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PubMed1975

Third component of complement (C3): structural properties in relation to functions.

The third component of complement (C3) fulfills a pivotal role in the functions of the complement system. We have investigated the topological relationships among its polypeptide chains, physiologic fragments, enzyme attack regions, and functional sites. C3 consists of two chains (alpha and beta) which are linked by disulfide bonds and noncovalent forces and which have molecular weights of, respectively, 120,000 and 75,000. C3 is activated by action of C3 convertase on the alpha-chain. With hydrolysis of one polypeptide bonds, C3a, the 9000 dalton activation peptide is dislocated from the NH2-terminal portion of the alpha-chain. A previously concealed binding region is thereby transiently revealed in the C3b-fragment (181,000 dalton) which displays affinity for apparently nonspecific acceptors present on biological membranes. Binding of nascent C3b membranes occurs through the C3d portion of the fragment because subsequent action of the C3b-inactivator or trypsin on bound C3b causes release of C3c, but not of C3d. Bound C3b and C3d possess stable sites that are capable of binding to specific receptors present on a limited variety of cells. We propose that all known physiologically occurring fragments of C3 arise by enzymatic cleavage of the alpha-chain: C3a, C3b, C3c, and C3d. Whereas C3a (alpha1) and C3e (alpha2) consist of a single chain and C3b consists of two chains (alpha' and beta), C3c is composed of the entire beta-chain and multiple fragments of the alpha-chain, each of which is linked by disulfide bonds to the beta-chain.

Binding Sites↗
PubMed1992

Effects of cell differentiation on the synthesis of the third and fourth component of complement (C3, C4) by the human monocytic cell line U937.

Association of complement synthesis with cell differentiation in U937 cells was investigated using granulocyte-macrophage colony-stimulating factor (GM-CSF), vitamin D3 and interferon-gamma (IFN-gamma) as differentiation-inducing agents. GM-CSF or vitamin D3 enhanced the synthesis of the third component of complement (C3) by U937 cells, but had no stimulatory effect on the synthesis of the fourth component of complement (C4). IFN-gamma increased both C3 and C4 synthesis by U937 cells. Combination of two of these three agents resulted in synergistic enhancement and all three agents caused maximal enhancement of C3 synthesis. Vitamin D3 enhanced IFN-gamma-induced C4 synthesis by U937 cells. These results were confirmed by ELISA and SDS-PAGE after biosynthetic labelling. GM-CSF, vitamin D3 or IFN-gamma increased the expression of complement receptor type 3 (CR3), one of the markers of monocyte/macrophage differentiation. Two of these agents caused a further increase and all three agents maximal increase in CR3 expression. Since C3 was synthesized in parallel with the degree of CR3 expression, the synthesis of C3, but not C4, by U937 cells is thought to be closely related to cell differentiation. It was reconfirmed that the synthesis of C3 and C4 by U937 cells was independently regulated.

Cell Differentiation↗
PubMed1975

Interactions of the third component of complement (C3) with cross-linked dextran. IV. Adherence of lymphocytes to C3 coated dextran gel particles.

In previous studies we could show that the third component of complement (C3) is bound from normal serum to cross-linked dextran (Sephadex) after activation via an alternate pathway. Data presented in this paper demonstrate that a subpopulation of human lymphocytes adheries to C3 coated Sephadex particles. The adhering subpopulation of lymphocytes is identical with or overlaps extensively with lymphocytes bearing easily detectable membrane Ig. This phenomenon can be used for the fractionation of lymphocyte subpopulations. After a single passage of tonsillar lymphocytes through C3 coated Sephadex bead columns, no membrane Ig positive lymphocytes were detectable in the effluent. 97-100% of effluent cells formed rosettes with untreated sheep red blood cells, thus resembling pure T cells. Apart from that, the use of C3 coated dextran gel particles allows also the recovery of adherent cells after dextranase digestion of the dextran gel particles. An investigation of retained cells showed enrichment of B cells, but also T cells were demonstrable. The retention of these T cells is probably due to nonspecific interactions.

Cell Separation↗
PubMed1977

Biosynthesis of the third component of complement (C3) in vitro by monocytes from both normal and homozygous C3-deficient humans.

