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PubMed2005

The combination of complement deficiency and cigarette smoking as risk factor for cutaneous lupus erythematosus in men; a focus on combined C2/C4 deficiency.

BACKGROUND: Although deficiencies in the early components of the complement system were among the first identified genetic risk factors for systemic lupus erythematosus (SLE), only a few studies addressed their significance in patients with cutaneous LE (CLE). Among environmental factors, it was postulated that cigarette smoking might intervene in the pathogenesis of LE. OBJECTIVES: To describe the clinical and biological features of patients with CLE and a complement deficiency. A secondary objective was to assess cigarette smoking in patients with CLE. PATIENTS AND METHODS: A retrospective study including all patients diagnosed as having LE between 1995 and 2003 in the Dermatology Department of Strasbourg University Hospital. Patient charts were reviewed and those patients in whom a C4 and/or C2 deficiency was diagnosed were included. Two patients with a combined C2/C4 deficiency were analysed in detail. RESULTS: There were 48 females and 37 males (F/M ratio = 1.3), with a mean age of 41 years at diagnosis; 73% of the patients had chronic LE and 27% subacute CLE. Among 32 screened patients, 24 patients with a mean age of 36 years had a complement deficiency; 17 had a C4A deficiency, five a C4B deficiency and two a combined C4A/C2 deficiency. A high proportion (58%) of these patients was male; 82% of the patients were smokers. This was especially true in males: 94% were smokers compared with 69% of females. CONCLUSIONS: Partial deficiency of C4, C2 or C4 and C2 is a common finding in patients with CLE. Most male patients with CLE are smokers. It is thus suggested that the combination of cigarette smoking and complement deficiency could be a risk factor for LE in men.

Adolescent↗
PubMed1989

Mouse strains with typical mammalian levels of complement activity.

Common laboratory mouse strains have very low complement levels relative to humans, rats, guinea pigs, rabbits and other mammals, which limits the value of the mouse as an experimental model. We therefore tested serum complement levels of 43 mouse strains and 11 rat strains, for the purpose of selecting a convenient laboratory animal having high complement levels. Total complement activity was determined with both erythrocytes and human tumor cells as targets. Eight mouse strains were identified that have complement levels comparable to those of other mammals. These mouse sera lyse tumor cell targets as well as sera from humans, rats or guinea pigs, although they are somewhat less active than rabbit sera. They are relatively inefficient in lysing erythrocyte targets, yet are as active as rabbit serum in this assay. Target cell lysis was demonstrated to be via the classical pathway of complement activation. Of the eight 'high complement' mouse strains, four were recently derived from wild mice, and one, SF/CamEi, was derived from wild mice in 1951. The three other strains, BUB/BnJ, DA/HuSn and RIIIS/J, were developed more than 40 years ago, but apparently were not tested previously for complement activity. Using the BUB mouse as a representative of the 'high complement' mice, we assayed levels of the nine complement components, in an attempt to identify the cause of high complement activity. No difference in levels of C1, C2, C4, C8 or C9 was detected between BUB and BDF1 mice. C2 activity was very low in both strains. C3, C5, C6 and C7 activities were higher in BUB mice than in BDF1 mice, indicating that variation in these complement components is responsible for the difference in total complement activity. The genes determining the 'high complement' phenotype appeared to be semi-dominant in F1 hybrids. The 'high-complement' mouse strains, and recombinant strains derived from them, will be useful in a wide range of biomedical research.

Animals↗
PubMed1975

Acute anaphylaxis associated with serum complement depletion.

A 45-year-old woman with rheumatoid arthritis developed anaphylaxis 6 min after receiving a subcutaneous injection of lidocaine, followed by an intra-articular injection of lidocaine mixed with methprednisolone acetate. One hour after the onset of anaphylaxis, serum complement component levels were markedly depressed and remained so far 18 hr. Circulating immune complexes and antibodies to lidocaine could not be demonstrated. Neither lidocaine nor methylprednisolone acetate activated the patient's complement system in vitro. Subsequently, total hemolytic activity (CH50) levels were variable, complement component protein concentrations of C1q, C1s, C4, C2, C3, C5, C6, C9, and Factor B were normal, but hemolytic activity of C4 and C2 was diminished. Serum C1 inhibitor concentrations were normal or slightly depressed. The patient has never had any symptoms suggestive of angiodema. It is postulated that the endogenous complement abnormality present in this patient may have contributed to the anaphylactic reaction.

