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PubMed2007

Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice.

We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa-/-) with low-density lipoprotein receptor knockout mice (Ldlr-/-). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa-/-/Ldlr-/- mice compared with Ldlr-/- mice (3.72 +/- 1.0% aortic root versus 1.1 +/- 0.4%; mean +/- SEM, P < 0.001). Furthermore, the cellular composition of lesions in C1qa-/-/Ldlr-/- was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa-/-/Ldlr-/- mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa-/-/Ldlr-/-, whereas apoptotic cells were not detected in Ldlr-/- mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa-/-/Ldlr-/- mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis.

Animals↗
PubMed1995

[Vitronectin in children with renal disease--1. Immunofluorescence study of vitronectin and C5b-9 in childhood IgA nephropathy].

Renal biopsy specimens from 54 children (33 boys, 21 girls) with IgA nephropathy were investigated by immunofluorescence microscopy to determine the localization of vitronectin and C5b-9. vitronectin and C5b-9 deposits were found within the glomeruli of all cases and the intensity of vitronectin and C5b-9 deposits was as follows: vitronectin: (3+) 17 cases, (2+) 21 cases, (1+) 16 cases and C5b-9: (3+) 28 cases, (2+) 18 cases, (1+) 8 cases. In 19 cases and C5b-9 deposits were shown to be more predominant than vitronectin (Group C) and the same or less intense in 35 cases (Group V). In 33 cases, vitronectin deposits were demonstrated in the mesangial area only (M type), while in 21 cases deposits were presented both the mesangial area and the capillary wall (MC type). Linear staining of vitronectin was noted in Bowman's basement membrane and in the tubular basement membrane. Granular staining of vitronectin was observed in Bowman's basement membrane (29 cases) and tubular basement membrane (46 cases). M type C5b-9 deposits were demonstrated in 34 cases and MC type in 20 cases. C5b-9 deposits were observed in Bowman's basement membrane (19 cases) and in tubular basement membrane (37 cases). Intensely stained vitronectin was found in the sclerotic glomeruli and segmental sclerotic portion of the tissues. In serial biopsy, the intensity of both vitronectin and C5b-9 deposits became less intense. It was found that many patients of Group C had heavy proteinuria (P < 0.05) and that nephrotic patients were more frequent in Group C than in Group V (p < 0.05). In the light microscopic examination, most cases with intense C5b-9 deposits had mesangial proliferation (p < 0.10) and an increase in mesangial matrix (p < 0.10). Mesangial sclerosis index was correlated with the intensity of vitronectin deposits (p < 0.05). These findings suggest that vitronectin and the terminal complement system may play a critical role as a mediator of immunological tissue injury, especially mesangial sclerotic lesion in childhood IgA nephropathy.

Adolescent↗
PubMed1992

Activation of the fifth component of human complement, C5, without cleavage, by methionine oxidizing agents.

Purified human C5 was incubated with chloramine T (Cl-T) or N-chloro-succinimide (N-Cl-S) in barbital buffer, pH 7.2. The treatment led to C5 activation: Cl-T- and N-Cl-S-treated C5 acquired a binding site for C6; upon incubation with C6 and subsequent addition of C7, C8 and C9 a membrane attack complex formed which lysed non-sensitized guinea pig red cells (reactive lysis). While the physiological activation of C5 follows its specific cleavage, the resulting fragment C5b representing the activated C5 and expressing the C6 binding site, the treatment with the mentioned chemicals does not lead to fragmentation of the C5 protein. So, functionally, the product of the chemical treatment is C5b-like, but chemically, it comprises the whole protein; no C5a is released. Cl-T and N-Cl-S are known to more or less selectively oxidize methionine residues in proteins, dependent on the conditions. Other sensitive amino acid residues are tryptophan and cysteine. Conditions were chosen for treatment of C5 with Cl-T which exclude attack on tryptophan, and we have ensured that human C5 does not contain free cysteine residues. Further, oxidation of about 60% of the methionine residues of C5 by Cl-T was demonstrated by amino acid analysis. So, all evidence points to methionine residue(s) as the site of attack of Cl-T and probably also of N-Cl-S. The oxidation product of methionine, its sulphoxide, may cause a change in structural conformation of C5 which involves expression of the C6 binding site. Earlier it was found that oxidation of C5 by hydroxyl radicals leads to its activation without cleavage. Since the properties of this C5b-like product resemble those of the product of treatment with Cl-T and N-Cl-S, it is suggested that the formerly found activation of human C5 by hydroxyl radicals is also mediated by oxidation of methionine residue(s) in the C5 protein.

