Platelet membrane receptors for the complement component C1q.
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Amino Acid Sequence↗
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Functional characterization of a recombinant form of the C-terminal, globular head region of the B-chain of human serum complement protein, C1q.
The first step in the activation of the classical pathway of the complement system by immune complexes involves the binding of the six globular heads of C1q to the Fc regions of IgG or IgM. The globular heads of C1q are located C-terminal to the six triple-helical stalks present in the molecule; each head is considered to be composed of the C-terminal halves (3x136 residues) of one A-, one B- and one C-chain. It is not known if the C-terminal globular regions, present in each of the three types of chain, are independently folded modules (with each chain having distinct binding properties towards immunoglobulins) or whether the different binding functions of C1q are dependent upon a globular structure which relies on contributions from all three chains. As a first step towards addressing this question, we have expressed the globular head region (residues 87-226) of the C1q B-chain (ghB) as a soluble fusion protein with maltose-binding protein (MBP) in Escherichia coli. The affinity purified fusion protein, designated MBP-ghB, behaved as a dimer on gel filtration and bound preferentially to aggregated IgG rather than to IgM. It could also inhibit C1q-dependent haemolysis of both IgG- and IgM-sensitized erythrocytes. After its release from MBP, by use of Factor Xa, the free ghB exhibited a tendency to aggregate and come out of solution. Since MBP is known to be a monomeric molecule, the dimerization of the MBP-ghB fusion polypeptide is probably brought about by the ghB region, perhaps through hydrophobic interactions within the ghB region. The functional behaviour of MBP-ghB indicates that the globular regions of C1q may adopt a modular organization, i.e. each globular head of C1q may be composed of three structurally and functionally independent domains, thus retaining multivalency in the form of a heterotrimer.
ATP-Binding Cassette Transporters↗
Effect of bursectomy on serum levels of chicken complement component C1q.
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Animals↗
Complement component C1q modulates the phagocytosis of Abeta by microglia.
Recent studies showing that microglia internalize the amyloid beta-peptide (Abeta) suggest that these cells have the potential for clearing Abeta deposits in Alzheimer's disease, and mechanisms that regulate the removal of Abeta may therefore be of clinical interest. Previous studies from this laboratory showing that C1q enhances phagocytosis of cellular targets by rat microglia prompted the current investigations characterizing the effects of C1q on microglial phagocytosis of Abeta. Microglia were shown to phagocytose Abeta1-42, in agreement with observations of other investigators. Uptake of Abeta1-42 was observed for concentrations of 5-50 microM, and phagocytosis of peptides containing (14)C or fluorescein (FM) labels was not affected by the interaction of microglia with C1q-coated surfaces. However, inclusion of C1q (125 nM-1.4 microM) in solutions of 50 microM Abeta1-42 inhibited the uptake of (14)C-Abeta1-42 and FM-Abeta1-42, suggesting that C1q blocks the interaction of Abeta with microglia. Uptake of Abeta was partially blocked by the scavenger receptor ligands polyinosinic acid and maleylated BSA. Inhibition of Abeta uptake by C1q may contribute to the accumulation of fibrillar, C1q-containing plaques that occurs in parallel with disease progression. These data suggest that mechanisms which interfere with the binding of C1q to Abeta may be of therapeutic value both through inhibition of the inflammatory events resulting from complement activation and via altered access of Abeta sites necessary for ingestion by microglia.
Alzheimer Disease↗
Binding of complement subcomponent C1q to mouse IgG1, IgG2a and IgG2b: a novel C1q binding assay.
A C1q binding assay is presented which is suitable for use in comparison of the binding ability of different antibodies, and which allows the quantitative determination of their binding constants. The assay system uses IgG bound to a hapten-derivatized Affigel support. No non-specific binding is observed to a DNP-derivatized support, allowing the use of anti-DNP antibodies. With mouse anti-DNP hybridoma IgGs it was found that C1q binding followed the series IgG2a greater than IgG2b much greater than IgG1, in accordance with the complement fixing ability of these subclasses. Since it is relatively simple to couple any antigen to Affigel , this assay system should be generally applicable to any antibody-antigen system.
