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PubMed1998

Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgA-N) is considered the most common glomerular disease in the world and leads to renal failure in a substantial number of patients. Although many studies have looked at the pathogenesis of the disease, many points need to be clarified, including the mechanism of complement activation. Recent studies have shown that mannose-binding lectin (MBL or mannose binding protein, MBP) initiates activation of the complement cascade (lectin pathway) utilizing two types of MBP-associated serine protease, namely MASP-1 and MASP-2. The present study was undertaken to elucidate whether the lectin pathway was involved in the pathogenic mechanism of IgA-N. METHODS: Forty-five renal biopsy cases with IgA-N, 35 cases with other forms of glomerulonephritis (GN), and normal kidney tissues were collected and an immunohistochemical study was performed using monoclonal antibodies against MBL and MASP-1. Furthermore, clinicopathological and serological features were also analysed in the patients with IgA-N. RESULTS: Glomerular deposition of MBL, which was accompanied by MASP-1, was detected in 11 of 45 (24.4%) cases with IgA-N, while it was detected in only one case with other forms of GN. The deposited MBL/MASP-1 was observed to associate with C3b/C3c and C5b-9 but not with IgG, IgM, C1q, C4c, or properdin. Compared with MBL/MASP-1 negative cases with IgA-N, the positive cases with IgA-N were young and the renal biopsies had been performed at an early stage of the disease. No significant correlation was found between glomerular deposition of MBL/MASP-1 and proteinuria, haematuria, creatinine clearance, and serum levels of IgA, C3, or C4 at the time of renal biopsy. There were also no significant differences between MBL/MASP-1 positive cases and negative cases in the plasma levels of circulating immune complexes or soluble C5b-9. CONCLUSION: The lectin pathway of complement activation, which is initiated by the MBL/MASPs complex, evidently contributes to the development of glomerular injury in a significant number of cases with IgA-N. In addition, these findings will add insight to the pathogenesis of IgA-N, including its relation to infection, since MBL plays a crucial role in the host defense against various pathogens.

Adolescent↗
PubMed1994

Henoch-Schönlein purpura.

Henoch-Schönlein purpura (HSP) is the most common vasculitis syndrome of childhood. It is also known as anaphylactoid purpura, leukocytoclastic vasculitis, allergic vasculitis, and rarely, as rheumatoid purpura. It is generally a benign, self-limited disorder that follows an intercurrent illness, usually of the upper-respiratory tract. The classic triad of clinical symptoms and signs includes purpuric rash, abdominal cramping, and hematuria, but the spectrum of the clinical expression of HSP may vary from only minimal petechial rash to severe gastrointestinal, renal, neurologic, pulmonary, and joint disease. Most children have self-limited disease, and on long-term follow-up, systemic involvement or serious sequelae are not frequent. The current lack of knowledge about the factors underlying both the etiology and pathogenesis and the extent of clinical expression of HSP is illustrated in the recent literature. In addition, there is no agreement regarding the role of corticosteroids in the clinical management of HSP, and this subject has not received adequate attention during the past year. The recent clinical literature emphasizes the distinction between HSP and other hypersensitivity vasculitides and provides several in-depth reviews and multiple case reports illustrating the expanding clinical spectrum of the disorder. Exciting developments regarding immunologic aspects of HSP have been published and are summarized. The utility of antineutrophil cytoplasmic antibody as it applies to HSP remains to be elucidated.

Adrenal Cortex Hormones↗
PubMed1994

Formation of the terminal complement complex on agarose beads: further evidence that vitronectin (complement S-protein) inhibits C9 polymerization.

Vitronectin occupies the metastable binding site of C5b-7, which is unable to insert membranes as part of the complement lytic attack. Some evidence has been presented that vitronectin inhibits also membrane-associated pore formation by inhibiting C9 polymerization in the terminal complement complex (TCC). The authors wished to add to this background by studying the effect of vitronectin on formation of TCC on a carbohydrate surface like agarose beads, an alternative complement pathway activator. Bound TCC was detected by monoclonal and polyclonal antibodies to C9-neoepitopes. Soluble SC5b-7 and TCC (SC5b-9) did not bind to the agarose beads. Using serum or isolated complement factors for the alternative and terminal pathways, the authors found that vitronectin reduced the density of C9-neoepitopes on the beads. As there was no convincing evidence for association of vitronectin with the factors C5b-8 of the agarose-bound TCC, it was concluded that vitronectin bound directly to C9 in TCC and inhibited C9 polymerization within the complex. The authors have shown that TCC can bind to a carbohydrate surface like agarose (an alternating polymer of galactose moieties) in the absence of lipid. These results suggest that vitronectin can limit the lytic effect of membrane-bound TCC by inhibiting C9 polymerization.