Anaphylaxis↗
PubMed1991

Direct binding of complement component C1q to human immunodeficiency virus (HIV) and human T lymphotrophic virus-I (HTLV-I) coinfected cells.

Previous studies have shown that coinfection of the human T lymphotrophic virus type I (HTLV-I) chronically infected cell line MT4 with human immunodeficiency virus type 1 (HIV-1) results in cells which spontaneously activate complement via the classical pathway. This complement activation was antibody independent, yet required C2, suggesting either direct C1, C4, or C2 activation. Because some animal retroviruses have been shown to bind human C1q directly, the present study investigated the possible direct binding of C1q by HIV coinfected MT4 cells. Coinfected cells bound both C1q present in serum and highly purified C1q. Binding of C1q resulted in formation of active C1 on the cell surface, which could in turn activate complement as shown by C4 consumption. The C1q binding was not HIV-isolate specific since infection of MT4 cells with any of three diverse isolates all induced C1q binding. Purified collagen-like region (CLR) and globular region (GR) fragments of C1q both bound to coinfected cells, suggesting a mechanism of binding by C1q similar to that of fibronectin-C1q binding. However, culture of coinfected cells in serum-free (fibronectin-free) medium did not reduce C1q binding. A second HTLV-I chronically infected line, SLB-1, also displayed increased binding of C1q after HIV infection. The H9 cell line, which is not HTLV-I infected, did not bind C1q after HIV infection. These results suggest that a retrovirus protein expressed by coinfected cells directly binds C1q resulting in classical complement activation. This type of activation may have profound biological effects in persons coinfected with HIV-1 and HTLV-I.

Cell Line↗
PubMed1995

Complement analysis in adult patients with a history of bacteremic pneumococcal infections or recurrent pneumonia.

Complement deficiencies are known to be associated with increased susceptibility to bacterial infections. In the present study we investigated 80 patients with either a history of pneumococcal bacteremic infection, or recurrent pneumonia, or both. Hemolytic screening tests for complement deficiency were performed and serum concentrations of C1q, C1s, C2, C3, C4, C4 isotypes, factor B, factor D, and properdin were determined. Complete deficiencies of single complement proteins were not found. 10 patients (12%) had a C4 isotype deficiency, but the frequency of homozygous C4A and C4B deficiency was not significantly increased. Seven patients (9%) had hypocomplementemia with low concentrations of at least 2 complement proteins. One of these patients had profound depletion of classical pathway components and findings suggesting acquired C1 esterase inhibitor deficiency. 16 patients (20%) had minor complement aberrations. A majority of the patients with hypocomplementemia suffered from other conditions associated with pneumococcal infections. However, impaired complement function could be a significant predisposing factor in some patients with invasive pneumococcal infections or recurrent pneumonia.

Acute Disease↗
PubMed1992

Cytochrome c2 mutants of Rhodobacter capsulatus.

Although structurally related to other members of the class I c-type cytochromes, the cytochromes c2 have little amino acid sequence homology to the eukaryotic cytochromes c. Moreover, the cytochromes c2 exhibit distinct properties such as redox potential and an isoelectric point. In an effort to understand the differences between the cytochromes c2 and the other class I c-type cytochromes, we have developed a genetic system to study Rhodobacter capsulatus cytochrome c2 by site-directed mutagenesis. We describe here overproduction of R. capsulatus wild-type cytochrome c2 in cytochrome c2-minus strains of R. capsulatus and Rhodobacter sphaeroides. We demonstrate that R. capsulatus wild-type cytochrome c2 can transcomplement for photosynthetic growth in R. sphaeroides. Further, we describe the generation, expression, and in vivo functionality properties of nine R. capsulatus site-directed mutants. We show that mutants K12D, K14E, K32E, K14E/K32E, P35A, W67Y, and Y75F are overproduced and functional in vivo. In contrast, mutants Y75C and Y75S are expressed at low levels and exhibit poor functionality in vivo. These findings establish an effective system for the production of R. capsulatus site-directed mutants and demonstrate that interspecies complementation can be used to detect defective cytochrome c2 mutants.