2,4-Dinitrophenol↗
Human complement component C1q inhibits the infectivity of cell-free HTLV-I.
Human T cell leukemia virus type I (HTLV-I) is a retrovirus that is not lysed by human serum or complement. It has not been determined, however, whether HTLV-I directly binds to complement components or whether it retains infectivity after incubation with human serum. We investigated the effects of human serum on the infectivity of cell-free HTLV-I produced by human and animal cells. Plating of vesicular stomatitis virus (HTLV-I) pseudotypes prepared in cat or human cells and formation of HTLV-I DNA after infection of cell-free HTLV-I produced by cat or human cells were markedly inhibited by treatment with fresh human serum, but not by heat-inactivated serum. HTLV-I infection was also inhibited by treatment with C2-, C3-, C6-, or C9-deficient serum, but not by C1q-deficient serum. Inhibitory activities of normal human serum against HTLV-I were neutralized by anti-C1q serum. Furthermore, purified C1q inhibited HTLV-I infection. The direct binding of C1q to HTLV-I was confirmed by comigration of C1q with HTLV-I virion upon sucrose density gradient ultracentrifugation of HTLV-I virion treated with C1q. Binding assay using synthetic envelope peptides indicated that C1q bound to an extramembrane region of the gp21 transmembrane protein. These findings indicate that the human complement component C1q inactivates HTLV-I infectivity.
Animals↗
[Kinetics of the complement subcomponent C1q production of peritoneal macrophages in NZB/W F1 female mice].
To clarify the role of local production (exohepatic) of complement on primary host defense mechanisms against microbial infections in the host who decreased the amount of complement in serum, the kinetics of the complement production by the complement-producing cells in exohepatic tissue was examined by measuring the amount of C1q, subcomponent of the first complement component, in cultured supernatant of the monolayer of peritoneal macrophages (PM phi) collected from 5, 15, 35, and 48 weeks-old female mice of NZB/W F1 (B/W F1). The C1q production of PM phi in B/W F1 mice showed remarkable decrease at 15 weeks-old. After that, however, the C1q producibility of PM phi recovered gradually and, at mice 48 weeks old, the complement produced finally exceeded the amount observed in mice 5 weeks-old, contrariwise the C1q values in serum were significantly lowering in the same aged mice. The increased production of C1q of PM phi was observed in both 35 and 48 weeks-old mice, of which the value corresponded with increase of anti-nuclear antibody titer in serum and of the amount of protein in urine. On female mice of ddY (control), the amount of C1q production of PM phi in 5 weeks-old mice was two-fold higher than that of 5 weeks-old B/WF1 mice. But at 15 weeks, the production showed a 1/2 decrease in that of mice 5 weeks-old and the decreased values were kept to 35 weeks-old.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
C1q-binding proteins and C1q receptors.
Aggregated or immobilized complement C1q induces cellular responses in many different cell types. C1q-induced cellular responses may be involved in host defense and in protection against autoimmunity because C1q-deficient humans have infectious complications and a very high incidence of autoimmune disease. The search for the C1q receptor(s), which has been ongoing for 25 years, has led recently to the recognition that proteins identified as binding to C1q may be divided into two groups: C1q-binding molecules that are normally intracellular; and cell surface C1q receptors.
Carrier Proteins↗
Chemical studies on the isolated collagen-like and globular fragment of complement component C1q. Comparative studies on bovine and human C1q.
Both the collagen-like and the globular fragments of a subcomponent C1q of the first component of bovine and human complement were highly purified by enzymic digestion followed by gel filtration. Analyses by polyacrylamide gel electrophoresis showed that the former was composed of covalently linked peptide chains with an average molecular weight of 14 000, and that the latter was composed of three non-covalently linked peptide chains each having a molecular weight of approximately 15 000. Great similarities between amino acid compositions of the globular fragments and some similarities between those of the collagen-like fragments were found. Moreover, great similarities of amino acid compositions were found among three non-covalently linked chains of each globular fragment as well as between the corresponding chains of both globular fragments. These results suggested that both the collagen-like and the globular domains on the C1q molecule remained highly conserved in its evolution.
