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PubMed1995

X-linked vacuolated myopathy: complement membrane attack complex on surface membrane of injured muscle fibers.

We describe a probable recessive X-linked myopathy characterized by the presence of vacuolated muscle fibers. Four males and their shared maternal grandfather were affected. Clinical characteristics include juvenile onset, very slow progression, and predominant proximal muscle involvement. The clinical picture and the morphological findings are compared with those previously described in a family. By immunofluorescence, all histologically abnormal muscle fibers, in particular those vacuolated, showed a strong deposition of the complement C5b-9 membrane attack complex over the whole muscle fiber surface. Weak immunostaining for membrane attack complex was also found in endomysial capillaries and perimysial vessel walls. Muscle fibers showed sarcolemmal immunolabeling with anti-major histocompatibility complex I, which was also present on the margins of many vacuoles. All vacuoles were stained by antidystrophin antibody, which colocalized in most of them with antilaminin immunostaining. Taken together, these results suggest that the deposition of membrane attack complex on the damaged cell surface membrane could be important in the pathogenesis of this muscle disorder, and that the membrane-bounded vacuoles could be a consequence of sarcolemmal invagination.

Adult↗
PubMed1996

Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis)

The molecular pathogenesis of human membranous nephropathy (MN) is unknown, despite the relatively high incidence and severity of this glomerular immune disease. Heymann nephritis (HN) in rats is considered an instructive experimental model of MN. This study summarizes current molecular aspects of two key events common to both MN and HN, i.e., formation of characteristic subepithelial immune deposits in the glomerular basement membrane (GBM), and development of glomerular capillary wall damage resulting in proteinuria. In HN, the antigenic targets of immune deposit-forming antibodies were identified in cell membranes of glomerular epithelial cells as a 515-kd glycoprotein (megalin, or gp330), which is a polyspecific receptor related to the low-density lipoprotein receptor family, and an associated 44-kd protein (receptor associated protein, RAP). One epitope was recently narrowed to 14 amino acids in RAP, and several others on megalin/gp330 are under investigation. Proteinuria requires formation of the complement C5b-9 membrane attack complex, which is presumably triggered by antibodies directed against lipid antigens that associate with immune deposit-forming megalin/gp330 immune complexes. Sublytic C5b-9 attack on glomerular epithelial cells causes upregulation of expression of the NADPH oxidoreductase enzyme complex by glomerular cells, which is translocated to their cell surfaces, similar to activated neutrophil granulocytes in the respiratory burst reaction. Subsequently, reactive oxygen species (ROS) are produced locally, which reach the GBM matrix. Here formation of lipid peroxidation (LPO) adducts is found, preferentially on monomeric and dimerized NCl domains of covalently crosslinked Type IV collagen. These structural changes within the GBM could be of functional relevance because treatment with the potent LPO-antagonist probucol reduces proteinuria by < 80%. Intact or fragmented apoprotein E-containing lipoproteins were identified as potential sources of the polyunsaturated lipids required for the production of LPO adducts. Lipoproteins accumulate within immune deposits and show signs of oxidative damage, similar to oxidized LDL within atherosclerotic lesions. Collectively, the results obtained so far in HN permit the compilation of a sequence of events, linking formation of immune deposits with proteinuria. However, despite this relatively detailed knowledge of pathogenic events in HN, the bridge to human NM remains to be built.

Animals↗
PubMed1993

The application of selected histochemical and immunohistochemical markers and procedures to the diagnosis of early myocardial damage.