Chloramines↗
PubMed2001

Serum resistance in an invasive, nontypeable Haemophilus influenzae strain.

A common feature of many different organisms causing bacteremia is the ability to avoid the bactericidal effects of normal human serum. In Haemophilus influenzae encapsulated strains are particularly serum resistant; however, we found that a nonencapsulated strain (R2866) isolated from the blood of an immunocompetent child with meningitis who had been successfully immunized with H. influenzae type b conjugate vaccine was serum resistant. Since serum resistance usually involves circumventing the action of the complement system, we defined the deposition of various complement components on the surfaces of this H. influenzae strain (R2866), a nonencapsulated avirulent laboratory strain (Rd), and a virulent type b encapsulated strain (Eagan). Membrane attack complex (MAC) accumulation correlated with the loss of bacterial viability; correspondingly, the rates of MAC deposition on the serum-sensitive strain Rd and the serum-resistant strains differed. Analysis of cell-associated immunoglobulin G (IgG), C1q, C3b, and C5b indicated that serum-resistant H. influenzae prevents MAC accumulation by delaying the synthesis of C3b through the classical pathway. Among the initiators of the classical pathway, IgG deposition contributes most of the C3 convertase activity necessary to start the cascade ending with MAC deposition. Despite similar IgG binding, strain R2866 delays C3 convertase activity compared to strain Rd. We conclude that strain R2866 can persist in the bloodstream, in part by inhibiting or delaying C3 deposition on the cell surface, escaping complement mediated killing.

Bacterial Capsules↗
PubMed1989

Complement binding on serum-sensitive and serum-resistant transformants of Neisseria gonorrhoeae: effect of presensitization with a non-bactericidal monoclonal antibody.

The binding of C3 and C9 on serum sensitive (FA635) and serum resistant (FA638) transformants of serum sensitive Neisseria gonorrhoeae strain F62 was examined. Previous studies showed that these transformants have Protein IAs which are minimally different by proteinase K cleavage and primary structural and peptide mapping and bear LPS which vary slightly on SDS-PAGE. Binding of C3 and C9 on FA635 exceeded binding on FA638 in NHS and in adsorbed NHS. Monoclonal antibody 4G5, which binds to PI on FA638 but not FA635, increases C9 binding on FA638 to levels 3-3.5 fold greater than on FA635 but does not result in killing. The majority of additional 125IC9 deposited on FA638 following presensitization with 4G5 is released from the bacterial surface by trypsin. These results extend our earlier results with N. gonorrhoeae by showing that, although PI monoclonals can lead to substantial deposition of non-bactericidal C5b-9, this C5b-9 is not fully inserted into the gonococcal outer membrane.

Antibodies, Bacterial↗
PubMed1995

The pathogenetic significance of C5b-9 in IgA nephropathy.