Human monocytes synthesized the third component of complement (C3) up to 5 wk in vitro. Evidence for net C3 synthesis was based on (a) incorporation of 14C-labeled amino acids into C3 protein, (b) indentity of the allotype of C3 produced in vitro with that of the doner's serum C3, even in the presence of carrier C3 protein of a different allotype; (c) correspondence of electrophoretic mobility, size, and subunit structure of C3 protein produced in vitro with serum C3; (d) inhibition of C3 production with cycloheximide. Monocytes from two unrelated C3-deficient patients were studied under conditions that supported C3 synthesis by normal monocytes. Serum from each of the patients contained less than 1% of the normal C3 concentration, buth their monocytes produced C3 at approximately equal to 25% of the normal rate when studied after 2 wk in vitro. The C3 produced in vitro by monocytes from one of the patients had the molecular weight of normal serum C3 and dissociated appropriately under reducing conditions. Monocytes from C3-deficient patients could not be distinguished from normals on the basis of morphology, rosetting with C3-coated erythrocytes, or rates of C2, and total protein synthesis.

Blood Proteins↗
PubMed1977

Immunoelectronmicroscopical demonstration of in vivo bound complement C3 in psoriatic lesions.

The presence of in vivo bound complement (C3) within the stratum corneum of 4 psoriatic cases is demonstrated ultrastructurally by the use of the peroxidase-antiperoxidase multistep technique. The positive reaction product was located in the intercellular space and on the surface of the parakeratotic cells within the horny layer. The membranes of the horny cells were not altered and peroxidase granules could also not be detected within their cytoplasm. The explanation of this finding as well as its pathogenetic significance is discussed.

Animals↗
PubMed1992

Serum immunoglobulin and complement C3 levels in workers exposed to lead.

Serum immunoglobulin and complement C3 levels were measured in workers exposed to lead at a secondary lead refinery and a solder factory. In the first survey, significant correlations were found between blood lead and IgA with a correlation coefficient of 0.296, and between blood lead and IgE with a correlation coefficient of 0.314. No other significant correlations were found among the indicators of lead exposure and humoral immunity. In the second survey, no significant correlations were found between blood lead and IgG and IgA. A significantly higher number of subjects with IgE of more than 400 IU/ml was found in the group with blood lead of more than 60 micrograms/100 g.

Adolescent↗
PubMed1990

Molecular basis of complement C3 deficiency in guinea pigs.

In experiments to ascertain the biochemical basis of a genetically determined deficiency of the third component of complement (C3) in guinea pigs, we found that C3-deficient liver and peritoneal macrophages contain C3 messenger RNA of normal size (approximately 5 kb) and amounts, that this mRNA programs synthesis of pro-C3 in oocytes primed with liver RNA and in primary macrophage cultures. In each instance, heterodimeric native C3 protein was secreted with normal kinetics but the C3 protein product of the deficient cells failed to undergo autolytic cleavage and was unusually susceptible to proteolysis. These data and a selective failure of C3 in plasma of deficient animals to incorporate [14C]methylamine suggested either a mutation in primary structure of the C3 protein or a selective defect in co- or postsynthetic processing affecting the thiolester bridge, a structure important for C3 function. A mutation in the primary structure of C3 was ruled out by comparison of direct sequence analysis of C3 cDNA generated from two C3 deficient and two C3 sufficient guinea pig liver libraries. Three base pair differences, none resulting in derived amino acid sequence differences were identified. Finally, restriction fragment length polymorphisms were identified in the C3 gene that are independent of the deficiency phenotype. This marker of the C3 gene permits testing of these hypotheses using molecular biological and classical genetic methods.

Amino Acid Sequence↗
PubMed1990

Synthesis of the third component of complement (C3) by lectin-activated and HTLV-infected human T-cells.

The third component of complement (C3) plays key roles in complement activation of both the classical and alternative pathways. The liver is the major site of C3 synthesis; monocytes, B-lymphocytes and leukemic cell lines of the myeloid lineage also synthesize C3. Here we report that the C3 gene is inactive in fresh T-cells, but active in T-cells treated with the lectin phytohemagglutinin (PHA). Northern blot hybridization studies show that PHA-activated T-cells and all the T-cell lines tested express the 5.3 kb RNA transcript reported for C3 in HepG2, a hepatoma cell line, and monocytes. We used radioimmune precipitation followed by polyacrylamide gel electrophoresis to show that PHA-stimulated T-cells and T-cell lines, which are not infected with the human T-lymphotropic virus (HTLV), synthesize and release C3 proteins with molecular masses of 185, 115 and 80 kD; HTLV-infected T-cell lines release C3 proteins of 170, 115 and 70 kD. In contrast, monocytes produced C3 proteins of 115 and 70 kD similar to the serum form of this protein. The role of T-lymphocyte C3 and the implications of HTLV-infection are discussed.