Histochemical (= HIS) methods (haematoxylin-eosin, luxol fast blue, chromotrope aniline blue) and various immunohistochemical (= IH) markers (myoglobin, desmin, fibrinogen, complement C5b-9) were applied in parallel to test the efficiency, specificity and sensitivity for the recognition of early ischemic myocardial damage. The whole series was subgrouped into cardiac deaths (N = 35) and controls (N = 13). Cardiac deaths were sub-divided into 3 groups: 1. infarction visible in gross examination (N = 15), 2. coronary thrombosis without infarction (N = 11), 3. stenosing coronary atherosclerosis without infarction (N = 9). The control group (group 4) consisted of unnatural deaths with presumed short agonal periods (N = 13). Group 1 cases usually exhibited extended coagulation necrosis of the diffuse type and the contraction type in combination (1 exception). Group 2 showed mainly a patchy type of coagulation necrosis and contained 1 cases where all methods failed to react and 3 more cases where only the HIS methods failed to react. Group 3 and 4 were associated with a disseminated type of single and/or grouped fibre necrosis. In addition, the average reaction strengths showed a decrease from group 1 to group 4 which was more pronounced in the HIS reactions compared with the IH reactions. One case in group 1 showing negative IH reactions cannot be explained. Positive IH reactions observed in a few cases in group 2 contrasting with negative HIS reactions would indicate a greater sensitivity of this methodology and this interpretation also applies to groups 3 and 4. From pathophysiological considerations, the positive cases in groups 3 and 4 can be well explained.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Trypanosoma lewisi: restriction of alternative complement pathway C3/C5 convertase activity.

The rat parasite Trypanosoma lewisi was incubated in vitro with rat or human serum, washed, and extracted in detergent. Extracts were fractionated by electrophoresis in denaturing gels, transferred to nitrocellulose, allowed to renature, then immunoblotted with polyclonal antibodies to rat complement component C3 and human complement components C3, C5, and factor B. Molecules that reacted with these antibodies were detected in the extracts. Fragments of rat C3 were detected in extracts of parasites that had not been exposed to serum in vitro. Additional complement deposition occurred during in vitro incubations; human complement components deposited in vitro could be distinguished from rat components deposited in vivo. Complement deposition in vitro required magnesium ions and did not occur when heat inactivated serum was used. Components reacting with antibodies to human C3 included a group of bands with molecular weights higher than C3 alpha or beta chains. Blotting with affinity purified, chain specific antibodies demonstrated that a 68 kDa component on parasites is C3 beta and that a 44 kDa molecule is derived from C3 alpha. A 73 kDa component that was difficult to resolve from C3 beta is probably also a C3 alpha fragment. This suggests that an inactive iC3b-like molecule is present on parasites. Kinetic studies showed that cleavage of C3 alpha is rapid and that the amount of C3 alpha fragments and C3 beta on intact parasites reached a steady state after 15 min. When parasites were trypsinized prior to incubation in C5 or C6 deficient serum, the rate and extent of C3 and C5 deposition increased. Unprocessed C3 alpha' and C5 alpha' chains were detected. Trypsinized parasites were lysed by the alternative complement pathway in normal serum. Intact parasites could be lysed by complement in the presence of antibody. The data support our previous suggestion that trypsin sensitive surface proteins on intact T. lewisi limit alternative pathway activity by restricting C3/C5 convertase activity.

Animals↗
PubMed1994

[Vascular manifestations of dermatomyositis and polymyositis. Clinical, capillaroscopic and histological aspects].

Polymyositis is characterized by a T-cell-mediated and MHC-I-restricted cytotoxic process, whereas dermatomyositis is a primitively vascular disease with microangiopathy mediated by the complement C5b-9 membranolytic attack complex. We have tried to estimate the frequency of vascular abnormalities in polymyositis as defined by Bohan and Peter. We have retrospectively studied 17 patients with dermatomyositis and 15 patients with polymyositis. Vascular abnormalities have been defined by clinical, capillaroscopic and histologic (muscle biopsy and minor salivary glands biopsy) features. After clinical features, 5/17 dermatomyositis had a Raynaud's phenomenon, against 6/15 polymyositis. Digital necrosis has been observed for 2/17 dermatomyositis and 2/15 polymyositis. In capillaroscopy, 14/17 dermatomyositis had a microangiopathy with or no enlarged capillary loops, against 7/15 polymyositis. None of these polymyositis had enlarged capillary loops. The muscle biopsy showed a predominantly perivascular or perimysial inflammatory infiltrate (vascular process) for 10/16 dermatomyositis against 4/13 polymyositis; a perifascicular atrophy for 3/16 dermatomyositis against 2/13 polymyositis. The histological study of minor salivary glands, showed vascular lesions for 2/11 dermatomyositis and for 1/8 polymyositis. Finally, Bohan and Peter's classification is now inadequate to distinguish between dermatomyositis and polymyositis. Indeed, some dermatomyositis sine dermatitis, may exist and be recognized by their vascular features. To distinguish between dermatomyositis and polymyositis is important, to evaluate the risk of cancer which is more frequent in dermatomyositis.

