SEARCH · PubMed Health

Results for “Complement Pathway, Alternative”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,423 records · Page 79Linked to original sources

PubMed2003

Genetic evidence for involvement of classical complement pathway in induction of experimental autoimmune myasthenia gravis.

Abs to acetylcholine receptor (AChR) and complement are the major constituents of pathogenic events causing neuromuscular junction destruction in both myasthenia gravis (MG) and experimental autoimmune MG (EAMG). To analyze the differential roles of the classical vs alternative complement pathways in EAMG induction, we immunized C3(-/-), C4(-/-), C3(+/-), and C4(+/-) mice and their control littermates (C3(+/+) and C4(+/+) mice) with AChR in CFA. C3(-/-) and C4(-/-) mice were resistant to disease, whereas mice heterozygous for C3 or C4 displayed intermediate susceptibility. Although C3(-/-) and C4(-/-) mice had anti-AChR Abs in their sera, anti-AChR IgG production by C3(-/-) mice was significantly suppressed. Both C3(-/-) and C4(-/-) mice had reduced levels of B cells and increased expression of apoptotis inducers (Fas ligand, CD69) and apoptotic cells in lymph nodes. Immunofluorescence studies showed that the neuromuscular junction of C3(-/-) and C4(-/-) mice lacked C3 or membrane attack complex deposits, despite having IgG deposits, thus providing in vivo evidence for the incapacity of anti-AChR IgGs to induce full-blown EAMG without the aid of complements. The data provide the first direct genetic evidence for the classical complement pathway in the induction of EAMG induced by AChR immunization. Accordingly, severe MG and other Ab- and complement-mediated diseases could be effectively treated by inhibiting C4, thus leaving the alternative complement pathway intact.

Animals↗

PubMed2002

The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice.

The complement system is an important component of the innate immune response to bacterial pathogens, including Streptococcus pneumoniae. The classical complement pathway is activated by antibody-antigen complexes on the bacterial surface and has been considered predominately to be an effector of the adaptive immune response, whereas the alternative and mannose-binding lectin pathways are activated directly by bacterial cell surface components and are considered effectors of the innate immune response. Recently, a role has been suggested for the classical pathway during innate immunity that is activated by natural IgM or components of the acute-phase response bound to bacterial pathogens. However, the functional importance of the classical pathway for innate immunity to S. pneumoniae and other bacterial pathogens, and its relative contribution compared with the alternative and mannose-binding lectin pathways has not been defined. By using strains of mice with genetic deficiencies of complement components and secretory IgM we have investigated the role of each complement pathway and natural IgM for innate immunity to S. pneumoniae. Our results show that the proportion of a population of S. pneumoniae bound by C3 depends mainly on the classical pathway, whereas the intensity of C3 binding depends on the alternative pathway. Furthermore, the classical pathway, partially targeted by the binding of natural IgM to bacteria, is the dominant pathway for activation of the complement system during innate immunity to S. pneumoniae, loss of which results in rapidly progressing septicemia and impaired macrophage activation. These data demonstrate the vital role of the classical pathway for innate immunity to a bacterial pathogen.

Animals↗

PubMed1995

Antibody-independent binding of complement component C1q by Legionella pneumophila.

Incubation of Legionella pneumophila Philadelphia 1 in normal human serum depleted of either classical-pathway component C1q or alternative-pathway component factor B resulted in activation of the complement system. Experiments focused on the role of the classical pathway in complement activation revealed that legionellae bound C1q independently of antibody. Purified preparations of L. pneumophila major outer membrane protein but not serogroup 1 lipopolysaccharide bound C1q independently of antibody. This suggests that antibody-independent binding of C1q by L. pneumophila can result in activation of the classical pathway in normal human serum and that major outer membrane protein may be a C1q acceptor on the L. pneumophila cell surface.

Antibodies, Bacterial↗

PubMed1989

Immune system response in Alzheimer's disease.

