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PubMed1978

Direct demonstration and quantitation of the first complement component in human serum.

The first component of complement, C1, can be demonstrated and quantitated in normal and pathological human serums by simple immunochemical techniques. All of the C1q, C1r, and C1s detected in normal serum was found to be in the C1 complex. A simple modification of these methods permitted the quantitation of free C1s in the presence of macromolecular C1, a technique which may prove useful in screening pathological serums.

Calcium↗
PubMed1984

Binding and activation of the first complement component by soluble immune complexes: effect of complex size and composition.

The interaction between soluble immune complexes and the first component of complement (C1) was studied. Complexes were prepared from purified bovine thyroglobulin (BTg) or tetanus toxoid (TT) and immunospecific IgG antibodies. Purified human precursor C1 was incubated with dilutions of the preparations, and the inhibition of C1 haemolytic activity was determined as a measure of C1-binding. The activation of C1 was assessed by measuring the amount of C4 consumed by generated C1. The molar antibody/antigen (Ab/Ag) ratio of BTg--anti-BTg mixtures strongly influenced their C1-binding and C1-activating capacities: mixtures with high Ab/Ag ratios were by far the most efficient. On the other hand, the Ab/Ag ratio had only a limited influence on the activity of TT--anti-TT complexes. The effect of complex size was investigated by ultracentrifugation of antibody-antigen mixtures on calibrated sucrose density gradients followed by C1-binding and -activation experiments with the fractions obtained. For both types of immune complex, the C1-binding and -activating capacities increased markedly with increasing complex size. Thus, both the size and the Ab/Ag ratio of soluble immune complexes influence their capacity to activate the classical complement pathway. The effect of the Ab/Ag ratio, however, may also be dependent on the antigen molecule(s) present in the complexes.

Animals↗
PubMed1980

Assembly of subcomponents C1r and C1s of first component of complement: electron microscopic and ultracentrifugal studies.

Monomeric C1s (Mr, 85,000; s20,w, 4.3S), a subcomponent of first component of complement (C1), the dimer (Mr, 170,000; s20,w, 6.7 S) of C1r, another subcomponent, and the tetrameric complex (C1r,C1s)2 (Mr, 340,000; s20,w, 8.7 S) are elongated molecules. Hydrodynamic equivalents of cylindrical shape have a diameter of 3.3 nm and lengths of 20 nm for C1s, 36 nm for (C1r)2, and 64 nm for (C1r,C1s)2. In electron micrographs the C1r,C1s complex appears as a chain composed of six to eight globular domains with a contour length of 51 nm. A structure is proposed in which (C1r)2 forms a core to which C1s protomers are associated at both ends. The C1 complex (s20,w, 16.3 S) reconstituted from C1q, C1r, and C1s dissociates under the conditions used for electron microscopy. Some features of the C1 complex are revealed in the dissociation products.

Centrifugation, Density Gradient↗
PubMed1976

Reversible binding of a T cell factor on IgG-coated sepharose beads.

Supernatants of alloantigen-activated T cells contain a number of factors, including an immunoglobulin-binding factor (IBF) which inhibits complement-induced hemolysis of sheep erythrocytes coated with anti-Forssman IgG antibodies and a factor which suppresses IgM antibody synthesis in vitro. These two factors may be identical, since they are simultaneously retained on Sepharose beads to which IgG has been coupled and can be recovered by elution at pH 2.8. They do not bind to Sepharose beads to which IgM of F(ab')2 fragment of IgG has been coupled, demonstrating that they have a selective affinity for the Fc region of IgG. In addition, the fixation of IBF on the Fc portion of IgG reversibly inhibits subsequent binding of the first component of complement (C1), thus indicating that IBF does not irreversibly alter the C1 binding site(s) of IgG.

Animals↗
PubMed1979

The physical state of membrane lipids modulates the activation of the first component of complement.

Activation of the first component of human complement (C1) by bilayer-embedded nitroxide spin label lipid haptens and specific rabbit antinitroxide antibody has been measured. The nitroxide spin label hapten was contained in host bilayers of either dimyristoyl phosphatidylcholine or dipalmitoyl phosphatidylcholine in the form of both liposomes and vesicles. At a temperature of 32 degrees C, which is intermediate between the hydrocarbon chain-melting temperatures of the two phospholipids, activation of C1 in such vesicles and liposomes is more efficient in the fluid membrane. Studies of C1 activation in binary mixtures of cholesterol and dipalmitoyl phosphatidylcholine indicate that the activation of C1 is not limited by the lateral diffusion of the lipid haptens in these membranes.

Cholesterol↗
PubMed1979

Prophylaxis of attacks of hereditary angioedema.

Danazol, an attentuated androgen, has been suggested as an effective agent for the prophylaxis of attacks of hereditary angioedema. Four patients, with a clinical history of hereditary angioedema and a demonstrated depression of the serum inhibitor of the first component of complement (C1 INH) and the fourth component of complement (C4), were entered into a study to determine the minimum effective dose of this agent. All four of the patients had been experiencing attacks at least monthly, but they had only six attacks during a total of 60 patient months of Danazol therapy. The minimum effective dose varied from 100 to 400 mg/day. The drug appeared to work by increasing the level of serum C1 INH which reached the normal range in two of four patients. Side effects were only the anticipated menstrual irregularities in the female patients. Danazol appears to be an efficacious drug for prophylaxis of hereditary angioedema.

