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PubMed1977

Anticomplementary activity of Fusobacterium polymorphum in normal and C4-deficient sources of guinea pig complement.

Fusobacterium polymorphum has been isolated from the gingival crevice in humans and has been implicated in the immunopathology of periodontal diseases. The presence of alternative complement pathway factors in gingival crevice material suggests the contribution of this process in the manifestation of the local host response. A complement consumption assay was used to show that the anticomplementary activity of a cell-wall preparation from F. polymorphum in guinea pig complement progressed optimally at 37 degrees C and suboptimally at 0 degrees C. Similar levels of complement consumption were recorded at both temperatures, but a higher concentration of cell walls was required to demonstrate maximum activity in the cold. Augmentation experiments with additional normal and heat-treated complement showed the presence of heat-labile factors that controlled and limited the consumption of complement to a constant proportion of the total amount present. These same experiments indicated that there were no reactive antibodies in the complement used in the assay. Similar tests with C4-deficient guinea pig sera confirmed that F. polymorphum cell walls were capable of generating alternative complement pathway activity in guinea pig sera.

Cell Wall↗
PubMed1981

Variability in the degree of opsonization and phagocytosis of strains of Staphylococcus aureus isolated from patients with disseminated intravascular coagulation.

Patients with septicemia due to Staphylococcus aureus occasionally manifest DIC. We studied the ability of organisms isolated from 30 patients with S. aureus (5 with DIC) to be opsonized and phagocytosed by normal human PMNs in the presence of normal human serum chelated with MgEGTA as a possible measure of alternative complement pathway activation. By this assay, nine S. aureus strains were found to be opsonized at 50% level or greater. Five of those organisms were isolated from the five patients who had clinical and laboratory manifestations of DIC, three of whom died. Patients from whom the other four activating strains were isolated were more seriously ill (by a method of grading clinical severity of disease) than the remaining 21 patients. Four of the nine patients from whom activating strains were isolated died compared to only four of the other 21 patients. The accelerated phagocytosis of staphylococcal strains from patients with DIC after incubation in MgEGTA-chelated serum suggests that surface factors on these strains interacted with serum factors differently than did strains from patients not developing DIC. However, all (except one) staphylococcal strains, from patients both with and without DIC, depleted hemolytic complement activity in MgEGTA-chelated serum; therefore a direct relationship between activation of the alternative complement pathway and opsonization seems not to exist. Thus strains of S. aureus capable of being opsonized by PMNs in human serum chelated with MgEGTA were associated with more severe infections often associated with DIC.

Disseminated Intravascular Coagulation↗
PubMed1987

Isolation of bovine complement factor H.

A bovine serum protein, initially recognized by its inhibitory effect on the hemolytic activity of the bovine alternative pathway was isolated from fresh bovine serum by polyethylene glycol precipitation and chromatography on DEAE-Sephacel, CM-Sephadex A-50 and Sephadex G-200. The protein, a single chain polypeptide with an apparent molecular weight of 158,000, was identified as factor H, a regulatory protein of the alternative complement pathway. Functional characterization of this protein as factor H was based on the following properties: binding to C3b, inhibition of factor B binding to C3b, cofactor activity in the cleavage of C3b by factor I, inhibition of fluid phase alternative pathway C3 convertase (C3b.Bb) formation and activity, and species-specific inhibition of the alternative pathway mediated hemolysis of heterologous erythrocytes. A monospecific rabbit antiserum against bovine factor H failed to react with human serum factor H.

Animals↗
PubMed1993

Preferential formation of C3b-IgG complexes in vitro and in vivo from nascent C3b and naturally occurring anti-band 3 antibodies.

Naturally occurring anti-band 3 antibodies appear to have tissue homeostatic functions in the clearance of senescent red cells and in eliciting selective phagocytosis of oxidatively stressed red cells by mediating C3b deposition under conditions that favor the alternative complement pathway (Lutz, H. U., Bussolino, F., Flepp, R., Fasler, S., Stammler, P., Kazatchkine, M. D., and Arese, P. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 7368-7372). They overcome the notoriously low affinities of naturally occurring antibodies by having affinity for C3 which renders these antibodies preferred targets of nascent C3b. Anti-band 3 antibodies preferentially formed covalently linked C3b-IgG complexes, when C3 was activated randomly by trypsin. IgG depleted of anti-band 3 antibodies had almost lost the ability to form C3b-IgG complexes. Likewise, anti-band 3 antibodies, but not anti-spectrin antibodies, preferentially formed C3b-IgG complexes on oxidatively stressed red cells in the presence of a 10(3)-fold excess of other serum IgG, when complement deposition was initiated by antibody binding in diluted serum. Moreover, anti-band 3 antibodies preferentially formed C3b-IgG complexes at a 10(5)-fold excess of other IgG on in vivo aging red cells, since C3b-IgG complexes from senescent red cells contained exclusively anti-band 3 antibodies with an affinity for C3. Thus, the low titer, low affinity naturally occurring antibody became functionally relevant by preferred generation of C3b-IgG complexes that can nucleate alternative complement pathway C3 convertases and represent the most effective opsonins (Fries, L. F., Siwik, S. A., Malbran, A., and Frank, M. M. (1987) Immunology 62, 45-51).