Animals↗
PubMed1991

Synovial fluid levels of complement SC5b-9 and fragment Bb are elevated in patients with rheumatoid arthritis.

To determine whether complement turnover in synovial fluids of patients with rheumatoid arthritis (RA) reflects activation by the classical or alternative pathway, we used novel immunoassays to measure products of complement activation (the membrane attack complex SC5b-9 and the cleavage fragments Bb and C4d). Mean synovial fluid levels of SC5b-9 were more than 8 times higher in RA than in crystal-induced arthritis (gout and pseudogout) and over 16 times higher than in degenerative joint disease (DJD). Similarly, Bb levels were more than 3 times higher in RA synovial fluids than in crystal-induced arthritis and over 7 times higher than in DJD. Levels of C4d did not differ among the groups. SC5b-9 levels correlated with synovial fluid C3 anaphylatoxin (C3a), Bb, and C4d levels (r = 0.81, 0.62, and 0.51, respectively). In patients with RA, synovial fluid SC5b-9 levels correlated with C3a and Bb (r = 0.6 and 0.56, respectively) but not with C4d. Therefore, novel assays for complement activation indicate that both classical and alternative pathways are involved in complement turnover and that the alternative pathway contributes more to complement activation in RA than in DJD or crystal-induced arthritis.

Arthritis, Rheumatoid↗
PubMed2006

Functional studies of the MACPF domain of human complement protein C8alpha reveal sites for simultaneous binding of C8beta, C8gamma, and C9.

Human C8 is one of five components of the membrane attack complex of complement (MAC). It contains three subunits (C8alpha, C8beta, C8gamma) arranged as a disulfide-linked C8alpha-gamma dimer that is noncovalently associated with C8beta. C8alpha, C8beta, and complement components C6, C7, and C9 form the MAC family of proteins. All contain N- and C-terminal modules and an intervening 40-kDa segment referred to as the membrane attack complex/perforin (MACPF) domain. During MAC formation, C8alpha binds and mediates the self-polymerization of C9 to form a pore-like structure on target cells. The C9 binding site was previously shown to reside within a 52-kDa segment composed of the C8alpha N-terminal modules and MACPF domain (alphaMACPF). In the present study, we examined the role of the MACPF domain in binding C9. Recombinant alphaMACPF and a disulfide-linked alphaMACPF-gamma dimer were successfully produced in Escherichia coli and purified. alphaMACPF was shown to simultaneously bind C8beta, C8gamma, and C9 and form a noncovalent alphaMACPF.C8beta.C8gamma.C9 complex. Similar results were obtained for the recombinant alphaMACPF-gamma dimer. This dimer bound C8beta and C9 to form a hemolytically active (alphaMACPF-gamma).C8beta.C9 complex. These results indicate that the principal binding site for C9 lies within the MACPF domain of C8alpha. They also suggest this site and the binding sites for C8beta and C8gamma are distinct. alphaMACPF is the first human MACPF domain to be produced recombinantly and in a functional form. Such a result suggests that this segment of C8alpha and corresponding segments of the other MAC family members are independently folded domains.

Binding Sites↗
PubMed2002

A possible role for complement in the pathogenesis of chronic chagasic cardiomyopathy.

The membrane attack complex (MAC) of complement participates in several inflammatory and proliferative processes by releasing pro-inflammatory cytokines and growth factors from target cells. Chronic Chagasic cardiomyopathy (CCH) is a parasitic dilated cardiopathy, characterized by severe fibrosis and inflammation, which differs from idiopathic dilated cardiomyopathy (DCM). Trypanosoma cruzi, the pathogenic organism of CCH, is a strong complement activator and can also induce alternative pathway activation by mammalian cells. This study explored whether the myocardium in CCH patients has increased MAC deposition, an expression of complement activation, compared to DCM patients. MAC was semi-quantified in endomyocardial human samples (29 CCH subjects, 18 DCM subjects, and four controls) by immunohistochemistry. MAC was present in the sarcolemma of 38% of CCH, 5.5% of DCM (p<0.02), and 0% of controls, and in interstitial inflammatory cells of CCH. No difference was observed in the expression of the complement regulatory protein CD59, indicating that increased MAC deposition is likely to be the result of complement activation rather than decreased protection. It is proposed that the increased MAC deposition found in CCH, but not in DCM or controls, may help to explain the diffuse myocardial fibrosis and inflammation characteristic of the disease.