Blotting, Northern↗
PubMed1990

[A comparative study of serum complement (C3 and C4) in inflammatory joint diseases].

The third and the fourth fraction of the complement (C3 and C4), haptoglobin, fibrinogen, alpha 1-glycoprotein, alpha 2-macroglobulin and transferrin were examined in 692 patients with inflammatory joint disease--rheumatism, rheumatoid arthritis, ankylosing spondylarthritis, psoriatic arthritis, Reiter's syndrome, sacroiliitis [correction of sacroileitis], reactive arthritis, gout, osteoarthrosis and nosologically undefined arthritis in active or nonactive phase and in 60 healthy controls. The complement fractions studied show an increase of various degree and importance in almost all groups of patients in both phases studied. The relations between the complement fractions and the other acute phase indices show significant correlations between them and the other acute phase indices. C3 and to a certain degree C4 could be added to the acute phase reacting indices. Their place in the downgrade scale is as follows: fibrinogen, haptoglobin, alpha 1-glycoprotein, C3, C4, alpha 2-macroglobulin, transferrin.

Acute-Phase Proteins↗
PubMed1992

[Complement (C3 and C4) in patients with rheumatoid arthritis during 6 months of treatment with gold salts].

The aim of research was to establish effect of gold-salts under protected name "Tauredon" Byk Gulden, on the dynamics of fraction of complements C3 and C4 at patients with rheumatoid arthritis. Following the dynamics of both parameters, was performed during 6 months continued application of "Tauredon", on 8 men and 35 women with certain diagnosis. Profile of the age of patients was 50 years old. With continuous observation of patients and their laboratory findings, in regular time intervals, we found out that "Tauredon" has significant influence on increase of level of C3 in serum of patients (P = 0.006) but not in increase of fraction of complement C4 (P = 0.117).

Adult↗
PubMed1979

A simple electrophoretic technique for the estimation of complement C3 conversion: specific application to the investigation of anaphylactoid response to I.V. agents.

A simple electrophoretic technique employing commercially available agarose films is described for the routine estimation of plasma complement C3 conversion. This technique has particular value in the investigation of anaphylactoid responses in patients following the administration of intravenous hypnotic drugs, plasma substitutes or radio-contrast media.

Alfaxalone Alfadolone Mixture↗
PubMed1977

The significance of serial measurement of serum anti-native DNA antibodies and complement C3 and C4 components in the management of patients with systemic lupus erythematosus.

Serial measurements were made over a period of three years of serum DNA-binding capacity and complement C3 and C4 levels in parallel with documentation of clinical features of disease activity in Glasgow patients with SLE. Raised DNA-binding levels were noted in 27 of the 32 patients over this time period. High levels (over 80%) were found in patients with both renal and non-renal disease. In some patients increases in DNA-binding capacity and decreases in C3 levels were associated with changes in disease activity. This pattern was commonest in patients with renal SLE. In others DNA-binding capacity was elevated without any relationship to SLE disease activity. A fall in serum C3 levels was usually significant while serum C4 levels frequently fell without any change in clinical features of disease activity. Very low serum C4 levels (below 15 mg/dl), however, were usually of clinical relevance. The uses of immunological measurements in the differential diagnosis of a major illness in a patient with SLE are discussed. The finding of such an illness in a patient with normal serum DNA-binding levels made it unlikely that the illness was due to an exacerbation of the SLE and more likely that an alternative cause such as supervening bacteraemia was responsible.

Antibodies↗
PubMed1979

Complement C3 and immunoglobulin in inflammatory acne vulgaris.

In patients with moderate to severe inflammatory acne, complement (C3) was detected by immunofluorescence in sixteen early inflammatory acne lesions but in only one of thirteen biopsies of non-inflamed skin from acne sites. C3 deposition occurred particularly in the walls of small dermal blood vessels and at the dermo-epidermal junction. IgM was identified in vessel walls in four of sixteen early lesions. In eight late inflammatory lesions C3 deposition was much less prominent and was present in vessel walls in only two. None of the late lesions showed vascular deposition of IgM. The observations indicate that complement activation occurs in inflammatory acne and it is suggested that this may play a pathogenic role in the inflammation.