Anion Exchange Protein 1, Erythrocyte↗
PubMed1999

The structural basis for complement receptor type 2 (CR2, CD21)-mediated alternative pathway activation of complement: studies with CR2 deletion mutants and vaccinia virus complement-control protein-CR2 chimeras.

The role of complement receptor 2 (CR2) short consensus repeats (SCR) in binding of hydrolyzed C3 (iC3) to form an alternative pathway (AP) convertase, and promoting C3 fragment deposition following AP activation, was examined. We used (1) K562 cells transfected with CR2 constructs, where the C3d-binding site of CR2 (SCR1+2) was replaced with the four-SCR vaccinia virus complement control protein (VCP), or truncation mutants thereof, and (2) COS cells transfected with wild-type (wt) CR2, or deletion mutants thereof. AP activation required iC3 binding in both systems. Thus, the VCP-CR2 chimera had an iC3 binding efficiency of 11.4 %, compared to wtCR2, and a relative AP activity of 5.5 %, the truncation mutants being inactive. Of the CR2 mutants, only EK (DeltaSCR10 - 11) had AP activity similar to wtCR2. NN (DeltaSCR6 - 8) and NOP (DeltaSCR6-mid14) had reduced AP activity, but near normal iC3 binding. XB (DeltaSCR3 - 6) and PP (DeltaSCR3-mid14) were inactive in both assays. We conclude that, whilst iC3 binding to CR2 via SCR1 - 4 is essential for AP activation, the efficiency of C3 deposition also depends on the midportion of CR2.

Animals↗
PubMed1999

Function of the factor I modules (FIMS) of human complement component C6.

In order to elucidate the function of complement component C6, truncated C6 molecules were expressed recombinantly. These were either deleted of the factor I modules (FIMs) (C6des-748-913) or both complement control protein (CCP) modules and FIMs (C6des-611-913). C6des-748-913 exhibited approximately 60-70% of the hemolytic activity of full-length C6 when assayed for Alternative Pathway activity, but when measured for the Classical Pathway, C6des-748-914 was only 4-6% as effective as C6. The activity difference between C6 and C6des-748-913 for the two complement pathways can be explained by a greater stability of newly formed metastable C5b* when produced by the Alternative Pathway compared with that made by the Classical Pathway. The half-lives of metastable C5b* and the decay of (125)I-C5b measured from cells used to activate the Alternative Pathway were found to be about 5-12-fold longer than those same parameters derived from cells that had activated the Classical Pathway. (125)I-C5 binds reversibly to C6 in an ionic strength-dependent fashion, but (125)I-C5 binds only weakly to C6des-FIMs and not at all to C6des-CCP/FIMs. Therefore, although the FIMs are not required absolutely for C6 activity, these modules promote interaction of C6 with C5 enabling a more efficient bimolecular coupling ultimately leading to the formation of the C5b-6 complex.

Animals↗
PubMed1976

Alternative pathway of complement: recruitment of precursor properdin by the labile C3/C5 convertase and the potentiation of the pathway.

In this study the physiological role of properdin and the differential subunit composition of the solid phase enzymes of the pathway have been explored. Cell-bound C3 and C5 convertase differ in their C3b requirement. Apparently one molecule of C3b is sufficient to allow formation of C3 convertase (C3b,B), whereas two or more are required for generation of C5 convertase (C3bn,B). This conclusion was drawn from results indicating the critical role of the spacial distribution of C3b molecules on the cell surface in enzyme formation. While the C3/C5 convertase is fully capable of acting on C5 and thereby initiating the assembly of the cytolytic membrane attack complex, it is exceedingly labile and vulnerable to destruction by the C3b inactivator. It is the apparent role of properdin to confer a degree of stability upon the labile enzyme and to protect its C3 convertase function against enzymatic destruction. To achieve these effects, precursor properdin (pre-P) is recruited in a binding-activation reaction by the labile C3/C5 convertase. Multiple C3b molecules appear to be needed for the formation of properdin-activating principle. Three modes of regulation have been described, which involve spontaneous dissociation enzymatic degradation by C3b inactivator and disassembly by beta1H. The functional differences of pre-P and activated properdin (P) were delineated, pre-P displaying a weak affinity for C3b and P the capacity of strong interaction, P generating a soluble C3 convertase in serum and pre-P being unable to do so. Because of the profound differences between native pre-P and the laboratory product P, the question was raised as to whether soluble P represents an unphysiological form of the protein. On the basis of this and other studies, the conclusion was reached that in vitro properdin recruitment constitutes the terminal event of the properdin pathway, and that properdin augments the function of C3/C5 convertase without changing its substrate specificity.

Animals↗