Adult↗
PubMed1990

Isolation and characterization of a membrane-attack-complex-inhibiting protein present in human serum and other biological fluids.

We have previously reported the isolation of a membrane-attack-complex-inhibiting protein (MIP) from human erythrocyte membranes [Watts, Patel & Morgan (1987) Complement 4, 236] and the production of polyclonal antibodies to this protein. Here we report the identification in plasma, urine, saliva and cerebrospinal fluid of a protein immunochemically identical with the membrane-derived MIP. The protein has been isolated from plasma by immunoaffinity chromatography on an anti-(erythrocyte MIP)-Sepharose column and shown by SDS/polyacrylamide-gel electrophoresis to be of similar molecular mass to the erythrocyte protein (55 kDa non-reduced and 65 kDa under reducing conditions). Monoclonal antibodies have been raised against plasma MIP and used to establish a two-site enzyme-linked immunoadsorbent assay, enabling quantification of MIP in plasma, urine and cerebrospinal fluid. Plasma MIP, though not able to incorporate spontaneously into membranes, was deposited on heterologous and homologous erythrocyte membranes during complement activation in a C8-dependent manner. Depletion of MIP from plasma resulted in enhancement of the lytic capacity of the plasma on heterologous erythrocytes.

Animals↗
PubMed1986

Complement-induced glomerular epithelial cell injury. Role of the membrane attack complex in rat membranous nephropathy.

In passive Heymann nephritis (PHN) in rats, antibody (anti-Fx1A) reacts in situ with a glomerular epithelial antigen and induces complement (C)-mediated cell-independent proteinuria. To assess the role of the membrane attack complex (MAC), we determined the need for C8 in the pathogenesis of proteinuria in an autologous-phase model of PHN. Isolated rat kidneys, containing nonnephritogenic, non-C-fixing gamma 2 sheep anti-Fx1A (planted antigen), when perfused in vitro with C-fixing guinea pig anti-sheep IgG and a source of C (fresh human plasma 50% vol/vol in buffer containing bovine serum albumin), developed marked proteinuria after 20 min (0.58 +/- 0.08 mg/min X g, n = 8) that increased further to 3.20 +/- 0.93 mg/min X g after 80 min. In contrast, identical kidneys perfused with antibody and heat-inactivated or C8-deficient human plasma and normal kidneys perfused with antibody and fresh plasma excreted only 0.27 +/- 0.03 (n = 6), 0.27 +/- 0.04 (n = 5), and 0.40 +/- 0.05 mg/min X g (n = 6) after 20 min, and 0.13 +/- 0.02, 0.22 +/- 0.03, and 0.32 +/- 0.05 mg/min X g after 80 min, respectively. When C8-deficient plasma was reconstituted with sources of C8 (n = 3), proteinuria was restored to the level observed with fresh normal plasma. Differences in protein excretion could not be explained by quantitative differences in glomerular antigen or antibody content. Extensive ultrastructural damage to glomerular visceral epithelial cells was exclusively seen in antigen-containing kidneys perfused with antibody and C8-replete plasma. Thus, glomerular injury in this model results from an antigen-specific, antibody-directed, C8-dependent reaction involving assembly of the MAC. The ultrastructural findings argue in favor of MAC-induced cytotoxicity of the glomerular visceral epithelial cells.

Animals↗
PubMed1995

Membrane attack complex in thickened cutaneous sensory nerves of leprosy patients.

Membrane attack complex (MAC) is a terminal end product produced as a result of complement activation. The deposition of MAC, in tissues, is known to have a local tissue damaging effect in several clinical conditions. Therefore, an attempt was made to demonstrate MAC in peripheral nerve biopsies, collected from leprosy patients. Interestingly, we could demonstrate deposition of MAC in involved cutaneous sensory nerves from most of the lepromatous leprosy patients. Contrary to this, majority of nerve biopsies from tuberculoid leprosy patients did not stain for MAC. Though MAC positive sections showed reactivity for S-protein, our observations support the possibility that MAC, either acting directly or indirectly, may be implicated in nerve damage, at least, in lepromatous leprosy patients.

Antigens, Bacterial↗
PubMed2004

Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes.

