Systemic lupus erythematosus, complement deficiency, and apoptosis.
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Adolescent↗
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The molecular genetics of components of complement.
Rapid progress has been made in establishing linkages and in chromosome allocation of the genes of some 9 complement components. In the MHC, C2, Factor B, and two C4 or C4 related genes have been placed in some detail in both man and mouse. The gene coding for the cytochrome P-450 21-hydroxylase has been shown to be duplicated and immediately 3' to the two C4 genes, though it appears to be functionally and structurally unrelated to the complement components. Thus six genes have been mapped to this region where particular haplotypes are associated with increased susceptibility to a number of diseases, some of which are autoimmune in character. The complete gene structure of Factor B has been solved in man and rapid progress is being made with the C2 and C4 genes. The structural basis of the polymorphisms of these genes is being established. In C4, the polymorphism is exceptionally complex with varying numbers of loci and probably more than 50 allotypes occurring in man. A structural basis has also been found for the big differences in the biological activity of some of the C4 allotypes in man. Apart from the genes in the MHC, linkage has been found between the genes coding for C4bp, CR1, and Factor H. Remarkably there are sequence homologies between these proteins and C2 and Factor B, probably related to the ability to bind to one or other of the structurally similar proteins C3b and C4b. The complete cDNA sequences of C3 and C4 in mouse and man have given much information on the many posttranslational modifications of these proteins. A partial structure has been obtained for the C3 gene and the homology shown between C3, C4, C5, alpha 2-macroglobulin, and pregnancy zone protein. Although the amount of detailed information in the molecular genetics of complement components is accumulating rapidly, there appears to be a reasonable prospect that linkages and homologies will classify the data into a comprehensible form.
Alleles↗
Human antibody effector function.
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Amino Acid Sequence↗
Preparation and properties of human C1 inhibitor.
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Animals↗
Stagnant versus dynamic conditions: a comparative adsorption study of blood proteins.
Haemodynamic parameters of flowing blood, such as diffusion, convection, flow and shear rates, are important as they determine the interaction of cells with vessel walls and prosthetic implants in the cardiovascular system. Most of the studies under flow conditions have been performed with platelets or other cells, and less attention has been paid to the effects that these parameters may cause on the adsorption of proteins. For this reason we studied how different shear rates affect the adsorption of human albumin, fibrinogen, total serum proteins, and complement factors 1q and 3c from human serum to silicon surfaces. The most relevant results indicate that during non-flow conditions the amount of adsorbed proteins is always lower than under flow. The different shear rates (225, 915, 1800 and 2700 s(-1)) all gave similar results, indicating that such a parameter is not very critical for single protein deposition. The differences in kinetics of complex protein solutions are conveniently highlighted by use of specific polyclonal antibodies. The difference between non-flow or low shear rate conditions and physiological flow conditions was enhanced for the complement cascade system.
Adsorption↗
Review article: Fc gamma receptors in the human placenta.
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Animals↗
Binding of complement component Clq to myelin oligodendrocyte glycoprotein: a novel mechanism for regulating CNS inflammation.
Myelin oligodendrocyte glycoprotein (MOG) is a myelin-specific protein restricted to the central nervous system (CNS). While MOG is considered a putative autoantigen in MS, its function(s) in myelin is unknown. As CNS myelin is able to activate the classical complement pathway, it must contain a Clq-binding/activating protein but the identity of this protein has not been reported. The data in this paper clearly demonstrate that MOG specifically binds Clq in a dose-dependent and saturating manner. This calcium-dependent interaction is mediated by the extracellular immunoglobulin-like domain of MOG. This MOG domain contains an amino acid motif similar to the core Clq-binding sequence previously identified in IgG antibodies. Purified MOG also inhibited the antibody-dependent lysis of RBC by complement. Taken together, these results demonstrate that MOG binds Clq near the IgG binding site and may be the protein responsible for complement activation in myelin. This direct interaction between a myelin-specific protein and Clq has significant implications for CNS inflammation and could be particularly important in demyelinating diseases such as multiple sclerosis.
Animals↗
Complement activation and CD59 expression in the motor facial nucleus following intracranial transection of the facial nerve in the adult rat.
Intracranial transection of the facial nerve has been shown to cause a massive neuronal cell death in the motor facial nucleus. Complement activation has been proposed to contribute to neuronal degeneration following axotomy. Using immunocytochemistry and in situ hybridization we show in the present study that there is complement activation in the facial nucleus after intracranial facial nerve transection as well as increase of the complement regulators CD59 and clusterin. We propose a neuroprotective role for the complement regulators CD59 and clusterin against homologous attack of complement to facial motor neurons.
Age Factors↗
B cell-mediated infection of stimulated and unstimulated autologous T lymphocytes with HIV-1: role of complement.
