PubMed Health⌕ Search

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 1,153 records · Page 64Linked to original sources

Suppression of vascular injury at the Arthus reaction site by a complement inhibitor, 5,5',5''-(1,3,6-naphthalene-triyl-tris[sulfonylimino])-tris (1,3-benzene disulfonic acid) hexasodium salt.

A novel polyanionic complement inhibitor 5,5,5''-(1,3,6-naphthalene-triyl-tris[sulfonylimino])-tris(1 ,3-benzene- disulfonic acid) hexasodium salt (compound IIb) was tested for its ability to suppress vascular injury at the site of the Arthus reaction (AR). In control animals in which AR was evoked without drug treatment, venules at AR sites ranged from normal (arbitrarily defined as stage I) to destroyed (stage V). Between these two ends of the spectrum were venules with an accumulation of cells and deposits of electron dense material (stage II), accumulations of cells and deposits and small endothelial gappings (stage III), and accumulations of cells and depositions which had spread into perivascular tissue and small gappings (stage IV). In animals treated with compound IIb, the AR stopped at stage III or IV depending on the dose, it never reached stage V. In other words compound IIb treatment resulted in protection of endothelium, basal lamina and other structures from the destruction which is characteristically observed in the AR. The effect of high doses of compound IIb was similar to that described before for suramin.

Animals↗

Lack of complement factor C3, but not factor B, increases hyperlipidemia and atherosclerosis in apolipoprotein E-/- low-density lipoprotein receptor-/- mice.

OBJECTIVE: To investigate the effect of complement deficiency on atherogenesis and lipidemia, we used mice deficient in the third complement component (C3-/-) or factor B (FB-/-). METHODS AND RESULTS: Complement-deficient mice were crossed with mice deficient in both apolipoprotein E and the low-density lipoprotein receptor (Apoe-/- LDLR-/-). The percent lesion area in the aorta at 16 weeks, determined by en face analysis, was 84% higher in C3-/- mice than in controls (11.8%+/-0.4% versus 6.4%+/-0.8%, mean+/-SEM, P<0.00005). The C3-/- mice also had 58% higher serum triglyceride levels (P<0.05) and a more proatherogenic lipoprotein profile, with significantly more low-density lipoprotein cholesterol and very-low-density lipoprotein triglycerides than control mice. The C3-/- mice weighed 13% less (P<0.01) and had a lower body fat content (3.5%+/-1.0% versus 13.1%+/-3.0%, P<0.01). There were no differences between FB-/- mice and controls. CONCLUSIONS: Complement activation by the classical or lectin pathway exerts atheroprotective effects, possibly through the regulation of lipid metabolism.

Animals↗

Intrapulmonary bacterial clearance of type III group B streptococcus is reduced in preterm compared with term rabbits and occurs independent of antibody.

Intrapulmonary clearance of type III group B streptococcus (GBS) and related phagocytic recruitment was studied in preterm and term rabbits at 4 and 8 h after aerosol infection using left lung homogenates to quantify GBS and right lung bronchoalveolar lavage (BAL) to recover phagocytes. Opsonophagocytosis of type III GBS by pulmonary alveolar macrophages (PAM) was studied in vitro with a modified differential fluorescence-quenching method using PAM lavaged from preterm, term, and adult rabbits. Sera of experimental animals were tested for opsonization of type III GBS using fluorescein-labeled antibodies to rabbit IgG and C3. Although term animals showed some clearance at 8 h, preterm animals had marked intrapulmonary proliferation of GBS. The number of PAM in BAL fluid was 20-fold higher in term than in preterm rabbits at 0 h, but by 8 h, preterm rabbits had a large influx of PAM, whereas PAM remained constant in term BAL fluid. Rates of phagocytosis of GBS were twice as high in term versus preterm PAM during in vivo and in vitro studies. Among PAM from term and adult animals, opsonization of GBS with MgEGTA-sera promoted phagocytosis in vitro at levels comparable to pooled adult sera, whereas opsonization with EDTA-sera resulted in a significantly lower rate of ingestion. None of the experimental animals' sera were able to deposit IgG, but all deposited C3 on the surface of GBS. In summary, preterm rabbits had a diminished bronchoalveolar PAM population that did not ingest GBS as well via the alternative complement pathway when compared with term rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Complement activation by vascular prostheses and its role in progression of arteriosclerotic lesions.

