membrane-attack complex (MAC) was investigated. None of the antibodies prevented C9 insertion into a preformed C5b-8 complex. One antibody (F1) directed to the C8 alpha subunit clearly inhibited formation of a functional MAC. It is proposed that this antibody prevents the C8 alpha subunit unfolding and distorting the bilayer to allow C9 insertion.

Animals↗
PubMed1989

[Assembly of the membrane attack complex of complement in pemphigus vulgaris skin].

The time course of the deposition of the membrane attack complex of complement (MAC) in the skin of a case of pemphigus vulgaris was studied by immunofluorescence technique using monoclonal antibodies to human C5, C6, C7, C8, C9 and C5b-9 neoantigens. Biopsy specimens of skin lesions always contained the MAC-related antigens in the ICS areas. No MAC could be detected in the non-lesional skin. It was also noted that MAC could be generated in vitro on cryostat-sectioned normal human skin by the patient serum in the presence of complement. The titer of this complement-fixing antibody rose during the clinically active phase. Results of these studies suggest that complement activation, with subsequent assembly of MAC, may be related to acantholysis in the pemphigus skin.

Complement Membrane Attack Complex↗
PubMed1987

Membrane attack complex of complement in leukocytoclastic vasculitis of the skin. Presence and possible pathogenetic role.

The presence of the membrane attack complex of complement (MAC) was studied by a two-step immunofluorescence method in 15 patients with leukocytoclastic vasculitis of the skin, using an antibody against MAC neoantigen. Perivascular deposits of MAC were present in 13 specimens of lesional skin and only two specimens of clinically uninvolved skin, suggesting a possible pathogenetic role for MAC in the development of a skin lesion. Control studies were performed on the clinically normal skin of 15 individuals (11 patients with various nonbullous skin diseases and four healthy volunteers) and on skin lesions of seven patients with inflammatory skin diseases. In the clinically normal skin of only one patient, perivascular deposits of MAC were detected. This patient had rheumatoid arthritis and a cutaneous eruption due to the administration of aurothioglucose. We conclude that the activation of the terminal components of the complement system may play an important role in the formation of lesions in leukocytoclastic vasculitis of the skin, but is not an indispensable condition.

Adult↗
PubMed1989

Immunohistochemical study of the membrane attack complex of complement and S-protein in idiopathic and secondary membranous nephropathy.

Twenty-eight renal biopsies from 12 patients with idiopathic membranous nephropathy (MN), eight patients with lupus MN, and eight patients with hepatitis B virus-(HBV) related MN were investigated by immunofluorescence for the presence of C5b-C9 neoantigens of the terminal sequence of complement and for S-protein, which is a regulatory component of the membrane attack complex (MAC). Glomerular MAC was detected in 50% of patients with idiopathic MN, in 75% of patients with lupus MN, and in only 12.5% of the HBsAg carrier with MN. Glomerular adhesions to Bowman's capsule were associated with a high incidence of glomerular MAC deposition only in patients with idiopathic MN. Lupus patients had a high incidence of MAC deposition and patients with HBV-related MN had a low incidence of MAC deposition, in both cases regardless of the presence of glomerular capsular adhesions. It is unlikely that deposition of S-protein could inhibit the glomerular damage in idiopathic or lupus MN because significant glomerular capsular adhesions and MAC deposition were observed despite the concomitant glomerular deposition of S-protein. It was concluded that activation of terminal components of complement may play a role in glomerular injuries in idiopathic and lupus MN. The rare occurrence of glomerular MAC deposition in HBV-related MN could be related to its distinct immunopathogenetic mechanism and its indolent clinical course.

Complement Membrane Attack Complex↗
PubMed1989

A serum protein SP40,40 modulates the formation of membrane attack complex of complement on erythrocytes.

SP40,40 was isolated from the soluble membrane attack complex (SC5b-9) by HPLC using a reverse-phase column. Amino acid compositions of its alpha- and beta-subunits were similar to each other with the exception of glycine content. Amino-terminal sequences of its alpha- and beta-subunits were identical to those of the subunits prepared from human serum, respectively, indicating that there was no degradation of SP40,40 during incorporation into SC5b-9. When guinea pig erythrocytes were incubated with C56f, C7, C8 and C9 in the presence of SP40,40, SP40,40 enhanced the hemolysis. The protein, however, inhibited the hemolysis when erythrocytes were pre-incubated with C56f and SP40,40 prior to the addition of C7, C8 and C9. These findings indicate that SP40,40 modulates the formation of membrane attack complex by interacting with C56f at the first step, and that the co-existence of other factors, besides C56f, is required for the enhancing activity of SP40,40.

Amino Acids↗
PubMed1987

Ultrastructural localization of the membrane attack complex of complement in human renal tissues.

Utilizing a monoclonal antibody (Poly C9-MA) to a neoantigen of the C9 portion of the membrane attack complex of complement (MAC), immunoelectron (IEM) and immunofluorescent (IF) microscopy were performed on kidney tissue from normal humans and patients with insulin-dependent diabetes mellitus (IDDM) and type II membrano-proliferative glomerulonephritis (MPGN II). Comparative studies were conducted using polyclonal antibodies to human C3, C5, IgG, IgA, and IgM. In normal human tissue, there was a close correlation between increasing chronologic age and the quantity of MAC deposited in the mesangial stalk, along the interstitial aspect of and within tubular basement membranes (TBMs) and in arteriolar walls. IF of kidney tissues from 12 patients with IDDM with varying degrees of mesangial expansion and glomerulosclerosis demonstrated a direct relationship between the degree of tissue damage and the amount of MAC deposited in the mesangium. IEM of three normal and four diabetic specimens revealed reaction product of Poly C9-MA on linear and circular membranous structures within the mesangium, TBMs, and vessel walls, and within the glomerular basement membranes (GBMs) in diabetic subjects. Evidence is presented that these structures, which have been previously described by routine electron microscopy, represent cellular debris in these loci on which Poly C9-MA has been deposited. In MPGN II, Poly C9-MA and C3 were distributed within subepithelial deposits, along either side of the dense deposits (DDs) within the GBMs and TBMs, and around circular masses of DDs within the mesangium.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