Involvement of the immune system in the pathogenesis of Alzheimer's disease was demonstrated in two ways: by the attachment of complement proteins to diseased tissue, and by the activation of cells associated with the immune system. Alzheimer brain tissue was stained immunohistochemically by antibodies to components of the classical, but not the alternative, complement pathway. Antibodies to C1q, C3d, and C4d stained senile plaques, dystrophic neurites, neuropil threads and some tangled neurons. Antibodies to a neoantigenic site on the C5b-9 membrane attack complex stained dystrophic neurites and many tangled neurons, but not senile plaques. Antibodies to Factor P and fraction Bb of Factor B, which are specific for the alternative complement pathway, did not stain Alzheimer brain tissue. The cellular immune response was evaluated by the presence of reactive microglia and by the infiltration of small numbers of T-cells into diseased brain tissue. Reactive microglia were identified by antibodies to HLA-DR, a class II major histocompatibility complex glycoprotein, and by enhanced staining with antibodies to leukocyte common antigen and the Fc gamma RI and Fc gamma RII receptors. T-cells were identified by antibodies to leukocyte common antigen, as well as the CD4 and CD8 surface proteins. Double immunostaining with antibodies to GFAP and MHC class I or class II antigens established that astrocytes, which are GFAP positive, do not express MHC antigens in Alzheimer's disease. Endothelial cells express MHC class I antigens while reactive microglia and some leukocytes express class II antigen.

Alzheimer Disease↗

PubMed2006

Properdin deficiency in a boy with fulminant meningococcal septic shock.

UNLABELLED: Bacterial meningitis is a rare presentation for congenital immunodeficiency, but meningococcal invasive diseases and meningitis have been associated with late complement component deficiencies and properdin deficiency. A 5-y-old boy of non-consanguineous parents was admitted to our hospital with meningococcal septic shock. He had previously been suffering from recurrent respiratory infections. His 13-y-old brother had also been treated for meningococcal meningitis when he was 7 y old. Immunological studies, done after recovery, on the patient and his two brothers revealed normal immunoglobulin, IgG subclasses, C3, C4 and CH50 levels. Haemolytic activity of the alternative complement pathway could not be detected, and properdin concentrations were <0.01 mg/l in serum samples from the patient and his brothers. The patient and family members received quadrivalent polysaccharide meningococcal vaccine. The patient was discharged on penicillin prophylaxis, and he remained healthy during the ensuing year. CONCLUSION: Our findings stress that measurement of the haemolytic activity of the alternative complement pathway in addition to classical pathway haemolytic complement activity should be performed in patients with meningococcal disease to reveal various forms of complement deficiency. This is particularly important when there is a family history, or recurrences or infection due to uncommon serogroups. Deficient individuals and affected family members might be protected from infection by vaccination.

Causality↗

PubMed1983

Quantitative variability in requirements for opsonization of strains within the Bacteroides fragilis group.

Requirements for opsonization of various strains within the species Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides vulgatus, and Bacteroides distasonis were investigated. The minimal concentration of normal human serum that facilitated maximal uptake by human peripheral leukocytes of 14C-labeled strains ranged from 5% to 80%. Heated (56 C at 30 min) serum produced less uptake than untreated serum, suggesting that complement was required for opsonization. Using human serum depleted of C4 by immunoadsorption as the source of opsonins, predominant utilization of the alternative complement pathway during opsonization was established. Acidic polyanionic exopolymer on the strains was also assessed by ruthenium red staining, electron microscopy, and India ink wet mounts. Strains of the species B thetaiotaomicron, B vulgatus, and B fragilis possessed exopolymer, and a unique configuration of this material was observed on two strains that resisted opsonization. Utilization of classical and/or alternative complement pathway activity during opsonization was not related to the presence of exopolymer.

Bacteroides fragilis↗

PubMed1994

Psoriasis is a visible manifestation of the skin's defense against micro-organisms.

The recent discovery that human epidermal cells themselves make and secrete the components necessary for activation of the alternative complement pathway appears to provide an explanation for how human skin is ordinarily able to avoid colonization by molds and other organisms. It also helps clarify the mechanisms underlying clinical and laboratory findings seen in chronic mucocutaneous candidiasis, dandruff, and psoriasis. Psoriasis seems best explainable as a visible, late stage of the inflammatory sequelae of activation of the alternative complement pathway in the epidermis.

Complement Activation↗

PubMed1981

Complement fixing properties of antibodies to double-stranded DNA in systemic lupus erythematosus.