Amino Acid Sequence↗
PubMed1981

The intrinsic coagulation-kinin pathway, complement cascades, plasma renin-angiotensin system, and their interrelationships.

Activation of the classical complement pathway is initiated by immune complexes consisting of IgM antibody or IgG subclasses 1, 2, and 3. Binding to Clq leads to activation of C1s and digestion of C4 and C2 to yield a C3 convertase. The alternative complement pathway is initiated by complex polysaccharides as well as immune complexes of the IgA class which interact with Factors B, D, C3, and properdin to yield a stabilized C3 convertase consisting of PC3Bb. Cleavage of C3 and C5 by either pathway yields the C3a and C5a anaphylatoxins which cause histamine release from mast cells and formation of the C5b6789 attack complex causes cell lysis. Both immunologic and nonimmunologic tissue damage can initiate the surface dependent pathways of coagulation, fibrinolysis, and kinin formation. Surface bound Hageman Factor interacts with complexes of prekallikrein and HMW-kininogen as well as Factor XI and HMW-kininogen to form activated Hageman factor, kallikrein, and Factor XIa. Factor XIa continues the coagulation pathway, kallikrein and Factor XIa convert plasminogen to plasmin and kallikrein digests HMW-kininogen to yield bradykinin. The Cl inhibitor, which inactivates Cls is the major plasma inhibitor of activated Hageman factor and kallikrein. In its absence, a potentially fatal form of angioedema is seen. The inactivator of the C3a and C5a anaphylatoxins is identical to carboxypeptidase N, the major plasma inactivator of bradykinin thus demonstrating the common control mechanisms which regulate the complement and kinin-forming pathways.

Blood Coagulation↗
PubMedDate not supplied

Intraarticular activation of the complement system in patients with juvenile rheumatoid arthritis.

Analyses of CH50, complement components, properdin factors, and kininogen in synovial fluid of patients with juvenile rheumatoid arthritis revealed evidence of activation of the classic complement pathway in all clinical subgroups. Juveniles with the adult pattern of disease had the greatest incidence of complement abnormalities. Evaluation of individual components by both activity determination and protein measurement showed decreased synovial fluid specific functional activity (activity per microgram protein) to the more marked in synovial fluids with profound depressions of complement activity. These findings provide further evidence that nonfunctional, antigenically intact component protein may remain after complement activation. Radial immunodiffusion measurements of properdin factors and kininogen failed to support their involvement in joint inflammation. Serum complement component measurements by activity but not protein concentration correlated with other parameters or inflammation. Four patients had isolated depressions of serum C2 activity. Immunoglobulin levels, particularly IgA, correlated with some complement measurements and with the sedimentation rate.

Adolescent↗
PubMed2003

Expression of complement messenger RNAs and proteins by human oligodendroglial cells.

Neurons, astrocytes, microglia, and endothelial cells are capable of synthesizing most, if not all, of the complement proteins. Little is known, however, about the capacity of oligodendroglial cells to generate complement components. This study evaluated expression of complement mRNAs and their protein products by human oligodendrocytes. Cells were isolated and cultured from white matter of seven adult cases that had undergone surgical temporal lobe resection for epilepsy. Oligodendroglial cultures were characterized by the expression of such cell type-specific mRNAs as myelin proteolipid protein (PLP), oligodendrocyte-specific protein (OSP), and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and were further characterized by immunostaining for such differentiation markers as myelin basic protein (MBP), PLP, CNPase, and O4. RT-PCR analysis showed that the oligodendroglial cells expressed detectable levels of complement mRNAs for the C1q B-chain, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 gamma subunit, and C9. Immunostaining was positive for C1q, C1s, C2, C3, C4, C5, C6, C7, C8, and C9. Double immunostaining for the oligodendrocyte marker O4 and the complement protein C3 demonstrated that all O4-positive cells were also positive for C3, indicating constitutive C3 expression. These results indicate that oligodendroglial cells may be a source of complement proteins in human brain and thus could contribute to the pathogenesis of several neurodegenerative and inflammatory diseases of the CNS, such as Alzheimer's disease, multiple sclerosis, and progressive supranuclear palsy, where complement-activated oligodendrocytes are abundant.