Adult↗
PubMed1988

Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy.

Immunopathologic studies over the past two decades have demonstrated that rapidly progressive glomerulonephritis (RPGN) can result from glomerular deposition of anti-GBM antibody, immune complexes, or from some as yet undefined mechanism that does not involve glomerular antibody deposition. The latter process may be cell mediated and resembles a small vessel vasculitis. Most cases of idiopathic RPGN are not accompanied by pathogenic glomerular immunoglobulin deposition. Recent experimental studies of immune mechanisms of glomerular injury have identified several new processes that can induce damage to the capillary wall sufficient to result in crescentic glomerulonephritis (GN). These include direct effects of anti-GBM antibody alone and of the complement C5b-9 (membrane attack) complex, nephritogenic effects of inflammatory effector cells that involve reactive oxygen species and glomerular halogenation, and injury mediated by sensitized lymphocytes independently of antibody deposition. Macrophages have been shown to participate in both intracapillary and extracapillary fibrin deposition and crescent formation as well as to mediate capillary wall damage. The role of resident glomerular cells and cell-cell interactions in glomerulonephritis is still under active investigation. Despite these several advances in understanding immune injury to the glomerulus, therapy for RPGN remains largely empiric. Although the prognosis in RPGN has clearly improved over time, no form of disease-specific therapy has been clearly shown yet to be beneficial in a controlled study. Interpretation of the existing literature on therapy is complicated by the availability of only historical rather than concurrent controls, lack of attention to several variables known to affect disease outcome, and uncertainty regarding bias in favor of reporting positive results. Available data suggests that optimal outcomes may be achieved in anti-GBM nephritis by treatment with steroids, immunosuppression and plasma exchange, particularly when therapy is directed at patients with mild but rapidly progressive disease before oliguria or severe azotemia develop. Pulse steroids are probably the most cost-effective therapy for the idiopathic form of RPGN, but treatment with cytotoxic agents should be considered if clinical or histologic evidence of vasculitis is present.

Glomerulonephritis↗
PubMed2001

X-linked myopathy with excessive autophagy: a clinicopathological study of five new families.

In 1988, Kalimo et al. (Ann Neurol 23 (1988) 258)described a new type of X-linked myopathy in a Finnish family. The clinical course was characterized by slow progression of muscle weakness without loss of ambulation in childhood and no evidence of cardiac, respiratory, or central nervous system involvement. Muscle fibers were not necrotic and showed excessive autophagic activity and exocytosis of the phagocytosed material. These authors proposed the name X-linked myopathy with excessive autophagy. Subsequently, only one French family has been reported with similar clinical and histopathological data. We report here five new families with a total of eight affected boys with the same clinical and histopathological features as reported in the original families. Histopathological findings of an asymptomatic mother are also reported. Vacuolar changes in muscle fibers result both from invaginations of the sarcolemma along with a variable component of basal lamina and from an autophagic process. The complement C5b-9 membrane attack complex associated with MHC class 1 antigen and calcium deposits is involved in muscle fiber damage. Among the X-linked myopathies, the identification of this new type is of great interest because of its favorable prognosis and unique morphological findings.

Adolescent↗
PubMed2003

The effect of immunoglobulin immunadsorptions on delayed xenograft rejection of human CD55 transgenic pig kidneys in baboons.