Amino Acids↗
Binding of complement component C1q by spectrin.
125I-labelled human C1q was found to bind to human spectrin. Scatchard plots for the binding process were non-linear, indicating the possible presence of multiple classes of binding sites for C1q on spectrin. The binding was ionic-strength-dependent; the extent of binding decreased with increasing ionic strength. Chemical modification of arginine and histidine residues on C1q as well as pretreatment of C1q at pH 4.45 or at 56 degrees C reduced its spectrin binding activity. The amount of 125I-labelled C1q bound to immune complexes was reduced by the presence of spectrin. Spectrin was also able to deplete the complement haemolytic activity of human serum in a dose-dependent manner.
Complement Activating Enzymes↗
Immunoglobulin M possesses two binding sites for complement subcomponent C1q, and soluble 1:1 and 2:1 complexes are formed in solution at reduced ionic strength.
Soluble complexes were formed between C1q, a subunit of the first component of human complement, and four different Waldenström IgM proteins at reduced ionic strengths. The equilibria between these complexes and the free proteins were studied in the ultracentrifuge. Complex formation was found to be a very sensitive function of the salt concentration, and at physiological ionic strength complex formation was negligible. The complexes were cross-linked with a water-soluble carbodiimide and separated by sucrose gradient centrifugation. Both 22 S 1:1 and 26 S 2:1 C1q X IgM complexes were formed; stoichiometry was established by cross-linking 125I-C1q with 131I-IgM and determining the ratios of the specific activities of the gradient-purified materials. The association process was studied as a function of protein concentration and was analyzed by Scatchard and Hill plots to yield stoichiometry, association constant, and degree of cooperativity. The results indicated that IgM has two identical and independent binding sites for C1q. The intrinsic association constant was found to vary between 10(6) M-1 at 0.084 M ionic strength to 10(4) M-1 at physiological ionic strength; the slope of the log-log plot gave a value of -6.0. The cross-linked complexes were examined by electron microscopy, and the C1q appeared to be attached to the IgM through the C1q heads, implying that the biologically significant binding sites were involved in this interaction. For the 2:1 complexes, the two C1q appeared to attach to opposite surfaces of the IgM, suggesting the presence of a pseudo-2-fold axis lying in the plane of the IgM disk.
Binding Sites↗
Effects of incorporation of immunoglobulin G and complement component C1q on uptake and degradation of Alzheimer's disease amyloid fibrils by microglia.
Microglia are macrophage-like immune system cells found in the brain. They are associated with Alzheimer's Disease plaques, which contain fibrillar beta-amyloid (fAbeta) and other components such as complement proteins. We have shown previously that murine microglia bind and internalize fAbeta microaggregates via the type A scavenger receptor, but degradation of internalized fAbeta is significantly slower than normal degradation. In this study, we compared internalization by microglia of fAbeta microaggregates to that of anti-Abeta-antibody-coated fAbeta (IgG-fAbeta) microaggregates and found that the uptake of the latter is increased by about 1.5-fold versus unmodified fAbeta. The endocytic trafficking of IgG-fAbeta is similar to that of fAbeta microaggregates, following an endosomal/lysosomal pathway. We also compared the internalization of fAbeta microaggregates to that of complement protein, C1q-coated fAbeta microaggregates, and found that the levels of uptake are also increased by about 1.5-fold. Rates of degradation of both types of modified fAbeta microaggregates are unchanged compared with unmodified fAbeta microaggregates. We demonstrated by blocking studies that internalization of IgG-fAbeta is mediated by Fc receptors. These data suggest that, in vivo, several different microglial receptors may play a part in internalizing fAbeta, but the involvement of other receptors may not increase the degradation of fAbeta.
Alzheimer Disease↗
Measurement of macromolecular interactions between complement subcomponents C1q, C1r, C1s, and immunoglobulin IgM by sedimentation analysis using the analytical ultracentrifuge.