Adult↗
PubMed1995

Protection of retroviral vector particles in human blood through complement inhibition.

The rapid inactivation of murine-derived retroviral vectors in human or nonhuman primate sera is largely attributed to the activity of complement mediated through the classical pathway. In this study, we have further investigated the relationship between the human complement cascade and retrovirus inactivation. Preincubation in normal human serum effectively inactivated LXSN retroviral vector particles, whereas the vector maintained the ability to transduce cells following incubation in sera deficient in either the C1, C2, C3, C5, C6, C8, or C9 human complement proteins. Preincubation of serum with monoclonal antibodies (mAbs) that functionally block specific complement components, including C5, C6, C8, and C9, successfully protected the LXSN vector from complement-mediated inactivation. Treatment of serum with cobra venom factor, which consumes terminal complement, also effectively protected the vector from inactivation. LXSN vector survival in serum corresponded inversely to the level of complement activity following treatment of serum with anti-C5 mAb as assessed in an erythrocyte hemolytic assay. Additionally, pretreatment of human whole blood with anti-C5 mAb effectively inhibited inactivation of the LXSN vector. Taken together, these data demonstrate that formation of the membrane attack complex (MAC, C5b-9) is required for the inactivation of the murine-based LXSN retroviral vector in human blood and that this process can be abrogated with the use of soluble complement inhibitors.

3T3 Cells↗
PubMed1987

Platelet-mediated cytotoxicity. Role of antibody and C3, and localization of the cytotoxic system in membranes.

Platelets are one of several cell types capable of mediating antibody-dependent cellular cytotoxicity. We have developed a plasma-free system in which washed mouse platelets lyse washed antibody and complement-sensitized SRBC targets in the presence of EDTA. The dose-response curve is concave to the abscissa, indicating that lysis is a one-hit reaction. Determination of the actual number of platelets required to lyse a target shows that each platelet could lyse a single target. A limited degree of lysis is observed when platelets are incubated with SRBC sensitized with monoclonal IgG2a alone, but no lysis occurs with SRBC bearing comparable amounts of other isotypes. In the presence of C1 through C3, but not C1 through C2, efficient lysis is triggered by complement-fixing monoclonal IgG2a, IgG2b, and IgG3. In contrast, IgM and non-complement-fixing IgG1 and IgE are inactive. To achieve efficient lysis, it appears that platelets require both target cell-bound antibody and C3 fragments in close proximity. It is unlikely that proteases, pore-forming proteins, or toxic oxygen metabolites are involved in platelet-mediated lysis. Freezing and thawing of platelets, sonication, or sonication followed by hypotonic shock causes severe depletion of cytoplasmic and granular contents, as shown by electron microscopy and marker assays. However, the membrane fraction of these preparations retains cytolytic activity. When platelets are treated with trypsin or heated, lytic activity is eliminated, indicating that at least one component of this system is protein. These findings, as well as the fact that platelets do not lyse unsensitized innocent bystander SRBC, suggest that the complete cytotoxic system of platelets capable of specific recognition and lysis resides in their membranes.

Animals↗
PubMed2003

Meconium is a potent activator of complement in human serum and in piglets.

Meconium aspiration syndrome (MAS) is a clinical condition in the newborn infant with a significant morbidity and mortality. The complex pathophysiology of MAS, leading to both pulmonary and systemic complications, is characterized by an incompletely understood inflammatory reaction. Treatment is symptomatic, mainly limited to airway cleaning and ventilatory support. In this study, we show for the first time that meconium is a potent activator of complement, a key mediator of inflammation. In vitro, meconium activated the alternative complement pathway in human umbilical cord serum as judged by a substantial increase in the alternative pathway convertase C3bBbP. The activation proceeded through C3 (C3bc) and the terminal C5-9 pathway (terminal SC5b-9 complement complex), whereas the classical and lectin pathways were not activated (C1rs-C1-inhibitor complexes and C4bc). The lipid fraction, containing, e.g. free fatty acids, and the water fraction, containing, e.g. bile acids, contributed equally to the complement activation. A blocking antibody to factor D (alternative pathway) completely inhibited the meconium-induced complement activation, whereas blocking antibodies to mannose-binding lectin (lectin pathway) and C2 (classical and lectin pathway) had no effect. In vivo, meconium induced systemic complement activation in a piglet model of MAS, paralleling the increase in lung dysfunction. In conclusion, meconium is a potent activator of the complement system both in vitro and in vivo. Complement may be important in the pathogenesis of MAS, and specific complement inhibition might be a possible treatment approach in MAS.