This study, using C3a, C4a, and C5a assay and crossed immunoelectrophoresis in vitro and in vivo, was designed to determine whether vascular prostheses activate the complement system. The degree of complement activation and the pathway of activation were also studied. The complement levels (C3, C4, CH50) in different arterial diseases were measured, and the relationship of complement levels to serum lipids in patients with arteriosclerosis obliterans (ASO) was also investigated, in order to clarify a relationship between the complement system and arteriosclerosis or other arterial diseases. Bovine graft, dacron, and PTFE activated the complement system in vitro. In order of the degree of complement activation, bovine graft ranked first, followed by dacron and PTFE. The patient group with acute arterial occlusion showed high C3 and C4 levels. The healthy elderly group showed higher C3 and C4 levels than the healthy persons in their twenties. In ASO patients, C3 levels correlated with serum lipid levels. Judged from the relation of complement activation by vascular prostheses to the progression of arteriosclerotic changes, vascular prostheses should be assessed with regard to complement activation.

Arterial Occlusive Diseases↗

The diagnosis of acute anaphylactoid reactions to anaesthetic drugs.

Patients with a presumptive diagnosis of an acute anaphylactoid reaction to anaesthesia were investigated to determine the cause of the reaction and the drug responsible by intradermal testing, patch and prick testing, sequential complement measurement, passive transfer testing and challenge. The most valuable information was provided by intradermal testing and a diagnosis could be made in 150 of 165 patients. When analphylactoid reactions to anaesthetic drugs occur, intradermal testing one month after the reaction and sequential complement measurements in the immediate post reaction period will enable the diagnosis to be established in the majority of cases. Intradermal testing is of no value for trivial reactions or reactions to colloid solutions or contrast media.

Anaphylaxis↗

Opportunities for new therapies based on the natural regulators of complement activation.

While the complement system is an essential component of immunity, shutting down all or part of it could be beneficial in a wide range of clinical situations. Designer, small-molecule, protease inhibitors and antagonists of protein-protein interactions are under development, while an approach based on a humanized monoclonal antibody to the C5 component works effectively against the later stages of complement activation and is close to completing clinical trials. The cobra venom factor depletes plasma of essential complement components, and a humanized (nonimmunogenic) version is being sought. Perhaps the most promising approach to comprehensive complement downregulation, however, is the exploitation of innate regulators of complement activation, with two products in clinical trials. The potential for more efficacious complement blockers of this kind is growing because of better targeting, but a deeper knowledge at the atomic level of mechanisms of action of these regulators is needed to underpin a rational approach to design of still more potent complement inhibitors.

Complement Activation↗

Attachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology.

Complement is a central element of innate immunity and this vital defense system initiates and coordinates immediate immune reactions which attack and eliminate microbes, foreign particles and altered self cells. Newly generated activation products are extremely toxic and consequently, activation is highly restricted in terms of time and space. The initial activation of the alternative complement pathway occurs continuously and the early phase acts indiscriminatoryl and forms on any surface. However, the system discriminates between self and foreign, and therefore allows activation on foreign surfaces e.g. microbes, and restricts activation on host cells. Consequently, self cells and tissues are protected from the harmful activation products. This protection is mediated by specific regulators or inhibitors, which exist in the fluid phase and/or in membrane-bound forms. Here we review a novel mechanism, i.e. the attachment of the soluble complement regulator factor H to the surface of self cells. This attachment, which is demonstrated experimentally by means of immunofluorescense microscopy and by flow cytometry, increases the inhibitory potential at the cell surface and mediates protection by reducing the local formation of toxic inflammatory products. This attachment is highly relevant and has pathophysiological consequences in several human diseases, including Factor H-associated hemolytic uremic syndrome (FH-HUS), membrano-proliferative glomerulonephritis type II, recurrent microbial infections and chronic inflammation, e.g. rheumatoid arthritis and immune evasion of tumor cells. Defects of this safeguard activity have been recently understood in patients with FH-HUS. Point mutations in the Factor H gene occurring in the C-terminus of the protein result in impaired cell binding capacity of Factor H and, consequently, during an inflammatory insult endothelial cells are not properly protected and are damaged.

Animals↗

Meningococcal disease in congenital absence of the fifth component of complement.

We describe a family in which 2 brothers had meningococcal infection, 1 of them twice. Their parents were first degree cousins. The brothers showed a complete, isolated deficiency of C5, both antigenic and functional. The parents had half-normal values, and the data are compatible with an inherited C5 deficiency where the defect is transmitted as an autosomal codominant trait.

Adult↗

Some aspects of the humoral and neutrophil functions in post-comatose nawareness patients.

Post-comatose unawareness (PCU) is one of the possible outcomes of severe brain injury. Patients with severe brain injury have an increased susceptibility to severe nosocomial infections for multifactorial reasons, including immune suppression at different levels. We studied different immunological aspects in 11 PCU patients. Impaired humoral immunity was found in 27% of them. Two patients had decreased haemolytic activity of the classical complement pathway, associated with decreased levels of the components C1q, C1r and C4. Another patient had very low levels of IgG2 and IgG4. The neutrophil killing activity was impaired in these three patients, but was completely restored with the addition of a heterologous serum, suggesting a humoral defect. Neutrophils showed normal chemotaxis and random migration, and the superoxide anion release by neutrophils was also found to be normal. Understanding the immunological events in PCU patients contributes to a better and more intensive therapeutic approach, which might accelerate the rehabilitation of these patients.