Anti-DNA antibodies were assessed in 33 patients with active systemic lupus erythematosus (SLE) by the immunofluorescence Crithidia luciliae (CL) and the Farr assays. Eleven patients demonstrated complement (C3) fixation in the CL assay. Although 6 out of 9 patients with active nephritis showed complement fixation, 6 patients without overt renal disease were also positive in this assay. The ability to fix C3 was strongly associated with the total amount of anti-DNA antibodies as determined by both the CL and Farr assays (P less than 0.001). IgM anti-DNA antibodies were detected only in sera with complement fixing anti-DNA antibodies. Isolated whole IgG, but not the F(ab')2 fragment containing anti-DNA activity, fixed C3 on the Crithidia substrate. In depletion and reconstitution studies with human complement components, it was established that anti-DNA antibodies fixed C3 through the classical complement pathway although factors B and D of the alternative pathway were effective in C3 amplification. Properdin was also detected on the antigen-antibody complex but did not appear to be essential for maximal C3 fixation. Anti-DNA antibodies therefore fix complement by their Fc portion, form a classical pathway convertase, and recruit factors B and D of the C3b amplification loop when they bind to a fixed antigen.

Antibodies↗

PubMed1993

Induction of complement resistance in cloned pathogenic Entamoeba histolytica.

The lytic effect of complement activated through the alternative pathway (AP) was studied on pathogenic and nonpathogenic Entamoeba histolytica recently isolated from stool samples. Recent nonpathogenic isolates were nearly unaffected by exposure to AP whereas recent pathogenic stool isolates were highly susceptible to AP dependent complement-mediated lysis. Complement susceptible pathogenic stool isolates developed complement resistance in vivo during hamster liver passage and in vitro during cultivation in the presence of increasing concentrations of normal human serum (NHS). Since a clone of pathogenic HM-1:IMSS which initially was highly susceptible also acquired complement resistance during cultivation in the presence of NHS, it is concluded that complement resistance was caused by induction rather than by selection alone. Because cultivation in the presence of heat-inactivated NHS did not affect complement susceptibility of the cloned HM-1:IMSS, complement activation itself might induce complement resistance in pathogenic E. histolytica.

Animals↗

PubMed1990

Change of biological activities of (1----3)-beta-D-glucan from Grifola frondosa upon molecular weight reduction by heat treatment.

Changes of biological activities manifested by (1----6)-branched (1----3)-beta-D-glucans of various molecular weights obtained by heat treatment of the corresponding intact beta-glucan at 150 degrees C (HD-LE) were examined. The activities assessed in this study were as follows: an antitumor activity, activation of alternative complement pathway, glucose consumption by macrophages, macrophage-mediated lysosomal enzyme activity in culture supernatant and cell lysate, interleukin-1 (IL-1) activity, and adjuvant activity. HD-LE could be classified into three groups: 1) HD-LE 0 h (MW 800000) which activated all of the biological activities tested, 2) HD-LE 0.5 and 3 h (MW 250000 and 21000) which lacked or exhibited low levels of activities such as activation of alternative complement pathway and lysosomal enzyme secretion, 3) HD-LE 6 h (MW 6400) which only activated glucose consumption and synthesis of lysosomal enzyme. These results suggest that an antitumor glucan is not always a multiple enhancer of host defense mechanisms and that a large molecular weight is required to augment multiple immunological activities.

Animals↗

PubMed1982

Recurrent pyogenic infections in individuals with absence of the second component of complement.

While deficiency of the terminal components of complement (C3-C8) has classically been associated with recurrent pyogenic infections, it has become apparent that C2 deficiency is also associated with recurrent infections in some individuals. The patient presented here had two major pyogenic infections prior to 1 year of age and was found to lack the second component of complement. Studies of alternative complement pathway and humoral and cellular immunity were found to be within normal limits. Family studies suggest an autosomal codominant pattern of inheritance for the C2 defect, which also corresponded to the inheritance of the HLA A10 B18 haplotype. A review of the literature revealed nine other cases of C2-deficient patients with well-documented recurrent infections. In these patients, Streptococcus pneumoniae is the organism most frequently implicated in infectious processes, whether or not their alternative complement pathway is intact.

Antibodies, Antinuclear↗

PubMed1992

Human umbilical vein endothelial cells synthesize S-protein (vitronectin) in vitro.