Delayed xenograft rejection (DXR) remains a major obstacle in discordant xenotransplantation. As strategies of complement inhibition and xenogeneic natural antibody (Ab) removal have been shown to give prolonged xenograft survival, we endeavored to determine whether combining these two strategies would lead to an additive effect in terms of graft survival. The study was initiated with two groups, A and B, where group A received normal kidneys and group B received hCD55 transgenic kidneys. Both groups underwent pre-transplant (day-1) total immunoglobulin (Ig) immunoadsorption (IA) and received an immunosuppression of cyclophosphamide, cyclosporine A, mycophenolate mofetil and corticosteroids. Two subsequent groups (C and D) receiving hCD55 transgenic pig kidneys were then performed with an 'optimized' immunosuppression (Cyclophosphamide starting 1 day earlier) but only group D recipients were immunoadsorbed. Biopsies taken during the post-transplantation period were analyzed for Ab deposition, compliment activation and cellular infiltration. No hyperacute rejection was observed. In the initial immunoadsorbed groups A and B, all baboons underwent DXR, which started surprisingly early (day 5 in most cases. In the subsequent two groups, the immunoadsorbed group D baboons also underwent DXR, again as early as day 5. In contrast, group C baboons did not show any signs of DXR on their day 6 biopsy or at their time of death. Analysis of graft biopsies from the kidneys undergoing rejection or with stable function showed strong deposition of anti-Gal IgM in all cases whereas strong complement C5b-9 deposits were only observed in biopsies at rejection. Cellular infiltration consisted mostly of monocytes/macrophages, was more pronounced in biopsies taken at rejection and was associated with a pro-inflammatory environment involving interleukins 1alpha, 6 and 8. Our findings suggest non-specific Ig (anti-Gal and non-Gal Ig of all isotypes) IA or even incomplete IA in immunosuppressed baboon recipients of transgenic pig kidneys is detrimental to graft survival by being associated with an Ab and compliment driven rejection. We speculate that the IA were insufficient in terms of Ig depletion or frequency inducing an Ab rebound or that this total Ig depletion also removed components facilitating graft survival.

Animals↗
PubMed1999

Mechanism of complement-dependent haemolysis via the lectin pathway: role of the complement regulatory proteins.

Mannan-binding lectin (MBL) is an acute phase protein which activates the classical complement pathway at the level of C4 and C2 via two novel serine proteases homologous to C1r and C1s. We recently reported that haemolysis via this lectin pathway requires alternative pathway amplification. The present experiments sought to establish the basis for this requirement, and hence focused on the activity and regulation of the C3 convertases. Complement activation was normalized between the lectin and classical pathways such that identical amounts of bound C4 and of haemolytically active C4,2 sites were present on the indicator cells. Under these conditions, there was markedly less haemolysis, associated with markedly less C3 and C5 deposited, via the lectin pathway than via the classical pathway, particularly when alternative pathway recruitment was blocked by depletion of factor D. Lectin pathway activation was associated with enhanced binding in the presence of MBL of complement control proteins C4bp and factor H to C4b and C3b, respectively, with decreased stability of the C3-converting enzyme C4b,2a attributable to C4bp. Immunodepletion of C4bp and/or factor H increased lectin pathway haemolysis and allowed lysis to occur in absence of the alternative pathway. Thus, the lectin pathway of humans is particularly susceptible to the regulatory effects of C4bp and factor H, due at least in part to MBL enhancement of C4bp binding to C4b and factor H binding to C3b.

Animals↗
PubMed2001

Complement activation products in plasma after heart transplantation in humans.

BACKGROUND: Complement activation has recently been implicated as a contributing factor to early and late allograft dysfunction in cardiac transplantation. The current study was designed to determine whether measurement of plasma complement fragments C4d and SC5b-9 would be useful in detecting acute rejection or accelerated graft atherosclerosis (AGA) in cardiac allograft recipients. METHODS: We measured complement activation products, C4d (classical pathway) and SC5b-9 (terminal pathway), at the time of routine endomyocardial biopsy in heart transplant recipients. Ten patients in the immediate posttransplantation period (0-100 days) and 19 patients more than 6 months after transplantation were studied. RESULTS: No correlation was found between plasma levels of complement activation fragments and the presence of biopsy-proven acute allograft rejection or AGA (assessed by coronary angiography). However, plasma C4d and SC5b-9 were significantly elevated in 9 of 10 and 7 of 10 patients, respectively, in the immediate posttransplantation period. This was followed by progressive decrease in the levels of C4d and SC5b-9 fragments during the first 4-6 weeks after transplantation. CONCLUSION: We conclude that measuring plasma levels of fragments C4d and SC5b-9 is not a useful noninvasive method for detecting acute rejection or AGA after heart transplantation. However, this study provides further evidence that early complement activation after heart transplantation may play a pathogenic role in allograft injury.