Age Factors↗
PubMed1992

Mutations in the VP1 coding region of polyomavirus determine differentiating stage specificity.

Polyomavirus mutants capable of replicating in undifferentiated murine C2 myoblasts were selected and characterized. These mutants grow normally in 3T6 mouse fibroblast cells, and they do not complement the wild-type virus in coinfection experiments of C2 myoblasts. Of 12 isolates, 10 possess duplications of the regulatory region including the enhancer A domain. On the bases of the regulatory region structure and the presence and length of the enhancer duplication, the mutant viruses could be grouped into three classes. One mutant class (e.g., PyMB3) possesses an enhancer duplication of 91 bp identical to that of a previously characterized polyomavirus mutant, PyNB11/1. We have demonstrated that this enhancer duplication gives rise at its junction to a novel recognition motif for the transcriptional factor NF-1 (M. Caruso, C. Iacobini, C. Passananti, A. Felsani, and P. Amati, EMBO J. 9:947-955, 1990). The regulatory region PyMB3 virus recombined in a wild-type genome context maintains the mutant phenotype. The other two types of mutants, one with a 30-bp enhancer duplication (e.g., PyMB40) and one with a wild-type enhancer structure (e.g., PyMB27), possess two similar but distinct 6-bp deletions in the same region of the VP1 coding gene. In both cases, the ability to replicate in undifferentiated C2 myoblasts is strictly correlated to the mutation in the VP1 coding region.

Amino Acid Sequence↗
PubMed1998

Complement regulation in innate immunity and the acute-phase response: inhibition of mannan-binding lectin-initiated complement cytolysis by C-reactive protein (CRP).

Mannan-binding lectin (MBL) is an acute-phase protein which activates complement at the level of C4 and C2. We recently reported that the alternative pathway also is required for haemolysis via this 'lectin pathway' in human serum. CRP is another acute-phase reactant which activates the classical pathway, but CRP also inhibits the alternative pathway on surfaces to which it binds. Since serum levels of both proteins generally increase with inflammation and tissue necrosis, it was of interest to determine the effect of CRP on cytolysis via the lectin pathway. We report here that although CRP increases binding of C4 to MBL-sensitized erythrocytes, which in turn enhances lectin pathway haemolysis, it inhibits MBL-initiated cytolysis by its ability to inhibit the alternative pathway. This inhibition is characterized by increased binding of complement control protein H and decreased binding of C3 and C5 to the indicator cells, which in turn is attributable to the presence of CRP. Immunodepletion of H leads to greatly enhanced cytolysis via the lectin pathway, and this cytolysis is no longer inhibited by CRP. These results indicate that CRP regulates MBL-initiated cytolysis on surfaces to which both proteins bind by modulating alternative pathway recruitment through H, pointing to CRP as a complement regulatory protein, and suggesting a co-ordinated role for these proteins in complement activation in innate immunity and the acute-phase response.

Acute-Phase Reaction↗
PubMed2001

Continual low-level activation of the classical complement pathway.

There is evidence that the classical complement pathway may be activated via a "C1-tickover" mechanism, analogous to the C3-tickover of the alternative pathway. We have quantitated and characterized this pathway of complement activation. Analysis of freshly collected mouse and human plasma revealed that spontaneous C3 activation rapidly occurred with the generation of C3 fragments in the plasma. By the use of complement- and Ig-deficient mice it was found that C1q, C4, C2, and plasma Ig were all required for this spontaneous C3 activation, with the alternative complement pathway further amplifying C3 fragment generation. Study of plasma from a human with C1q deficiency before and after therapeutic C1q infusion confirmed the existence of a similar pathway for complement activation in humans. Elevated levels of plasma C3 were detected in mice deficient in complement components required for activation of either the classical or alternative complement pathways, supporting the hypothesis that there is continuous complement activation and C3 consumption through both these pathways in vivo. Blood stasis was found to stimulate C3 activation by classical pathway tick-over. This antigen-independent mechanism for classical pathway activation may augment activation of the complement system at sites of inflammation and infarction.