Micro- and macrovascular diseases are major causes of morbidity and mortality in the diabetic population, but the cellular and molecular mechanisms that link hyperglycemia to these complications remain incompletely understood. We proposed that in human diabetes, inhibition by glycation of the complement regulatory protein CD59 increases deposition of the membrane attack complex (MAC) of complement, contributing to the higher vascular risk. We report here 1) the generation and characterization of an anti-glycated human CD59 (hCD59) specific antibody, 2) the detection with this antibody of glycated hCD59 colocalized with MAC in kidneys and nerves from diabetic but not from nondiabetic subjects, and 3) a significantly reduced activity of hCD59 in erythrocytes from diabetic subjects, a finding consistent with glycation inactivation of hCD59 in vivo. Because hCD59 acts as a specific inhibitor of MAC formation, these findings provide a molecular explanation for the increased MAC deposition reportedly found in the target organs of diabetic complications. We conclude that glycation inactivation of hCD59 that leads to increased MAC deposition may contribute to the extensive vascular pathology that complicates human diabetes.

Aged↗
PubMed1998

Pathogenesis of leukocytoclastic vasculitis.

There is compelling animal and human experimental evidence that leukocytoclastic vasculitis is a hypersensitivity vasculitis, similar in nature to the experimental Arthus reaction. The immune complexes formed in antigen excess circulate until some event occurs that cause deposition in blood vessel walls. Adhesion molecules and cytokines released by endothelial cells and activated neutrophils represent a key factor in this process. The membrane attack complex of complement plays a significant role in altering the endothelial cell membrane integrity. Activated neutrophils release proteolytic enzymes, especially collagenases and elastases, along with free oxygen radicals that damage the vessel walls and the surrounding tissues. It remains uncertain whether antineutrophilic cytoplasmic antibodies, anti-endothelial antibodies and anti-cardiolipin antibodies are epiphenomena or are directly involved in the disease process. Apoptotic cell death mediated by the Fas/Bc12 system is a feature of leucocytoclastic vasculitis. In conclusion, the post-capillary venule is the active orchestrator of neutrophils in leukocytoclastic vasculitis which mediate a complex series of endothelial/leukocyte interactions.

Antibodies, Anticardiolipin↗
PubMed1987

Structural requirements for the neutralization of heparin-like saccharides by complement S protein/vitronectin.

S protein, a major inhibitor of the assembly of the membrane attack complex of complement, has recently been shown to be identical to the serum spreading factor vitronectin. It also neutralizes the anticoagulant activities of heparin. We have studied the structural requirements for the heparin neutralizing properties of S protein/vitronectin using heparin, heparan sulfate, and heparin oligosaccharides with well defined anticoagulant specificities. The abilities of heparin fractions, Mr 7,800-18,800, with high affinity for antithrombin, and of the International Heparin Standard, to accelerate the inactivation of thrombin and Factor Xa by antithrombin were readily neutralized by S protein/vitronectin. Binding and neutralization of heparin by S protein/vitronectin was inhibited by heparin with low affinity for antithrombin, indicating that S protein/vitronectin can interact with a region on the heparin chain that might serve as a proteinase binding site. S protein/vitronectin efficiently neutralized oligosaccharides of Mr 2,400-7,200, unlike the two other physiologically occurring heparin neutralizing proteins histidine-rich glycoprotein and platelet factor 4. Furthermore, S protein/vitronectin neutralized the anti-Factor Xa activity of a synthetic pentasaccharide comprising the antithrombin-binding sequence of heparin. High molar excess of a synthetic tridecapeptide corresponding to part (amino acids 374-359) of the proposed glycosaminoglycan binding domain of S protein/vitronectin neutralized high affinity heparin and some oligosaccharides, but failed to neutralize the synthetic antithrombin-binding pentasaccharide. Like platelet factor 4, but unlike histidine-rich glycoprotein, S protein/vitronectin readily neutralized the anticoagulant activities of heparan sulfate of Mr approximately 20,000. These findings suggest that S protein/vitronectin may interact through its glycosaminoglycan binding domain(s) with various functional domains of the heparin (heparan sulfate) molecule, including the antithrombin-binding pentasaccharide sequence. Furthermore, the results suggest that S protein/vitronectin may be a physiologically important modulator of the anticoagulant activity of heparin-like material on or near the vascular endothelium.

Antithrombins↗
PubMed1984

Molecular weight of poly(C9). 12 to 18 C9 molecules form the transmembrane channel of complement.