Complement Activation↗
PubMed2002

Myopathy with antibodies to the signal recognition particle: clinical and pathological features.

OBJECTIVES: To study myopathies with serum antibodies to the signal recognition particle (SRP), an unusual, myositis specific antibody associated syndrome that has not been well characterised pathologically. METHODS: Clinical, laboratory, and myopathological features were evaluated in seven consecutive patients with a myopathy and serum anti-SRP antibodies, identified over three years. The anti-SRP myopathy was compared with myopathology in other types of inflammatory and immune myopathies. RESULTS: The patients with anti-SRP antibodies developed weakness at ages ranging from 32 to 70 years. Onset was seasonal (August to January). Weakness became severe and disability developed rapidly over a period of months. Muscle pain and fatigue were present in some patients. No patient had a dermatomyositis-like rash. Serum creatine kinase was very high (3000 to 25 000 IU/l). Muscle biopsies showed an active myopathy, including muscle fibre necrosis and regeneration. There was prominent endomysial fibrosis, but little or no inflammation. Endomysial capillaries were enlarged, reduced in number, and associated with deposits of the terminal components of complement (C5b-9, membrane attack complex). Strength improved in several patients after corticosteroid treatment. CONCLUSIONS: Myopathies associated with anti-SRP antibodies may produce severe and rapidly progressive weakness and disability. Muscle biopsies show active myopathy with pathological changes in endomysial capillaries but little inflammation. Corticosteroid treatment early in the course of the illness is often followed by improvement in strength. In patients with rapidly progressive myopathies and a high serum creatine kinase but little inflammation on muscle biopsy, measurement of anti-SRP antibodies and pathological examination of muscle, including evaluation of endomysial capillaries, may provide useful information on diagnosis and treatment.

Adult↗
PubMed1989

Activation-dependent epitopes in the terminal complement pathway.

Assembly of the terminal complement complex (TCC) during complement activation is associated with considerable antigenic changes in the individual C5, C6, C7, C8 and C9 components. Numerous neoepitopes specific for the TCC are exposed. Similarly, native-restricted epitopes specific for the nonactivated components are concealed in the TCC. The present paper reviews these antigenic changes with special reference to available monoclonal antibodies and their utilization in assays to detect and quantify the TCC. Application of such assays in clinical medicine is discussed. Finally, a recommended terminology for the terminal complement pathway is put forward.

Antibodies, Monoclonal↗
PubMed1993

Glomerular epithelial cells produce endothelin-1.

Endothelin-1, a vasoactive peptide originally isolated from vascular endothelial cell culture supernatants, has constricting or mitogenic effects on smooth muscle and glomerular mesangial cells. Whether or not cultured rat glomerular epithelial cells synthesize endothelin-1 was assessed. Under basal culture conditions, the synthesis and release of endothelin-1 peptide by glomerular epithelial cells was time dependent, reaching 0.231 +/- 0.017 pg/1,000 cells at 24 h. For comparison, unstimulated bovine pulmonary artery endothelial cells and rat mesangial cells produced 0.982 +/- 0.237 and 0.004 +/- 0.002 pg of endothelin-1 peptide/1,000 cells per 24 h, respectively. In addition to endothelin-1 peptide, unstimulated glomerular epithelial cells expressed preproendothelin-1 mRNA. Transforming growth factor-beta, complement C5b-9, thrombin, and phorbol myristate acetate significantly enhanced endothelin-1 peptide synthesis in glomerular epithelial cells (45, 15, 55, and 25% above basal levels at 24 h, respectively), whereas epidermal growth factor had no effect. Thrombin and phorbol myristate acetate appeared to stimulate endothelin-1 peptide by activating protein kinase C, because the protein kinase inhibitor 1-(5-isoquinolinyl-sulfonyl)-3-methyl-piperazine abolished the thrombin- and phorbol myristate acetate-induced rise in endothelin-1 but had no effect on basal production. The stimulatory effect of thrombin was also markedly diminished in glomerular epithelial cells that had been depleted of protein kinase C by prolonged preincubation with a high dose of phorbol myristate acetate. Thus, glomerular epithelial cells may be an important source of endothelin-1, which might influence glomerular vasoconstriction or proliferation of target cells, particularly in the presence of proinflammatory molecules in the glomerulus.