Animals↗
PubMed1976

Humoral immunostimulation. VI. Increased calcium uptake by cells treated with antibody and complement.

When L cells were treated with anti-L cell antibody in medium depleted of complement, rapid increases in calcium uptake were obtained over a wide range of antiserum concentrations. Concomitant cell growth and viability studies demonstrated that stimulation of cell growth occurred at higher dilutions of antiserum whereas cytotoxicity occurred at lower dilutions. The stimulatory and toxic effects of antibody on cell growth were potentiated by complement as was the enhancement in calcium uptake. Sera deficient in C1R, C2,4D, C4, C3-C9 did not increase the calcium uptake response to antibody whereas augmentation did occur with C6-deficient serum. A specific role for complement was further indicated by the ability of purified complement components to restore the response to complement in complement-deficient sera. C3 with C3-C9 deficient serum, but not C2, C5, and C6 with C3-C9 deficient serum restored augmentation effects. Taken together with the results of previous studies it is apparent that complement augments both calcium and nucleoside uptake and that the effect is primarily via the classical complement pathway through C3. Substrate saturation studies demonstrated that antibody activated the facilitated diffusion of calcium altering the Vmax but not the Km of transport whereas addition of complement altered both the Vmax and Km. These findings suggest that one of the early effects of enhancing antibody upon tumor cell metabolism in vitro is to stimulate uptake of calcium. In view of the suspected role of Ca++ in cell proliferation the increase in cell-associated calcium may be important in the subsequent proliferative response.

Antigen-Antibody Reactions↗
PubMed1985

Effect of different sulfonamides on the human serum complement system.

Incubation of normal human serum with different sulfonamides led to a dose-dependent inactivation of total hemolytic complement activity. A decrease of the activities of C1, C2, C3, C5 and one or several of the components C6-9 was observed after treatment of normal human serum with the sulfonamide sulfisomidine. Inactivation of complement components by sulfonamides seems to result from direct interaction with the drug as well as, to a minor extent, from activation of the alternative pathway. At relatively high concentrations, sulfonamides caused a conformational change in C3 and C4. The observed structural change is equivalent to that induced by cleavage of the internal thiolester bond in these molecules. The generation of such structurally altered C3 (C3b-like C3) as well as an antagonizing effect of sulfonamides towards the action of the regulatory protein factor I might be responsible for alternative pathway activation. The physiological relevance in vivo of the observed effects of sulfonamides remains to be assessed.

Complement C3↗
PubMed1993

Synthesis of the third component of complement (C3) by human gastric cancer-derived cell lines.

This is a study of complement components secreted by gastric cancer-derived cell lines (MKN28, MKN45, MKN74 and KATO-III), each of which has a different histological origin. Haemolytic activity of complement component was detected only in the culture supernatant of KATO-III (C2 activity) and in that of MKN45 (C5 activity). However, the third component of complement, C3, was detected by an ELISA assay in the supernatants of all cell lines. In our studies focusing on C3 production by these cell lines, we have found that: (i) tumour necrosis factor (TNF) induced an increase in the amount of secreted C3 in a dose- and time-dependent fashion; (ii) TNF (10 U/ml) stimulated C3 secretion by these cell lines to levels of 25.4-62.9 ng C3/10(6) cells per 24 hours; (iii) C3 haemolytic activity was detected in supernatants of TNF-stimulated cell lines. The mean specific activities of C3 by TNF (10 U/ml)-stimulated cell lines were 1.2-5.6 x 10(5) effective molecules/ng (e.m./ng), when that of C3 in normal human serum (NHS) was 1.7 x 10(6) e.m./ng; (iv) de novo synthesis of C3 by these cell lines was demonstrated by the effect of cycloheximide and by the incorporation of 35S-methionine into secreted C3; (v) immunoblot analysis of culture supernatants indicated that secreted C3 was mainly composed of C3 alpha and C3 beta chains, but pro-C3 was also present. These results, which show the de novo synthesis and secretion of C3 by all the tested gastric cancer-derived cell lines in response to TNF, suggest the possibility that C3 may be secreted in the gastric wall as part of its normal physiology, or as a result of tumour pathology, and thereby participate in local immune or inflammatory responses.

Complement C3↗