Poly(C9), the tubular 27 S complex forming the transmembrane channel of the membrane attack complex of complement, was purified to homogeneity by gel filtration and sucrose density gradient ultracentrifugation. The molecular weight of poly(C9) was determined by two independent methods in addition to sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. First, sedimentation equilibrium analysis using 0.2% SDS or 1% deoxycholate containing buffer as solvents yielded a point weight average molecular weight exclusive of bound detergent of 0.9 to 1.3 X 10(6) and a weight average molecular weight of all poly(C9) complexes of 1,050,000 +/- 40,000 (S.D.). SDS and deoxycholate binding to poly(C9) was measured in an air-driven ultracentrifuge and was determined to be 0.53 +/- 0.065 (S.D.) g of SDS and 0.26 +/- 0.015 (S.D.) g of deoxycholate/g of poly(C9), respectively. Second, the mass of 27 S poly(C9) devoid of bound detergent was determined by electron scattering of unstained specimens in the scanning transmission electron microscope. The molecular weight obtained by this method was 1,078,000 +/- 194,000. The inner diameter of poly(C9) tubules imaged in top view projections by negative staining electron microscopy varied between 9 and 12 mm. The accumulated data suggest a true heterogeneity of the molecular weight of poly(C9) due to polymers with varying protomer numbers. Using a mean value of 73,500 for the molecular weight of monomeric C9, the protomer number of poly(C9) tubules appear to vary between 12 and 18 C9 subunits. Approximately 50-75% of the tubules have 14 to 16 subunits as deduced from the mass distribution determined by electron scattering and from ring size measurements. It is suggested that poly(C9) tubules with various protomer numbers may arise due to limited flexibility in the C9-C9 interaction.

Complement C9↗
PubMed2001

Targeted deletion of the CD59 gene causes spontaneous intravascular hemolysis and hemoglobinuria.

The glycolipid-anchored glycoprotein CD59 inhibits assembly of the lytic membrane attack complex of complement by incorporation into the forming complex. Absence of CD59 and other glycolipid-anchored molecules on circulating cells in the human hemolytic disorder paroxysmal nocturnal hemoglobinuria is associated with intravascular hemolysis and thrombosis. To examine the role of CD59 in protecting host tissues in health and disease, CD59-deficient (CD59(-/-)) mice were produced by gene targeting in embryonic stem cells. Absence of CD59 was confirmed by staining cells and tissues with specific antibody. Despite the complete absence of CD59, mice were healthy and fertile. Erythrocytes in vitro displayed increased susceptibility to complement and were positive in an acidified serum lysis test. Despite this, CD59(-/-) mice were not anemic but had elevated reticulocyte counts, indicating accelerated erythrocyte turnover. Fresh plasma and urine from CD59(-/-) mice contained increased amounts of hemoglobin when compared with littermate controls, providing further evidence for spontaneous intravascular hemolysis. Intravascular hemolysis was increased following administration of cobra venom factor to trigger complement activation. CD59(-/-) mice will provide a tool for characterizing the importance of CD59 in protection of self tissues from membrane attack complex damage in health and during diseases in which complement is activated.

Animals↗
PubMed2000

Detection of activated complement complex C5b-9 and complement receptor C5a in skin biopsies of patients with systemic sclerosis (scleroderma).

OBJECTIVE: Upregulated matrix synthesis is a hallmark of systemic sclerosis (SSc). There are indications that growth factors such as platelet derived growth factor (PDGF) are involved in proliferative pathways in SSc lesions. As activated complement releases PDGF from endothelial cells, we searched for activated complement and the complement receptor for C5a (C5aR) in skin biopsies of patients with SSc. METHODS: Snap frozen sections of 8 patients with early SSc and 5 patients with longterm SSc were examined. Using monoclonal antibodies against activated complement complex C5b-9 and the C5aR, skin biopsies derived from both clinically involved and non-involved skin were examined by APAAP immunohistochemistry. RESULTS: A pattern of activated complement C5b-9 and the CSaR could be detected in SSc microvasculature. Eleven of the 13 patients (7/8 patients with early SSc) showed positive staining for C5b-9. The CSaR was detected in 6 of the 8 patients with early SSc. In 3 patients with longterm disease, C5aR expression could also be detected in non-involved skin. CONCLUSION: Activated complement and complement receptors could be detected in early and late stages of SSc skin lesions. The presence of complement receptors in non-involved skin may indicate preclinical activation of pathways resulting in growth factor dependent matrix synthesis.