Animals↗
PubMed2002

Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells.

C4b and C3b deposited on host cells undergo limited proteolytic cleavage by regulatory proteins. Membrane cofactor protein (MCP; CD46), factor H, and C4b binding protein mediate this reaction, known as cofactor activity, that also requires the plasma serine protease factor I. To explore the roles of the fluid phase regulators vs those expressed on host cells, a model system was used examining complement fragments deposited on cells transfected with human MCP as assessed by FACS and Western blotting. Following incubation with Ab and complement on MCP(+) cells, C4b was progressively cleaved over the first hour to C4d and C4c. There was no detectable cleavage of C4b on MCP(-) cells, indicating that MCP (and not C4BP in the serum) primarily mediates this cofactor activity. C3b deposition was not blocked on MCP(+) cells because classical pathway activation occurred before substantial C4b cleavage. Cleavage, though, of deposited C3b was rapid (<5 min) and iC3b was the dominant fragment on MCP(-) and MCP(+) cells. Studies using a function-blocking mAb further established factor H as the responsible cofactor. If the level of Ab sensitization was reduced 8-fold or if Mg(2+)-EGTA was used to block the classical pathway, MCP efficiently inhibited C3b deposition mediated by the alternative pathway. Thus, for the classical pathway, MCP is the cofactor for C4b cleavage and factor H for C3b cleavage. However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation.

Animals↗
PubMedDate not supplied

[The humoral and cellular factors of glomerular damage].

The present review summarizes current concepts on glomerular non-inflammatory and inflammatory immune injury. Non-inflammatory glomerular injury can be ascribed to mechanisms involving antibody alone, terminal component of complement (C5b-9) or cytokines having as primary target the glomerular epithelial cells. These mechanisms induce changes in cell cytoskeleton and in surface distribution of adhesion molecules leading to functional alterations which may account for loss of glomerular permselectivity. Inflammatory glomerular injury is mediated by neutrophils, macrophages, platelets and lymphocytes as well as by resident glomerular cells. Cell derived mediators include proteases, reactive oxygen species, cationic proteins, cytokines and growth factors that may variably affect recruitment of inflammatory cells, proliferation of resident glomerular cells and production of extracellular matrix. These alterations may determine proteinuria, impairment of renal function and eventually progression of glomerular injury to sclerosis. The inflammatory type of glomerular injury is mainly initiated by subendothelial-mesangial immune deposits and/or activation of cell mediated immunity. The role of factors such as the nature, intensity and persistence of initiating mechanisms, the types of inflammatory cells involved and the response of intrinsic glomerular cells, in expression and progression of glomerular injury are discussed.

Antibody Formation↗
PubMed1992

[Detection of ischemic myocardial damage].

Cases of cardiac death (myocardial infarction, coronary artery thrombosis, coronary artery sclerosis) were investigated with histochemical and immunohistochemical methods. Histochemical staining methods (HE, LFB, CAB) were used, with immunohistochemical methods were detected the proteins Desmin, Myoglobin, Fibrinogen and Complement C5b-9. Macroscopically visible myocardial infarctions were detected with both methods clearly. The damage pattern was associated to the type of destruction. At myocardial infarction the changes were focal at the other groups more disseminated.

Coronary Artery Disease↗