Renal biopsies from 20 patients with IgAN were retrospectively studied using monoclonal antibodies against T cells, monocytes/macrophages (MM), HLA-DR-related antigen and the C5b-9 neoantigen. Glomerular C5b-9 deposits were mainly found in the mesangial areas and showed an association with IgA (P < 0.005) and C3 deposits (P < 0.001). Interstitial T cells and MM were highly correlated with the interstitial DR + ve cells (P < 0.001 and P < 0.0005 respectively). Tubular C5b-9 deposition was observed on the tubular basement membranes and related to the numbers of interstitial T cells (P < 0.005), MM (P < 0.005) and DR + ve cells (P < 0.01) as well as to the tubular DR expression (P < 0.025). The severity of tubular atrophy and interstitial fibrosis showed a positive correlation with the interstitial T cells, MM and DR + ve cells, as well as with the intensity of tubular C5b-9 deposition (P < 0.05 and P < 0.05 respectively). Plasma creatinine on presentation was correlated with the numbers of interstitial T cells (P < 0.05), MM (P < 0.01), interstitial DR + ve cells (P < 0.005), and tubular C5b-9 deposits (P < 0.005). No correlation between glomerular T cells, MM, and C5b-9 deposits with plasma creatinine was seen. During follow-up, renal function deteriorated in those patients with the more extensive tubular C5b-9 deposits. In conclusion, glomerular C5b-9 deposition seems to be secondary to the IgA and C3 deposition. In contrast, tubular C5b-9 is related to the numbers of interstitial T cells and MM. Activated interstitial mononuclear cells may lead to the tubular deposition of C5b-9, which eventually might contribute to the development of tubulointerstitial lesions (TIL) and renal function impairment.

Adult↗
PubMed1998

Pathogenesis of glomerular damage in glomerulonephritis.

Although glomerular disease remains the most common cause of end-stage renal disease worldwide, major advances have been made recently in understanding the cellular and molecular mechanisms which mediate these disorders. Nephrotic syndrome in non-inflammatory lesions such as minimal change/focal sclerosis and membranous nephropathy results from disorders of the GEC which can be simulated in animal models by antibodies to various GEC membrane epitopes. Clarification of how these antibodies effect the GEC to induce a loss of glomerular barrier function should substantially improve understanding of the pathogenesis of minimal change/focal sclerosis. In MN, proteinuria is mediated primarily by C5b-9 through similar mechanisms that also involve the GEC as a target and GEC production of oxidants, proteases and TGF beta in response to sublytic C5b-9 attack. C5b-9 also mediates mesangial proliferative glomerulonephritis induced by anti-measangial cell antibodies and thrombotic microangiopathy induced by antibodies to the glomerular endothelial cell. In all of these lesions induced by antibodies to glomerular cells, cell-bound complement regulatory proteins are important in modulating the injury observed. Upregulation of complement regulatory proteins may prove an effective therapeutic manoeuver in the future. Inflammatory glomerular lesions are induced by circulating inflammatory cells or proliferating resident glomerular cells. Understanding of how these cells induce tissue injury has also evolved considerably over the past decade. Neutrophil-induced disease involves leukocyte adhesion molecules in regulating neutrophil localization; proteases, oxidants and MPO in mediating injury and platelets in augmenting these processes. The activated mesangial cell following immune injury exhibits altered phenotype and proliferation with release of oxidants and proteases. Mesangial cell proliferation may be initiated by bFGF and is maintained by an autocrine mechanism involving PDGF. TGF beta is important in the subsequent development of sclerosis. Finally, recent studies establish the nephritogenic potential of cell-mediated mechanisms alone without humoral immunity, and these mechanisms may be important in glomerulonephritis which occurs in the absence of antibody deposits. As understanding of these areas evolves, numerous new therapeutic strategies can now be devised including agents which selectively block or inhibit complement effects, leukocyte adhesion molecules, oxidants, proteases, growth factors and other cytokines and activated T cells. Appreciation of the role of several natural inhibitors of these mechanisms may also allow therapeutic manipulations that upregulate regulatory proteins with a consequent therapeutic benefit. Thus, these changes in basic understanding of the mechanisms of glomerular disease are likely to translate into new and more specific and effective forms of therapy in the next decade.

Antibodies↗
PubMed1989

Effect of complement on the lateral mobility of erythrocyte membrane proteins. Evidence for terminal complex interaction with cytoskeletal components.