Antigens, CD↗
PubMed1994

Aeromonas salmonicida resistance to complement-mediated killing.

The resistance of Aeromonas salmonicida to complement-mediated killing was investigated by using different strains and their isogenic mutants that had been previously characterized for their surface components. We found that the classical complement pathway is involved in serum killing of susceptible A. salmonicida strains, while the alternative complement pathway seems not to be involved. All of the A. salmonicida strains are able to activate complement, but the smooth strains (with or without the A-layer) are resistant to complement-mediated killing. The reasons for this resistance are that C3b may be bound far from the cell membrane and that it is rapidly degraded; therefore, the lytic final complex C5b-9 (membrane attack complex) is not formed. Isogenic rough mutants are serum sensitive because they bind more C3b than the smooth strains, and if C3b is not completely degraded, then the lytic complex (C5b-9) is formed.

Aeromonas↗
PubMed1992

CD59 expressed by human endothelial cells functions as a protective molecule against complement-mediated lysis.

CD59 is a 18-20-kDa membrane glycoprotein that inhibits formation of the membrane attack complex of complement (C) on homologous cells. In the present study we analyzed the expression and function of CD59 on human endothelial cells. Immunohistochemical analysis of renal cortex demonstrated a predominant expression of CD59 on peritubular capillary endothelial cells and glomerular endothelial cells. Flow cytometry analysis showed that human umbilical vein endothelial cells (HUVEC) expressed CD59 and the fluorescence intensity was approximately four times that of peripheral blood lymphocytes. CD59 is detected on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a single 20-kDa molecule in 2% deoxycholate extracts of HUVEC. CD59 was released from the surface of HUVEC by phosphatidylinositol-specific phospholipase C, demonstrating that it is attached to the cell membrane by means of a glycolipid anchor. The functional activity of CD59 expressed on HUVEC was studied. Blocking of CD59 antigen with F(ab')2 fragments of polyclonal anti-CD59 enhanced markedly the susceptibility of HUVEC to C-mediated lysis. This effect was dependent on the amount of blocking antibodies added. Northern blot analysis revealed the presence of three species of mRNA expressed in HUVEC, which hybridized to a cDNA probe specific for CD59, with sizes of about 800, 1400 and 2000 bp. These findings suggest that CD59 may be important in protection of endothelial cells against C-mediated damage at local sites of inflammation, thereby maintaining the vascular integrity in vivo.

Antigens, CD↗
PubMed1997

Glomerular handling of immune complex in the acute phase of active in situ immune complex glomerulonephritis employing cationized ferritin in rats. Ultrastructural localization of immune complex, complements and inflammatory cells.

The ultrastructural localization of immune complex (IC) and inflammatory mediator systems in the glomerulus was investigated in active in situ IC glomerulonephritis employing cationized ferritin in rats. Glomerulonephritis was induced by unilateral renal perfusion of cationized ferritin as antigen (Ag) in preimmunized rats, and anti-ferritin antibody (Ab), C3 and the rat C5b-9 complex were localized by means of immunogold electron microscopy. Ag-Ab complexes were initially formed subendothelially, associated with C3, and attracted platelets, polymorphonuclear leucocytes (PMN) and monocytes. Then Ag-Ab complexes, without C3, passed across the glomerular basement membrane to re-aggregate subepithelially accompanied by C3 deposition after 1 day. Ag-Ab complexes without C3 accumulated in the inter-podocyte space within 1 day and were seen in the epithelial cells at 6 h. C5b-9 complexes were found in subepithelial immune deposits and in membrane vesicles of the epithelial cells, but only in very small amounts in subendothelial immune deposits. Accumulated platelets, PMN, and monocyte were in direct contact with endothelial cells or subendothelial IC. PMN and monocytes contained Ag, Ab and C3 in intracytoplasmic vacuoles. Ag-Ab complexes were also found in the mesangial matrix adjacent to the subendothelial region after 2 h and increased slightly in number, with expansion of the mesangial area thereafter. Most ICs formed in the subendothelial space rapidly formed lattices of a size that activated C3 and were then translocated to the subepithelial space. The potential ability of C3 to solubilize ICs in the subendothelial region may be important in this process. Endocytosis of subendothelial ICs by PMN and/or monocytes and the movement of ICs to the mesangial matrix may also contribute to the removal of IC from the subendothelial space.

Acute-Phase Reaction↗