S-protein, also named vitronectin, is a multifunctional glycoprotein with molecular weight (MW) of about 75 kDa and a serum concentration of 0.14-0.60 mg/ml. It is synthesized mainly in the liver, but synthesis has also been found in monocytes/macrophages. We used human umbilical vein endothelial cells (EC) which were incubated with agarose beads, an activator of the alternative complement pathway. By radioimmunoassay (RIA) based on monoclonal and polyclonal S-protein antibodies, we detected S-protein on harvested agarose beads. The time-dependent increase in the amount of S-protein was significantly reduced by the presence of cycloheximide (10 micrograms/ml) in the cell cultures. We also found a strong binding of S-protein antibodies to agarose beads preincubated in native serum, which was strongly reduced (70-80%) by inactivation of the alternative complement pathway (50 degrees C, 20 min). Our results show that EC synthesize S-protein in vitro.

Cells, Cultured↗

PubMed1994

Acylation of the lipid A region of a Klebsiella pneumoniae LPS controls the alternative pathway activation of human complement.

Two mechanisms of direct activation of the complement system by LPS have been extensively documented: (i) activation of the alternative pathway (AP) by the polysaccharide region, and (ii) activation of the classical pathway (CP) by the lipid A region. Here we demonstrate that LPS from the Klebsiella pneumoniae I-145 strain activates the AP by a mechanism dependent on the acylation of the lipid A region. Cleavage of C3 by K. pneumoniae LPS in EGTA was blocked by polymyxin B. Two 34 kDa derivatives were prepared from a membrane extract of this K. pneumoniae strain: (i) an acyl-poly (1,3) galactoside containing two galactosamine-bound ester-linked and two amide-linked fatty acids (EFA-APG), and (ii) an acyl-poly (1,3) galactoside devoid of ester-linked fatty acids (APG). APG and EFA-APG share the structure of LPS molecules, with a long polysaccharidic chain, a core, and a lipid A region. The AP was activated by EFA-APG but not by APG nor by the isolated polygalactose chain GC-APG, indicating a critical role for ester-linked fatty acids in AP activation. Polymyxin B which binds to the lipid A region of LPS completely inhibited AP activation by EFA-APG. A small part of EFA-APG was shown to form aggregates in saline, but aggregation was not decreased by polymyxin B. Furthermore, APG formed aggregates of similar size although it was not able to activate AP. Therefore the role of lipid A acylation in triggering AP activation is not exclusively mediated by aggregation of the molecule. LPS from the rough strain of Salmonella minnesota (Sm Re LPS) directly activates the CP but not the AP. However, when mixed with the polygalactose chain GC-APG, Sm Re LPS activated the AP. The data demonstrate a cooperation between the lipid A region and the polysaccharidic chain in activation of the AP. Similar cooperation may occur with other LPS molecules.

Acylation↗

PubMed1978

Interaction of human serum and neutrophils with Escherichia coli strains: differences between strains isolated from urine of patients with pyelonephritis or asymptomatic bacteriuria.

Strains of Escherichia coli isolated from the urine of children with pyelonephritis (n = 18) or asymptomatic bacteriuria (ABU) (n = 20) were serotyped and compared with respect to opsonic requirements, sensitivity to serum, amount of chemiluminescence produced by normal neutrophils during phagocytosis of the various strains, and amount of capsular antigen. Strains isolated from cases of ABU more often had the capacity to activate the alternative complement pathway than had strains causing pyelonephritis. The ABU strains were also better opsonized in fresh human serum and were more often serum sensitive than the pyelonephritic strains. There were individual variations in neutrophil chemiluminescence during phagocytosis of the various strains, but the two groups of strains did not differ significantly. The strains from pyelonephritis cases produced a greater amount of capsular antigens than the ABU strains. There was no correlation between presence of a particular O or K antigen and capacity to activate the alternative complement pathway. The observed differences between strains isolated from patients with ABU and those isolated from patients with pyelonephritis may be relevant for further studies on differences in bacterial virulence or host defense factors.

Antigens, Bacterial↗

PubMed2004

[The role of the complement system in the defence against infections and new ways of assessing the activation routes].