The lateral mobilities of erythrocyte membrane proteins and terminal complement complexes (TCC) were measured on C-treated erythrocyte ghosts by the technique of fluorescence redistribution after photobleaching. Results showed that the lateral diffusion coefficient of the bulk membrane proteins decreased with the assembly of TCC on the membrane at low C dose and was significantly reduced with assembly of the full membrane attack complex (C5b-9), even in the absence of cell lysis. At high serum doses, the mobility of the membrane proteins increased slightly above that of the control cells. The diffusion coefficients of the TCC on the erythrocyte membrane range from 1.18 to 4.37 x 10(-11) cm2/s, values characteristic of anchored membrane proteins. Spectrin-depletion of the C-lysed erythrocytes results in 25- and 45-fold increases in the diffusion coefficients of the membrane proteins and the C5b-9 complex, respectively. Conversely, oxidative cross-linking of spectrin by diamide reduced the diffusion coefficients of both membrane and C proteins. These studies indicate that the deposition of TCC on an erythrocyte can result in a substantial change in the physical and structural properties of the target membrane, aside from the creation of functional lesions. The low mobilities of the terminal complexes on the target membrane suggest possible interactions with cytoskeletal elements or with anchored membrane proteins.

Animals↗
PubMed2001

Structure/function of C5 convertases of complement.

C5 convertases are serine proteases that cleave both C3 and C5. Alternative pathway C3/C5 convertases formed with monomeric C3b (C3b,Bb) because of their weak interaction with C5 primarily cleave C3 thereby opsonizing the cell surface with C3b. In contrast, C3/C5 convertases formed with a high density of C3b/cell exhibit higher affinities for C5 as indicated by Km values well below the physiological concentration of C5 in blood. These C3/C5 convertases bind C5 efficiently and cleave it at a velocity approaching Vmax thereby switching the enzyme from C3 cleavage to production of the cytolytic C5b-9 complex. Studies of the structure of C3/C5 convertases have postulated that C4b-C3b and C3b-C3b dimers from high affinity C5 binding sites while indel studies have shown two binding sites in C5 for the convertase in addition to the C5 cleavage site. Together, these studies indicate that with increasing deposition of C3b on the surface, C3b complexes are formed which through multivalent attachment bind the substrate C5 with higher affinities, thereby converting the low affinity C3/C5 convertases to high affinity C5 convertases. The process underlying the formation of high affinity C5 convertases during complement activation is discussed.

Animals↗
PubMed2004

Functional insights from the structure of the multifunctional C345C domain of C5 of complement.

The complement protein C5 initiates assembly of the membrane attack complex. This remarkable process results in lysis of target cells and is fundamental to mammalian defense against infection. The 150-amino acid residue domain at the C terminus of C5 (C5-C345C) is pivotal to C5 function. It interacts with enzymes that convert C5 to C5b, the first step in the assembly of the membrane attack complex; it also binds to the membrane attack complex components C6 and C7 with high affinity. Here a recombinant version of this C5-C345C domain is shown to adopt the oligosaccharide/oligonucleotide binding fold, with two helices packed against a five-stranded beta-barrel. The structure is compared with those from the netrin-like module family that have a similar fold. Residues critical to the interaction with C5-convertase cluster on a mobile, hydrophobic inter-strand loop that protrudes from the open face of the beta-barrel. The opposite, helix-dominated face of C5-C345C carries a pair of exposed hydrophobic side chains adjacent to a striking negatively charged patch, consistent with affinity for positively charged factor I modules in C6 and C7. Modeling of homologous domains from complement proteins C3 and C4, which do not participate in membrane attack complex assembly, suggests that this provisionally identified C6/C7-interacting face is indeed specific to C5.

Amino Acid Sequence↗
PubMed1998

Effect of complement on the rheological properties of the erythrocyte membrane.

The effect of complement (C) on the erythrocyte deformability was investigated. Sheep erythrocytes (E) were sensitized with specific antibodies (A) and treated with various doses of human C. Gravity filtration of unlysed EAC showed a C dose-dependent decrease in whole cell deformability, which was shown to be due to an impairment of the membrane rheological properties. As the fluidity of the lipid bilayer, sensed by a spin label, was not modified, the observed effects should be related to an interaction between C and the cytoskeleton. The influence of C3b and C3d in these processes seems unlikely, as similar hemagglutination titers were found, respectively, for anti-C3c and anti-C3d antisera against the varying EAC. The study of the degree of spontaneous hemolysis of EAC in buffers with solutes of different Stokes radii showed that differing-sized functional C lesions were produced, and that the formation of larger-sized lesions was favored by incubation with higher C doses. These results suggest that the insertion of proteins from the membrane attack complex, C5b-9 (MAC), into the erythrocyte membrane may be responsible for the effect of C on the rheological properties of the erythrocyte membrane.