In vivo, human immunodeficiency virus type 1 (HIV-1) is opsonized with complement fragments and virus-specific antibodies (Ab). Thus, HIV is able to interact with complement receptor (CR) - and Fc receptor (FcR) - positive cells such as B cells, follicular dendritic cells or macrophages. In this study we demonstrate that the interaction between B cells and HIV has an impact on autologous primary T cell infection in vitro. We confirmed the presence of complement-fragments and virus-specific Ab on serum-treated HIV using a virus-capture assay. In experiments with CR2-specific Ab we showed that the virus/B cell interaction was mainly dependent on CR2. In infection experiments immobilisation of HIV on stimulated tonsil B cells greatly enhanced the infection of interleukin (IL)-2-activated autologous tonsil T cells. Surprisingly, enhancement of T cell infection by B cell-HIV complexes was observed even in the absence of mitogenic stimuli such as PMA and was independent of the addition of exogenous IL-2. Taken together, these results indicate that primary B cells are able to efficiently transmit opsonised HIV to autologous primary T cells and induce a massive enhancement of infection. These in vitro experiments mimic the in vivo situation in the lymphoid tissue and suggest an alternative mechanism for the infection of primary T cells.
B-Lymphocytes↗
Lichen planus in two immunodeficient hosts.
The exact pathogenic mechanism involved in lichen planus (LP) remains obscure. Two patients who have severe immunodeficiency diseases and who developed LP during the course of their illness are reported here. Both patients had hypogammaglobulinemia and disturbed immune function prior to the development of LP. Although such an association could be coincidental, the development of LP may be related to the underlying immune disturbances. Association of LP with several other disorders of the immune system has been previously observed. Other evidence for the possible involvement of an immunopathogenic mechanism in LP includes (1) deposition of immunoglobulin within the colloid bodies and at the dermoepidermal junction, (2) predominantly T cell dermal infiltrate in LP lesions, and (3) existence of clinical and histologic similarities between graft-versus-host disease and LP.
Agammaglobulinemia↗
Inherited disorders of complement.
Isolated complement component deficiencies are uncommon. Deficiencies of all eleven components and two inhibitors of the classical pathway have been described. Complete absence of the components of the alternative pathway has not been described. The consequences of a single defect in complement are often predictable from an understanding of the biologic activities associated with activation of the complement system. Deficiency of C1 esterase inhibitor gives rise to the disease, hereditary angioedema; deficiency of the early components of the classical pathway are associated with lupus erythematosus; C3 and C3 inactivator deficiencies with pyogenic infections; C5 dysfunction with Leiner's disease; deficiencies of the terminal components with recurrent Neisseria bacteremia; and C9 deficiency with normal health. The complement system and its associated biologic activities are reviewed. The present knowledge of the inherited complement deficiencies and associated diseases, with particular emphasis on the dermatologic manifestations, genetics, and diagnosis, is summarized.
Angioedema↗
Patterns of complement activation in idiopathic membranoproliferative glomerulonephritis, types I, II, and III.
Complement profiles on 22 hypocomplementemic patients with membranoproliferative glomerulonephritis (MPGN) type I, on 11 with MPGN II, and on 16 with MPGN III, gave evidence that the nephritic factor of the amplification loop (NFa) is responsible for the hypocomplementemia in MPGN II and the nephritic factor of the terminal pathway (NFt) for the hypocomplementemia in MPGN III. In contrast, in MPGN I, there was evidence for three complement-activating modalities, NFa, NFt, and immune complexes. As a result, four different patterns of complement activation were seen. NFa, found in MPGN II, produces a complement profile characterized mainly by C3 depression. In addition, four of seven (57%) severely hypocomplementemic MPGN II patients (C3 less than 30 mg/dL) had slightly depressed levels of factor B, and one of seven (14%) of properdin, but in all the C5 concentration was normal. In contrast, all eight severely hypocomplementemic patients with MPGN II had depressed C5 and properdin levels, and six of eight (75%) depressed levels of C6, C7, and/or C9. Of eight MPGN III patients with moderate hypocomplementemia, 50% had depressed C5 and properdin levels and the remainder, depressed C3 only. This spectrum of profiles is most likely produced by varying concentrations of NFt. In MPGN I, nine of 23 (39%) had a profile indicating only classical pathway activation; seven of 23 (39%), a pattern compatible with NFt alone; four of 23 (9%), evidence for both classical pathway activation and NFt; and three of 23 (13%), a pattern compatible with NFa. The unique multifactorial origin of the hypocomplementemia in MPGN I, often giving evidence of classical pathway activation, together with previously reported differences in glomerular morphology and clinical features at onset, makes it distinct from MPGN III. Depressed C8 levels were found to some extent in all hypocomplementemic states. The levels were uncommonly depressed in patients with NFa, most markedly depressed with NFt, and moderately reduced with classical pathway activation. The cause is not known. Diagnostically, profiles showing classical pathway activation and low levels of C6, C7, and/or C9 are specific for MPGN I. Those showing only classical activation are likewise diagnostic of MPGN I if systemic lupus erythematosus (SLE) and chronic bacteremia are ruled out.