The complement system is of major importance in the defence against infections. Deficiencies in one of the three pathways of activation of the complement system can cause serious infections; the classical pathway, the alternative pathway and the lectin pathway. A new ELISA assay has been developed to enable the assessment of the functional activity of the whole lectin pathway and to determine the classical and the alternative pathway functional activity in a simple uniform design.

Bacterial Infections↗

PubMed1985

The development of complement activating ability as an age related factor in murine brains.

We recently reported on the ability of the myelin fraction of the murine brain to activate the complement system through the classical pathway, which might be important in the induction of secondary inflammation in various pathological conditions where brain tissue has been exposed to the complement. The present study was undertaken to investigate the relationship between the appearance of complement activity in the mouse brain and the synthesis of myelin in ICR mice up to ninety days of age. Here, we show that anti-complementary activity in the murine brain is closely related to murine brain weight and that its activity seems to be dependent on the amount of myelin in the murine brain. Myelin was isolated from brains of equal weight taken from both two-day old and ninety-day-old mice, and we found that ninety-day-old myelin consumed a much greater amount of complement (C) than two-day-old myelin. However, for equal concentrations of myelin, almost an equal amount of C was consumed by the myelin of the two-day-old mice and by that of the ninety-day-old mice. It was suggested that the difference of anti-complementary activity was caused by the myelin contents of the murine brains, but the possibility of maturation of myelin was not excluded. The mechanism involved in the anticomplementary activity of the myelin was found to be related to the consumption of complement, mainly via the classical pathway but also less activity via the alternative pathway.

Aging↗

PubMed1981

Murine defense mechanism against Candida albicans infection. II. Opsonization, phagocytosis, and intracellular killing of C. albicans.

The phagocytic and intracellular killing activities of normal mouse phagocytes against Candida albicans were studied to elucidate the role of these activities in nonspecific and specific defense mechanisms. In the presence of fresh normal mouse serum, viable C. albicans cells were ingested by mouse peripheral blood leukocytes (PBLs) and peritoneal macrophages (PMPs) at the same rate. Serum-chelation experiments indicated that the factors involved in the alternative complement pathway are opsonins for C. albicans. PBLs killed intracellular C. albicans more effectively than PMPs. Lymphokine-activated PMPs manifested marked intracellular killing activity and the occurrence of increased superoxide anion- and singlet oxygen production, in the absence of increased myeloperoxidase (MPO) production, suggests that the enhanced, MPO-independent, oxidative mechanism may play an important role in the candidacidal activity. Specific rabbit antibodies played no role in the phagocytosis and intracellular killing of C. albicans. These results suggest that PMNs and factors involved in the alternative complement pathways, and lymphokine-activated macrophages play major roles in the protection of mice against C. albicans infection.

Animals↗

PubMed1994

Proinflammatory properties of molluscum bodies.

Molluscum contagiosum, a condition characterized by benign viral tumours, occasionally becomes inflamed and regresses spontaneously, an event probably initiated by a host cell-mediated immune rejection against the lesion, but it inevitably involves the disruption of the epidermal tissue to expose the molluscum bodies to the tissue fluids of the dermis. It has been suggested that the molluscum bodies induce inflammation by a mechanism similar to that involved in ruptured epidermal cysts or in acne. Despite the occasional development of inflammation in molluscum contagiosum, the proinflammatory properties of molluscum bodies have never been studied in vitro. Thus, in the present study we sought to determine whether molluscum bodies exert a proinflammatory effect by inducing neutrophil chemotaxis. When exposed to fresh serum in vitro, water-insoluble components of molluscum bodies activated the alternative complement pathway to produce chemotactic C5a/C5a des Arg. We also found that an aqueous extract of molluscum bodies exerted potent chemotactic activity for neutrophils. Remarkably high amounts of the immunoreactive proinflammatory cytokines IL-8 and GRO alpha were present in the extract even when compared with psoriatic scale extracts. Gel filtration HPLC of the extract demonstrated the presence of neutrophil chemotactic activity over a wide range of molecular mass. These data suggest that disruption of the epidermal wall of molluscum bodies induces acute inflammatory changes by activation of the alternative complement pathway on exposure to the tissue fluids, and that the molluscum bodies themselves release proinflammatory cytokines and other neutrophil chemotactic factors on decomposition.

Chemotaxis, Leukocyte↗