Complement research: biosynthesis, genetics, immunoregulatory role and clinical studies (original) (raw)
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Genetic linkage between serum levels of the third component of complement and the H-2 complex
Journal of Experimental Medicine, 1975
(1) studied the HLA pedigree of a family with a complement deficiency (C2) and showed evidence for a close linkage between the C2 defect and the HLA loci . Complement (C)-dependent hemolytic activity of mouse serum is also genetically controlled . One locus, He (hemolytic complement, with two alleles He' and He') determines the presence or absence of C5 (2-4) and is not linked to the H-2 major histocompatibility complex (5) . In addition, Demant et al . (6) showed that the S region of the H-2 complex, which contains genes controlling serum levels of Ss and Sip proteins, influences the hemolytic activity of mouse complement . However, they provided no information regarding the specific component involved . We show here that serum levels of C3 in mice are determined by gene(s) linked with the H-2 complex.
1975
Certain anti-H-2 sera contain an antibody-like activity which specifically inhibits EAC rosette formation by lymphoid (and not myeloid) cells of certain mouse strains. Studies in congenic recombinant mouse strains strongly indicate that at least part of the control of susceptibility to inhibition by these antisera is mediated by H-2 linked genes, mapping in the I-C subregion or the S region. The strain distribution of the trait CRIS indicates that certain H-2 identical mice behave differently from one another, pointing toward a component of non-H-2 modulation of the H-2 linked gene (or to a previously unsuspected H-2 difference). Positive sera were usually raised across differences in the D end of the H-2 complex. The complex implications of this system must be considered in the light of known S region involvement in complement metabolism.
Journal of Experimental Medicine, 1980
The S region of H-2 controls a polymorphism of the gamma-chain of C4 (gamma 1, gamma 2, and gamma 3) as shown by differences in their isoelectric points. The G region of H-2 was defined by the presence of an alloantigen (H-2.7) on erythrocytes and serum. We found that antisera to H-2.7 immunoprecipitated C4 and no other protein from mouse EDTA-plasma. Furthermore, all H-2.7-positive strains bear C4-gamma 1, and conversely, H-2.7-negative mice bear C4-gamma 2 or gamma 3 (with one exception; see below). The H-2.7 specificity resides on C4d, a 45,000-mol wt fragment generated from the cleavage of the alpha'-chain of C4b by serum control proteins. Because the C4d fragment bears the labile binding site of C4 for cell membranes, it is likely that the erythrocyte alloantigen is acquired from serum as a result of the activation of C4. On the basis of these findings, the existence of a separate G locus is unlikely. Our results also show that C4-gamma 1 and C4-gamma 2 differ from each oth...
Effect of cytokines on the secretion of the fifth and eighth complement components by HepG2 cells
International Journal of Clinical & Laboratory Research, 1994
Liver cells can be induced by interleukin-1, tumor necrosis factor and interleukin-6 to secrete higher amounts of complement components. Information, so far available only for the early components, indicates that these cytokines exhibit different effects on various complement proteins. For instance, they promote the biosynthesis of C3 and B but have no effect on that of C4 and C2. These observations led us to evaluate the ability of interleukin-1, tumor necrosis factor and interleukin-6 to modulate the secretion of the late complement components by HepG2 cells, a human hepatoma-derived cell line known to produce several complement proteins. The amount of complement components in the culture supernatant was evaluated by a sensitive enzyme-linked immunosorbent assay revealing picogram levels of these proteins. The HepG2 cells were found to secrete a substantial amount of C3 (approximately 1 i.tg/106 cells), easily detectable C5 (approximately 150 ng/106 cells) and C8 (approximately 10 ng/106 cells) and a low amount of C6 (approximately 0.5 ng/106 cells), whereas the levels of both C7 and C9 could not be measured. The addition of interleukin-l, tumor necrosis factor and interleukin-6 to the cell culture resulted in an enhanced secretion of C8, whereas that of C5 was only marginally increased. None of these cytokines had a clear effect on the secretion of C6 nor induced the production of C7 and C9. The magnitude of increased levels of C3 and C8 in the culture medium was related to the cytokine used, since interleukin-6 induced a more substantial response of C8 than interleukin-l, and, conversely, interleukin-1 was more effective than interleukin-6 in enhancing the secretion of C3. No clear differences were found in the amount of the various components secreted in response to tumor necrosis factor.
Complement receptors on lymphocytes
Journal of Cancer Research and Clinical Oncology, 1981
Sheep erythrocytes coated with C3b, a fragment of the third component of complement (C3), are capable by means of the C3 fragment to adhere to certain cells, termed complement receptor positive cells (CR +C). This characteristic has been used to discern lymphocyte subpopulations .
Cellular Immunology, 1977
The responses of mouse lymphoid cell cultures to mitogens such as concanavalin A or antigen were inhibited by the addition of small amounts of fresh human serum. This inhibitory effect was reduced by specific decomplementation procedures such as heating at 50°C to inactivate factor B or absorption with zymosan at 17°C to deplete properdin from the serum. Human factor-B preparations reconstituted the inhibitory effect lost from human serum preparations heated at 50°C. These findings are interpreted to indicate a fundamental role of activation of the alternative complement pathway (ACP) as an underlying mechanism of inhibition. Additional experiments designed to demonstrate a role of natural antibodies activating the classical complement pathway, while successful in these respects, also provided confirmatory evidence for an antibody-independent role of the ACP. Furthermore, data derived from experiments utilizing mouse sera tested on syngeneic mouse lymphoid target cells, were qualitatively similar to the results obtained employing human sera. The data suggest that the functional activities of mouse lymphocytes in vitro are inhibited by antibody-independent activation of the ACP, implying that this pathway may exercise a role in regulating lymphocyte function. of natural antibody and of the classical and alternative complement pathways.