Complement Activation↗
C1qB and clusterin mRNA increase in association with neurodegeneration in sporadic amyotrophic lateral sclerosis.
We analyzed postmortem tissues of sporadic amyotrophic lateral sclerosis (SALS) for mRNA levels of two inflammatory proteins, complement C1qB and clusterin (apoJ). By Northern blot hybridization, SALS was associated with increased mRNA for C1qB and clusterin in the motor cortex (Brodmann area A4), but not in superior temporal cortex (A17), relative to neurologically normal controls. By in situ hybridization, SALS spinal cords showed increased C1qB and clusterin mRNA in areas undergoing neurodegeneration. This evidence implicates inflammatory mechanisms during neurodegenerative processes in SALS.
Adolescent↗
Acute glomerulonephritis in children. An evolutive morphologic and immunologic study of the glomerular inflammation.
This study deals with 80 children showing a clinically typical acute nephritic syndrome with proteinuria and/or hematuria, edema, and hypertension. Their ages ranged between 2 years 5 months and 16 years; 36 cases were female. In 73 cases a streptococcal infection was demonstrated; the remaining 7 cases did not show morphologic differences with the former. No previous renal disease nor familial history of nephropathies were elicited. In every case a renal biopsy was obtained in the first 60 days of clinical disease; in 46 cases a second renal biopsy was obtained sometime between 6 and 45 months since the beginning of the disease. In 3 cases the renal tissue was considered to be normal by light microscopy, immunofluorescence and electron microscopy in both the first and second biopsies. These 3 patients were not considered as cases of morphologic acute glomerulonephritis in spite of showing a typical clinical picture and they are not included in the evaluation of the glomerular inflammatory evolution. In all the remaining 77 cases C3 granular and segmentary intramembranous and mesangial dense deposits were found in the first biopsy. The second biopsy showed morphologic and immunologic normalization in 27% of the cases, slight lesions in 56% and an increase in severity in 17% of the cases.
Acute Disease↗
Activation of the complement cascade by Bordetella pertussis.
Bordetella pertussis must survive the defenses of the human respiratory tract including the complement system. The BrkA (Bordetella resistance to killing) protein prevents killing by the antibody-dependent classical pathway. In this study, the ability of B. pertussis to activate the human complement cascade by other pathways was examined. B. pertussis was not killed in serum depleted of C2, however serum depleted for factor B killed B. pertussis as efficiently as intact serum, suggesting complement activation occurred exclusively by the classical pathway. B. pertussis was not killed by serum depleted of antibody, suggesting the bacteria fail to activate the antibody-independent branches of the classical pathway, including the mannose binding lectin pathway. Mutants lacking the terminal trisaccharide of lipopolysaccharide retained the complement-resistant phenotype, suggesting this structure does not influence activation of complement.
Bordetella pertussis↗
Pathogenesis of heroin-associated glomerulonephritis. Correlation between the inflammatory activity and renal deposits of immunoglobulin and complement?
Renal specimens from 19 autopsies of persons known to be intravenous heroin-addicts and with severe lympho-monocytic glomerulonephritis were investigated to correlate the inflammatory activity and deposits of immunoglobulin and complement. In all sections, there were 10 or more LCA-positive cells/glomerulum, counted in 20 glomerula but only up to 3 LCA-positive cells in a control-group of 10 autopsied persons without drug addiction and any renal diseases. In some cases diffuse granular deposits of immunoglobulin were found together with deposits of Clq. Although these changes cannot be demonstrated in all cases, deposits of Clq point to an activation of the classical way of the complement binding system in heroin-associated glomerulonephritis. The underlying process, activation of the complement binding system by heroin/morphin itself and adulterants or by hepatitis B and C infection, which are frequent in heroin-addicts, is still unclear.
Adolescent↗
Schistosoma mansoni: complement activation in human and rodent sera by living parasites of various developmental stages.
Living Schistosoma mansoni of various developmental stages were studied with respect to their ability to activate the complement system in sera of humans, mice and rats. Immunofluorescence assays demonstrated that binding of human C3 occurred on fresh schistosomula as well as on schistosomula prepared from mouse lymph-nodes or lungs and on adult schistosomes. However, rodent C3 was deposited only on fresh schistosomula. Deposition of human C3 on the worms' surface required activation of the complement system. The alternative pathway was shown to be involved in deposition of human C3 on schistosomes of all ages, whereas activation of the classical pathway was demonstrable only with fresh schistosomula. Immunoelectrophoretic studies demonstrated a dose-dependent cleavage of human C3 and conversion of factor B by living adult schistosomes. The results demonstrate that the ability of living schistosomes to activate complement in vitro is dependent not only on their development stage but also on the species of the serum.
Animals↗