The interactions between the complement components and with immunoglobulins are greatly enhanced by lowering the ionic strength and become readily measurable by physical techniques. Thus, the binding between C1q and IgM was previously shown to be appreciable (k = 1 x 10(6) M-1) at 0.084 M ionic strength (Poon, P.H., Phillips, M.L., and Schumaker, V.N. (1985) J. Biol. Chem. 260, 9357-9365). We have now found that, at 0.128 M ionic strength, the binding between human C1- (the activated first component of complement) and IgM was strong at physiological concentrations (k = 1 x 10(7) M-1), while under the same conditions binding between C1q and IgM was not observed. To explore the nature of the interactions responsible for this enhanced binding by C1- over C1q, mixtures of the various subcomponents of C1- were studied alone and with IgM. C1r2 did not bind to C1q, even when the ionic strength was reduced to 0.098 M, nor did the presence of C1r2 enhance the binding of C1q to IgM. In contrast, two C1s2 independently bound to C1q (k = 1 x 10(6) M-1), and caused a marked increase in its association with IgM (k = 5 x 10(6) M-1) at 0.098 M ionic strength. No detectable interaction was found between C1s2 and/or C1r2 and IgM in the absence of C1q. Moreover, there was no detectable interaction between the C1(-)-like complex formed between C1r2C1s2 and the collagenous C1q stalks (pepsin-digested C1q) and IgM. These data suggest that the binding of C1s2 to C1q, either alone or together with C1r2, induces a conformational change in C1q which results in additional C1q heads binding to complementary sites on IgM.
Complement C1q↗
Arthritis-regulating determinants on the collagen-like complement component C1q.
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Amino Acid Sequence↗
Binding of complement component C1q to anti-beta2 glycoprotein I antibodies from patients with antiphospholipid syndrome.
OBJECTIVE: To determine if anti-beta2 GPI reactive with surface-bound beta2 GPI can bind C1q, i. e. to determine whether surface-bound beta2 GPI-anti-beta2 GPI immune complexes can initiate the classical pathway of complement activation. METHODS: Beta2 GPI was bound to chemically-activated microtiter plates which had previously been shown to promote anti-beta2 GPI reactivity with bound beta2 GPI. Wells with surface-bound beta2 GPI (capped with bovine serum albumin) were then reacted with complement-inactivated sera from antiphospholipid syndrome patients (APS) or with control sera. Following removal of unbound serum components, the wells were incubated with biotinylated C1q and probed with peroxidase-conjugated avidin D. Bound C1q was detected at 450 nm using tetramethyl benzidine/peroxidase as a substrate system and expressed as absorbance units (Abs). RESULTS: The identified 20 APS with elevated anti-beta2 GPI: 4 with IgG only, 4 with IgM only, 1 with IgA only, 1 with IgG and IgA, 6 with IgG and IgM and 4 with IgG, IgA and IgM. C1q binding from 20 healthy controls was 0.039 +/- 0.029 (SD). Of the APS, 17/20 (85%) had Abs >5 SD above controls. The 3 APS with C1q Abs within normal limits had, respectively, IgM only (1), IgA only (1), and both IgG and IgM (1). Statistical analyses (Kruskal-Wallis followed by Dunn's post test) suggest differences in IgG and IgG + IgM groups compared to con (Kruskal-Wallis: p = 0.0002; Dunn's: con vs. IgG, p < 0.05; con vs. IgG + IgM, p < 0.01). CONCLUSIONS: Anti-beta2 GPI from APS appear to have a variable degree of C1q affinity. Those patients with strong C1q binding responses are likely to have an inflammatory component to their disease processes.
Antigen-Antibody Complex↗
Mapping of the interaction between the immunodominant loop of the ectodomain of HIV-1 gp41 and human complement protein C1q.