Effect of interferon- γ on complement gene expression in different cell types
Biochemical Journal, 1992
We have studied the expression of the complement components C2, C3, factor B, Cl inhibitor (Cl-inh), C4-binding protein (C4-bp) and factor H in human peripheral blood monocytes, skin fibroblasts, umbilical vein endothelial cells (HUVEC) and the human hepatoma cell line G2 (Hep G2) in the absence and the presence of interferon-y (IFN-y). E.l.i.s.a. performed on culture fluids, run-on transcription assays, Northern blot and double-dilution dot-blot techniques confirmed that monocytes expressed all six components, whereas fibroblasts, HUVEC and HepG2 each expressed five of the six components. Fibroblasts and HUVEC did not synthesize C4-bp, and Hep G2 did not produce factor H. In addition to these differences, the synthesis rates of C3, Cl-inh and factor H were not the same in all cell types. However, the synthesis rates of C2 and factor B were similar in all four cell types. The half-lives of the mRNAs were shorter in monocytes than in other cell types. Monocyte factor H mRNA had a half-life of 12 min in monocytes, compared with over 3 h in fibroblasts and HUVEC. The instability of factor H mRNA in monocytes may contribute to their low factor H secretion rate. IFN-y produced dose-dependent stimulation of C2, factor B, C1-inh, C4-bp and factor H synthesis by all cell types expressing these proteins, but decreased C3 synthesis in all four cell types. Cell-specific differences in the response to IFN-y were observed. The increased rates of transcription of the Cl-inh and factor H genes in HUVEC were greater than in other cell types, while the increased rate of transcription of the C2, factor B and Cl-inh genes in Hep G2 cells was less than in other cell types. IFN-y did not affect the stability of C3, factor H or C4-bp mRNAs, but increased the stability of factor B and Cl-inh mRNAs and decreased the stability of C2 mRNA. Although these changes occurred in all four cell types studied, the half-life of Cl-inh mRNA in monocytes was increased almost 4-fold, whereas the increases in the other cell types were less than 30 %. These data show that the constitutive synthesis rates of complement components may vary in the different cell types. They also show that the degree of change in synthesis rates in response to IFN-y in each of the cell types often varies due to differences in transcriptional response, sometimes in association with changes in mRNA stability.
Clinical immunology and immunopathology, 1976
Guinea pig and fresh human serum inhibit the binding of aggregated human IgG to human peripheral B lymphocytes. It has been confirmed that this inhibition is mediated through the activated complement system. The presence of functionally active Cl was demonstrated on the surface of human peripheral lymphocytes. The role of surface Cl was studied in the activation of the complement system during the complement-mediated inhibition of the binding of IgG aggregates to Fc receptors of human B lymphocytes. Elimination of Cl from the surface of lymphocytes by EDTA treatment almost fully eliminated the inhibitory effect of serum on the aggregated IgG binding. The significance of the Cl on lymphocytes in the modulation of the immunoglobulin binding function of Fc receptors is discussed.
Biochemical Journal, 1984
The rosetting of defined C3-fragment-coated sheep erythrocytes to B-cell-enriched tonsil lymphocytes was measured. The rosetting lymphocytes were homogeneous with respect to expression of C3b, iC3b and C3d receptors. Isolation of receptors for C3 fragments from surface-radioiodinated lymphocytes by affinity chromatography on immobilized C3u, iC3b and C3d,g produced two proteins with partially overlapping specificities. A protein of 240 000 Mr, recognized by the monoclonal antibody To5 and identified as CR1 (complement receptor type 1), had affinity for C3u and iC3b. A protein of 145 000 Mr, recognized by the monoclonal antibody B2, had affinity for all three C3 fragments. Inhibition of rosetting by antibodies to these proteins indicates that CR1 is responsible for C3b-mediated rosetting and that the 145000-Mr receptor (CR2) is responsible for C3d-mediated rosetting. Partial inhibition by both anti-CR1 and anti-CR2 antibodies of iC3b-mediated rosetting indicates that both receptors a...
The Journal of Immunology, 2000
Deficiencies in C factors C2, C3, or C4 as well as lack of C receptors 1 and 2 (CR1/2) lead to impaired Ab production. Classical pathway activation plays a major role, as mice deficient in factor B, a key factor in the alternative pathway, have normal Ab production. Abs in complex with their specific Ag are known to feedback regulate the Ab response, and enhanced responses are initiated by IgM, IgE, and IgG. IgM acts via the C system, whereas IgE and IgG can operate independently of C via Fc receptors. Here we have investigated whether these isotypes are able to enhance Ab responses in mice lacking CR1/2. SRBC-specific IgM, administered with SRBC, does not enhance Ab responses in these animals. In contrast, 2,4,6-trinitrophenyl-specific IgE and IgG2a, administered with BSA-2,4,6-trinitrophenyl, induce potent Ab responses in CR1/2-deficient mice. Additionally, BSA administered with CFA or alum induced strong Ab responses in the absence of CR1/2. These results indicate that CR1/2 is needed to promote IgM-mediated induction of primary Ab responses. The data also show that the need for CR1/2 can be circumvented by Abs typical of a secondary immune response forming complexes with Ag or by conventional adjuvants, presumably mimicking physiological inflammatory reactions.