Adolescent↗

Physiology and pathophysiology of complement: progress and trends.

The complement system comprises a family of at least 20 plasma and membrane proteins that interact in a tightly regulated cascade system to destroy invading bacteria and prevent the deposition of immune complexes in the tissues. This brief review addresses the basic mechanisms of complement activation and control and describes the active fragments produced during complement activation. The biological importance of the complement system is amply illustrated in patients with complement deficiencies, who are susceptible to bacterial infections and immune complex diseases. The involvement of complement in other immunological diseases is an expanding area of clinical research, supported by the development of new assays for the identification of complement activation. This area is discussed here with particular reference to neurological diseases. A promising new prospect involves the use of complement inhibitory molecules in therapy of complement-mediated disease and this exciting area is also discussed. Novel physiological roles of complement also are being revealed and new evidence that complement and complement receptors play an important role in reproduction is summarized. It is hoped that this brief overview will convey some of the enthusiasm currently pervading research in this underappreciated area of immunology.

Animals↗

Complement and the host's defense against the pneumococcus.

The complement system plays a critical role in resistance to Streptococcus pneumoniae. In the last two decades, a great deal of new knowledge has been generated on both the complement system and on the pneumococcus. Not only has this new knowledge helped produce a better understanding of how the complement system serves the host in its defense against S. pneumoniae, but in a more general fashion, the lessons learned from the interaction of complement and the pneumococcus have also provided insight into how the complement system functions in the defense of the host against a wide variety of other microorganisms. The following review will attempt to summarize current knowledge about the complement system, how it interacts at the molecular level with the pneumococcus, the biologic consequences of that interaction, and their significance in pneumococcal infections.

Anemia, Sickle Cell↗

Biological correlates of capsular (quellung) reactions of Cryptococcus neoformans.

The capsular swelling or quellung reaction was reported almost 100 years ago and described the effect of Abs on the appearance of microbial capsules. Despite widespread use to assess Ab binding to capsules, relatively little is known as to the mechanism of this effect or its biological consequences. The fungus Cryptococcus neoformans is an attractive system to study capsule reactions because it has a large polysaccharide capsule that is readily visible by light microscopy. When viewed by differential interference contrast microscopy, binding of mAb to C. neoformans cells produced two distinct capsular reactions that depended on the Ab epitope specificity and the yeast serotype. In the first pattern, termed "rim," the capsule appears transparent with a highly refractive outer edge. In the second pattern, termed "puffy," the capsule appears opaque and lacks a highly refractive outer rim. mAbs that bind with a rim pattern suppress the overall rate of C3 deposition on the yeast via the classical and alternative complement pathways. In contrast, mAbs that bind with a puffy pattern do not affect C3 deposition. Protective and nonprotective IgM mAbs produce rim and puffy patterns, respectively. These results indicate that: 1) capsule reactions are a consequence of Ab-induced changes in capsular refractive index; 2) the type of capsule reaction depends on the Ab specificity; and 3) Ab-induced changes in refractive index correlate with biological activities important for host defense against C. neoformans. Our results provide the first evidence associating distinct capsule reaction patterns with Ab biological activity.

Antibodies, Monoclonal↗

Novel mechanism of antibody-independent complement neutralization of herpes simplex virus type 1.

The envelope surface glycoprotein C (gC) of HSV-1 interferes with the complement cascade by binding C3 and activation products C3b, iC3b, and C3c, and by blocking the interaction of C5 and properdin with C3b. Wild-type HSV-1 is resistant to Ab-independent complement neutralization; however, HSV-1 mutant virus lacking gC is highly susceptible to complement resulting in > or =100-fold reduction in virus titer. We evaluated the mechanisms by which complement inhibits HSV-1 gC null virus to better understand how gC protects against complement-mediated neutralization. C8-depleted serum prepared from an HSV-1 and -2 Ab-negative donor neutralized gC null virus comparable to complement-intact serum, indicating that C8 and terminal lytic activity are not required. In contrast, C5-depleted serum from the same donor failed to neutralize gC null virus, supporting a requirement for C5. EDTA-treated serum did not neutralize gC null virus, indicating that complement activation is required. Factor D-depleted and C6-depleted sera neutralized virus, suggesting that the alternative complement pathway and complement components beyond C5 are not required. Complement did not aggregate virus or block attachment to cells. However, complement inhibited infection before early viral gene expression, indicating that complement affects one or more of the following steps in virus replication: virus entry, uncoating, DNA transport to the nucleus, or immediate early gene expression. Therefore, in the absence of gC, HSV-1 is readily inhibited by complement by a C5-dependent mechanism that does not require viral lysis, aggregation, or blocking virus attachment.