Animals↗
PubMed1987

Deficiency of the homologous restriction factor in paroxysmal nocturnal hemoglobinuria.

The affected E of two patients with paroxysmal nocturnal hemoglobinuria (PNH) were enriched by lysing the unaffected, normal E with anti-human decay-accelerating factor (DAF) and guinea pig serum. The membranes of the unlysed, DAF-deficient cells (PNH-E) were dissolved and examined by SDS-PAGE and immunoblotting using an antiserum to homologous restriction factor (HRF). Whereas the 65 kD complement regulatory protein was readily detectable in the normal controls, it was completely lacking in both samples of PNH-E membranes. Functional studies likewise indicated the absence of HRF activity from PNH-E. When radiolabeled, isolated HRF protein was offered to PNH-E, it became firmly attached to the cell. Approximately 1,000 molecules of HRF per cell reduced the characteristic susceptibility of these cells to reactive lysis by C5b-9 to nearly normal levels. The results suggest that HRF, which is known to control the action of C8 and C9 on normal human E membranes, is deficient in PNH, as well as acetylcholinesterase and DAF.

Blood Proteins↗
PubMed1995

Immunohistochemical detection of C5b-9(m) in myocardium: an aid in distinguishing infarction-induced ischemic heart muscle necrosis from other forms of lethal myocardial injury.

Immunohistochemical detection of C5b-9(m) is a reliable marker of very early cell necroses due to myocardial infarction. However, it is conceivable that it is also present in myocardial cell necroses caused by other types of hypoxic injury or by direct external trauma. If so, this would greatly limit the diagnostic value of C5b-9(m) in forensic practice. To clarify this issue, we performed immunohistological staining for C5b-9(m) in myocardium of 67 cases of 'direct' or possible 'indirect' myocardial injury not due to infarction.

Adult↗
PubMed1977

The SC5b-7 complex: formation, isolation, properties, and subunit composition.

Activation of C in C8-depleted serum results in the formation of a soluble complex containing C5, C6, and C7. The complex has an electrophoretic mobility of an alpha-globulin, an s-rate of 18.5S, and a m.w. of 668,000 daltons. This complex was isolated and upon SDS polyacrylamide gel electrophoresis it was found to contain, in addition to C5b, C6 and C7, an 88,000 dalton glycoprotein. The protein was identified as the band V protein of the soluble C5b-9 complex. It is referred to as SIIIs-protein, or S-protein. Since the S-protein does not bind to C5b-6, it is concluded that it is incorporated during the fusion of C5b-6 with C7. The SC5b-7 complex exhibits the same neoantigen as the SC5b-9 complex, but compared to the C5b-6 complex it appears to contain an additionally qualitatively distinct neoantigen.

Animals↗
PubMed1999

Sublytic C5b-9 induces proliferation of human aortic smooth muscle cells: role of mitogen activated protein kinase and phosphatidylinositol 3-kinase.

Proliferation of vascular smooth muscle cells contributes to initimal hyperplasia during atherogenesis, but the factors regulating their proliferation are not well known. In the present study we report that sublytic C5b-9 assembly induced proliferation of differentiated human aortic smooth muscle cells (ASMC) in culture. Cell cycle re-entry occurred through activation of cdk4, cdk2 kinase and the reduction of p21 cell cycle inhibitor. We also investigated if C5b-9 cell cycle induction is mediated through activation of mitogen activated protein kinase (MAPK) pathways. Extracellular signal regulated kinase (ERK) 1 activity was significantly increased, while c-jun NH2-terminal kinase (JNK) 1 and p38 MAPK activity were only transiently increased. Pretreatment with wortmannin inhibits ERK1 activation by C5b-9, suggesting the involvement of phosphatidylinositol 3-kinase (PI 3-kinase). Both PI 3-kinase and p70 S6 kinase were activated by C5b-9 but not by C5b6. C5b-9 induced DNA synthesis was abolished by pretreatment with inhibitors of ERK1 and PI 3-kinase, but not by p38 MAPK. These data indicated that ERK1 and PI 3-kinase play a major role in C5b-9 induced ASMC proliferation.