Adult↗
PubMed1978

The first component of complement. A quantitative comparison of its biosynthesis in culture by human epithelial and mesenchymal cells.

Epithelial and mesenchymal cells synthesized and secreted all three subcomponents of the first component of complement (C1): C1q, C1r, and C1s. Quantitatively, however, columnar and transitional epithelial cells secreted 400--3,700 times more hemolytically active C1 than monocytes or fibroblasts. Only columnar epithelial cells synthesized C1 subcomponents with subunit structures similar to their serum counterparts. Transitional epithelial cells, fibroblasts, and monocytes produced C1q and C1s with subunits of apparent molecular weights larger than reported values. C1r from all cell lines was physiochemically similar to serum C1r.

Cells, Cultured↗
PubMed1974

Mechanisms of immune lysis of the red cells in hereditary erythroblastic multinuclearity with a positive acidified serum test and paroxysmal nocturnal hemoglobinuria.

The red cells of patients with hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), a form of congenital dyserythropoietic anemia, and the cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are lysed more readily than normal cells by certain antibodies, notably cold agglutinins (anti-I) and complement. With some but not other examples of anti-I, HEMPAS and PNH cells adsorbed more antibody than normal cells. Equal quantities of adsorbed antibody bound equal quantities of the first component of complement (C1) to normal, PNH, and HEMPAS cells. However, for a given quantity of bound antibody and C1, much more of the fourth component of complement (C4) was bound to HEMPAS cells than to normal cells. This resulted in the binding of proportionately larger quantities of the third component of complement (C3) to these cells. The same amount of bound C3 was found on the membranes of normal and HEMPAS cells for a given degree of lysis. Hence, the marked increase in lysis of HEMPAS cells is due to the increased adsorption of antibody and/or increased binding of C4.PNH cells bound the same amount of C4 per bound C1 as normal cells but bound more C3 than normal cells. However, the mean concentration of C3 on the membrane of PNH cells was one-third to one-fifth that on normal cells for a given degree of lysis. Hence, the increased lysis of PNH cells is due to the increased binding of C3 and increased hemolytic effectiveness of the bound C3.

Adsorption↗
PubMed1989

Identification of a human non-interferon lymphokine activating monocyte complement biosynthesis.

A monocyte-stimulating activity produced by mitogen-induced mononuclear cells has been defined by its ability to enhance the synthesis in vitro of complement C1 subcomponents, C2 and C3. A lymphokine responsible for this activity was purified from culture supernatants of peripheral blood mononuclear cells activated by staphylococcal enterotoxin A. From 0.5 litre of supernatant the purification procedure [(NH4)2SO4 precipitation, phenyl-Sepharose chromatography and preparative electrofocusing] yielded about 100 pmol of purified lymphokine. Its pI is 7.9 and its Mr, estimated by SDS/polyacrylamide-gel electrophoresis, is 14,600, 27,000 and 56,000, the high-Mr species representing oligomeric forms of the Mr-14,600 molecule. Its amino acid analysis reveals a high percentage of hydrophobic amino acids (34%); the absence of histidine residues suggests that it is a novel monocyte-activating lymphokine. It enhances C1r and C1s biosynthesis at a pretranslational level. From its structure and activity this lymphokine appears different from gamma-interferon.

Amino Acids↗
PubMed1982

Ultrastructure of the first component of human complement: electron microscopy of the crosslinked complex.

Electron micrographs are shown of the first component of human complement (C1) which has been crosslinked with a water-soluble carbodiimide to prevent dissociation into its C1q and C1r2C1s2 subunits. Two projections of the crosslinked molecule are seen in the electron micrographs, which are called "top" and "profile." In both views, the C1q heads are visible. From the top, the C1r2C1s2 tetrameric subunits appears to be located centrally on the C1q and folded to form a compact mass obscuring most of the arms and central bundle. In profile, the tetramer appears to be located in the region of the arms between the C1q heads and the central bundle. Both the heads and the rod-like central bundle appear to be free of C1r2C1s2 in these profile projections. Sometimes it is possible to count more than six domains in the region of the C1q heads, as though a portion of the tetramer had unfolded to protrude among the heads.

Complement C1↗
PubMed1981

Expression of biological effector functions by immunoglobulin G molecules lacking the hinge region.

Several biological effector functions mediated by sites on the Fc region of human IgG1 have been studied in two variant IgG1 kappa monoclonal proteins (Dob and Lec) which contain deletions corresponding to the entire hinge region of the heavy chains. Neither Dob nor Lec protein in aggregated form was able to activate the classical complement pathway, and this was shown to be due to an inability to bind the first component of complement (C1). By rosette inhibition assays, Dob and Lec proteins were shown to have no measurable affinity for Fc receptors on human B cells or neutrophils. Dob and Lec proteins had a much reduced affinity for Fc receptors on the murine macrophage-like cell line P388D1 when compared to normal human IgG1. Furthermore, the hinge-deleted proteins were able to compete with murine IgG2b for P388D1 receptors but not with murine IgG2a. In contrast, the binding of Dob and Lec proteins to protein A from Staphylococcus aureus was entirely normal. The functional consequences of the hinge deletion were parallel to those seen when normal IgG1 was reduced and alkylated. It was concluded that the functional impotency of Dob and Lec proteins was related to the close association between the Fab and Fc regions in these molecules and the limited degree of segmental flexibility permitted in the absence of the hinge region. The data also suggest a major role for the C gamma 2 domain (C is the constant region) in mediating effector functions in normal IgG1.

Animals↗