Adult↗

Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases.

We have investigated the molecular basis of selective and complete C1s deficiency in 2-year-old girl with complex autoimmune diseases including lupus-like syndrome, Hashimoto's thyroiditis, and autoimmune hepatitis. This patient's complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, and undetectable levels of C1s Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of genomic DNA by PCR followed by direct sequence analysis revealed a homozygous nonsense mutation in the C1s gene exon XII at codon 534, caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction site for endonuclease Fok-1 created by the mutation to detect this mutation in the genomic DNA of seven healthy family members. Four additional heterozygotes for the mutation were identified in two generations. Our data characterize for the first time the genetic defect of a selective and complete C1s deficiency in a Caucasian patient.

Age of Onset↗

The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance.

Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A approximately 29 kD fH-binding protein expressed in the meningococcal outer membrane was identified by mass spectrometry as GNA1870, a lipoprotein currently under evaluation as a broad-spectrum meningococcal vaccine candidate. GNA1870 was confirmed as the fH ligand on intact bacteria by 1) abrogation of fH binding upon deleting GNA1870, and 2) blocking fH binding by anti-GNA1870 mAbs. fH bound to whole bacteria and purified rGNA1870 representing each of the three variant GNA1870 families. We showed that the amount of fH binding correlated with the level of bacterial GNA1870 expression. High levels of variant 1 GNA1870 expression (either by allelic replacement of gna1870 or by plasmid-driven high-level expression) in strains that otherwise were low-level GNA1870 expressers (and bound low amounts of fH by flow cytometry) restored high levels of fH binding. Diminished fH binding to the GNA1870 deletion mutants was accompanied by enhanced C3 binding and increased killing of the mutants. Conversely, high levels of GNA1870 expression and fH binding enhanced serum resistance. Our findings support the hypothesis that inhibiting the binding of a complement down-regulator protein to the neisserial surface by specific Ab may enhance intrinsic bactericidal activity of the Ab, resulting in two distinct mechanisms of Ab-mediated vaccine efficacy. These data provide further support for inclusion of this molecule in a meningococcal vaccine. To reflect the critical function of this molecule, we suggest calling it fH-binding protein.

Adjuvants, Immunologic↗

Cutting edge: C1q protects against the development of glomerulonephritis independently of C3 activation.

C1q-deficient (C1qa-/-) mice develop antinuclear Abs and glomerulonephritis (GN) characterized by multiple apoptotic bodies. To explore the contribution of C3 activation to the induction of spontaneous GN, C1qa-/- mice were crossed with factor B- and C2-deficient (H2-Bf/C2-/-) mice. GN was present in 64% of the 45 C1qa/H2-Bf/C2-/- mice compared with 8% of the 65 H2-Bf/C2-/- mice and none of the 24 wild-type controls. IgG was detected in the glomeruli of diseased C1qa/H2-Bf/C2-/- kidneys. However, glomerular staining for C3 was absent. Increased numbers of glomerular apoptotic bodies were detected in undiseased C1qa/H2-Bf/C2-/- kidneys. These findings support the hypothesis that C1q may play a role in the clearance of apoptotic cells without the necessity for C3 activation and demonstrate that the activation of C3 is not essential for the development of GN in this spontaneous model of lupus-like disease.

Animals↗

Complement-mediated phagocytosis of Pseudomonas aeruginosa.

The nature of the opsonic factors in nonimmune human serum for six blood culture isolates of Pseudomonas aeruginosa was investigated by measuring uptake of [3H] adenine-labeled bacteria by human PMNs. Normal human serum, C2- and C4-deficient sera, zymosan-treated serum, and immunoglobulin-deficient sera were used as opsonic sources. Heat inactivation of each of these serum sources markedly reduced its opsonic capacity for all Pseudomonas strains, suggesting that the serum C system was essential for opsonization. Five strains were opsonized in the absence of the classical C pathway; however, kinetic studies revealed that opsonization proceeded at a faster rate when the classical pathway was present. In spite of markedly reduced factor B and C3 levels, zymosan-treated serum retained significant opsonic activity for one of the strains tested. Four strains were poorly opsonized by immunoglobulin-deficient serum, and C activation by these strains appeared to depend upon the presence of antibodies. Two strains, however, were effectively opsonized in a relative absence of antibodies. Thus, in the nonimmune state, phagocytosis of P. aeruginosa is mediated primarily via the C system, and antibodies appear to play a role in the opsonization of some but perhaps not all Pseudomonas strains.

Complement Factor B↗