Androstadienes↗
PubMed1996

The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis.

Although microvascular injury has been postulated as the pathogenetic basis of skeletal muscle injury in dermatomyositis (DM), its role in the genesis of the skin lesions, which are said to be difficult to distinguish light microscopically from systemic lupus erythematosus (SLE) and subacute lupus erythematosus (SCLE), has not been analyzed. The authors' intention was to assess the role of microvascular injury in the pathogenesis of skin lesions in DM, SLE, and SCLE. Light microscopic features of biopsies of lesional skin from 20 patients with myopathic DM and 11 with amyopathic DM were compared to eight lesional skin biopsies from eight patients with SLE and 12 lesional skin biopsies from 12 patients with SCLE. Vascular density was compared in the three groups using an immunohistochemical preparation with an antibody to factor VIII. In 12 biopsies from the DM group, and in 19 of 20 lupus erythematosus (LE) specimens, frozen tissue was available. An indirect immunofluorescence methodology was used to detect C5b-9 deposition, and direct immunofluorescence studies for other immunoreactants were performed in standard fashion. Compared with LE, lesions of DM showed a greater degree of endothelial injury, vascular ectasia, and vascular fibrin deposition; there were no differences between myopathic versus amyopathic DM. C5b-9 deposition in vessels was significantly greater in DM than in LE. The superficial vascular plexus density was reduced in lesions of DM versus LE control groups with the greatest reduction observed in myopathic DM. Epithelial injury and mucin was greatest in myopathic DM. Microvascular injury is the apparent pathophysiological basis of skin lesions in DM. Careful attention to microvascular pathology enables distinction of DM from SLE and SCLE. Indirect immunofluorescence testing using a monoclonal antibody to C5b-9 is a valuable tool to distinguish DM from LE in biopsies of lesional skin.

Adult↗
PubMed1999

Immunohistologic evaluation of mechanisms mediating hyperacute lung rejection, and the effect of treatment with K76-COOH, FUT-175, and anti-Gal column immunoadsorption.

Although most investigators agree that lung dysfunction occurs rapidly in various pig-to-primate hyperacute lung rejection (HALR) models, the basic mechanisms mediating this phenomenon remain in question. Here we describe an immunohistochemical method for assessment of mechanisms driving HALR. Using an established model wherein piglet lungs are perfused ex vivo with human blood, six experimental groups (K76 COOH; FUT-175; K76 with FUT; anti-alpha-Gal column adsorption; column with FUT; and column with K76) and two control groups (unmodified human blood; autologous pig blood) were studied. Each lung was biopsied serially during perfusion, and assessed using an immunohistochemical technique, with vWF staining as an internal control to quantitate binding of human IgM, IgG, C3, C5b-9, properdin, and C1q. The effect of each treatment and subsequent lung perfusion on IgG and IgM anti-alpha-Gal titers(by ELISA) and on pig endothelial cell cytotoxicity were correlated with histologic findings. We found that [1] the classical complement activation pathway was activated, as has been shown for other pig organs in primate or human blood environments [2]; alternative complement pathway activation is also seen, which has not been described for other organs in pig-to-primate models, but only in the context of classical pathway activation; and [3] anti-Gal column absorption, pharmacologic inhibition of complement, or combination therapy each was associated with histologic evidence of partial protection, consistent with what would be predicted for each intervention. Further, immunohistologic differences correlated with physiologic outcomes [8] and with antibody assay results, and revealed that treatments used were incompletely effective. Our data suggest that more complete inhibition of antibody- and complement-driven pathways than was achieved in these experiments will be necessary to prevent the antibody and complement-mediated facets of hyperacute lung rejection. This immunohistologic technique may also help us identify additional pathogenic mechanisms important to eventual clinical application of pig-to-human lung xenografts.

Acute Disease↗
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↗