The human immunodeficiency virus type 1 transmembrane envelope glycoprotein gp41 has been previously shown to activate the C1 complex of human complement through direct interaction with its C1q subunit. The major interaction site has been located within the gp41 immunodominant region (residues 590-620), and a synthetic peptide overlapping residues 601-613 of gp41 (sequence GIWGCSGKLICTT) was shown to inhibit binding of gp41 to C1q in vitro (Thielens, N.M., Bally, I.M., Ebenbichler, C.F., Dierich, M.P. & Arlaud, G.J. (1993) J. Immunol. 151, 6583-6592). The ectodomain of gp41 (s-gp41) was secreted from the methylotrophic yeast Pichia pastoris and purified by immunoaffinity chromatography. Enzymatic deglycosylation of the recombinant s-gp41 was necessary to allow its in vitro interaction with C1q. A solid-phase competition assay was used to monitor the effect of mutant peptides derived from segment 601-613 of gp41 on the binding of deglycosylated s-gp41 to C1q. Whereas mutation of Ser606 had no effect, replacement of Ile602, Trp603, Lys608, Leu609 and Ile610 by Ala abolished the ability of the resulting peptides to inhibit binding of s-gp41 to C1q, suggesting that these residues participate in the interaction between gp41 and C1q. These findings are discussed in the light of a structural model of the immunodominant loop of gp41. It is proposed that the recognition of gp41 by C1q is driven by hydrophobic interactions, and that the sites of gp41 responsible for interaction with gp120 and C1q partly overlap.
Amino Acid Sequence↗
Complement subcomponent C1q secreted by cultured human monocytes has subunit structure identical with that of serum C1q.
An enzyme-linked immunosorbent assay (e.l.i.s.a.) that is capable of quantifying C1q concentrations as low as 2 ng/ml and a sensitive haemolytic assay were used to study the appearance of material that cross-reacts with human serum C1q as well as C1q haemolytic activity in human monocyte culture media. This material was detected in the medium after 10-14 days and continued to be secreted through to day 28 of culture, at which time the cultures were terminated. Material specifically immunoabsorbed with Sepharose-anti-C1q antibody from a culture medium of cells that was metabolically labelled with [3H] proline or [35S] methionine demonstrated a polypeptide pattern identical with that of serum C1q on SDS/polyacrylamide-gel electrophoresis. Under non-reducing conditions two protein bands were detected migrating with the same Rf values as the serum C1q A-B and C-C dimers. On reduction three bands were evident, which migrated identically with the A, B and C chains of serum C1q. The amount of radioactivity in these bands increased with time in culture, consistent with the e.l.i.s.a. and haemolytic C1q assays. These bands were reactive with monospecific anti-C1q antibody after transfer to nitrocellulose.
Ascorbic Acid↗
Complement subcomponent C1q stimulates Ig production by human B lymphocytes.
The regulation of Ig production by human B lymphocytes is a complex process involving interactions among B cells, APC, T lymphocytes and soluble factors including activation, growth, and differentiation factors. Components of the complement system, including C3a, C3b, C3d, and C5a, have been shown to influence various stages in this process. In this study, we demonstrate that the C1q subcomponent of complement binds to both small resting and large activated B cells and stimulates immunoglobulin production by Staphylococcus aureus Cowan-activated tonsillar B lymphocytes. This effect is present whether C1q is added to the B cells either at the beginning or near the end of a 7-day culture period and is not associated with enhancement of proliferation. The C1q stimulation of Ig production is, however, associated with increased steady state levels of mRNA for the mu Ig H chain. Furthermore, C1q stimulated IgM production by the human B cell line SKW 6.4, which is capable of secreting IgM in response to B cell differentiation factors (BCDF). SLE is a disorder frequently associated with polyclonal activation of B lymphocytes. We studied the effect of C1q on B cells from two patients with this disorder and one with an SLE-like illness, all selected for the predominance of either IgM or IgG in serum. Spontaneous or BCDF-stimulated Ig secretion was of the isotype predominant in vivo, whereas C1q selectively stimulated B cells to produce the other isotype (IgG vs IgM). Thus, C1q interacts with B lymphocytes in a manner distinct from that of BCDF found in mixed lymphocyte supernatants. C1q may be an important factor influencing the production of Ig by B lymphocytes in normal individuals and in patients with abnormalities of B cell activity.
B-Lymphocytes↗