Acne Vulgaris↗
PubMed1977

Platelet-bound complement (C3) in immune thrombocytopenia.

The fixation of complement to the circulating platelet in immune thrombocytopenia was detected by measurement of one of the complement components, C3, on the surface of platelets from patients with idiopathic thrombocytopenic purpura (ITP) and systemic lupus erythematosus (SLE) using the anti-C3 consumption assay. The surface IgG was determined simultaneously using the previously described anti-IgG consumption assay. Washed platelets from normal controls had 3.5 fg (10(-15) g) of C3, or about 11,000 molecules, per platelet, an amount comparable to the IgG (4.1 FG, or 15,000 molecules, per platelet). For most patients with ITP both C3 and IgG were increased on the platelet surface, although for 5 of 16 patients only IgG was increased. Two patients with SLE and thrombocytopenia had an increase in both C3 and Ig, six patients with SLE who were not thrombocytopenic had normal amounts of membrane-bound C3 and IgG. In 5 patients, 3 with ITP and 2 with collagen vascular disease, both surface immunoproteins decreased with successful treatment of the thrombocytopenia.

Blood Platelets↗
PubMed1979

Immunoelectron-microscopical localization of in vivo-bound complement C3 in bullous pemphigoid with the use of the peroxidase-antiperoxidase multistep technique.

In vivo-bound complement C3 in bullous pemphigoid was precisely localized by means of the peroxidase-antiperoxidase multistep technique. In the nonbullous lesions peroxidase deposits filled the lamina lucida completely, i.e., the space between lamina densa and the cell membranes of the basal cells. In developed bullae, the reaction product was located both on the lamina densa and on the surface of separated keratinocytes. These findings may indicate that antigen components in bullous pemphigoid are localized almost exclusively within the ground substance which fills the lamina lucida and covers the surface of the basal cells.

Aged↗
PubMed1992

1 alpha,25-dihydroxyvitamin D3 regulates in vivo production of the third component of complement (C3) in bone.

We previously reported that 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] specifically stimulates production of the third component of complement (C3) by murine osteoblastic cells and marrow-derived stromal cells (ST2) in vitro. In the present study we examined tissue-specific production of C3 in vivo in vitamin D-deficient mice, some of which received supplemental 1 alpha,25-(OH)2D3. Western blot analysis indicated that the C3 protein band in bone was undetectable in vitamin D-deficient mice, but became distinct 48 h after 1 alpha,25-(OH)2D3 administration. The mRNA expression of C3 in bone was also undetectable in vitamin D-deficient mice and appeared as early as 24 h after 1 alpha,25-(OH)2D3 administration. mRNA expression apparently preceded the appearance of C3 protein. In contrast, there was no significant difference in the expression of hepatic C3 mRNA among normal mice fed laboratory chow and vitamin D-deficient mice with and without 1 alpha,25-(OH)2D3 administration. The serum concentration of C3 in vitamin D-deficient mice was almost identical to that in normal mice and was unchanged after 1 alpha,25-(OH)2D3 administration. 1 alpha,25-(OH)2D3 receptor (VDR) mRNAs were detected in the kidney and intestine, whereas no appreciable mRNA expression of VDR occurred in the liver. Osteopontin mRNA was expressed in response to 1 alpha,25-(OH)2D3 in the kidney, but not in the intestine. Immunohistochemical studies showed that in normal mice, the C3 protein was located mainly in the periosteal regions of calvaria and on the surfaces of bone trabeculae in the tibial metaphyses. These results demonstrate that 1 alpha,25-(OH)2D3 tissue-specifically regulates in vivo production of C3 in bone. The production of bone C3 cannot be attributed to the presence of VDR alone, and we speculate that other tissue-specific factors are required.

Animals↗
PubMed1992

Fc gamma R-dependent regulation of the biosynthesis of complement C3 by murine macrophages: the modulatory effect of IL-6.

The effect of murine IgG isotypes on the gene expression and secretion of the third component of complement (C3) has been studied using the monocytoid cell line P388D1 and oil-elicited mouse peritoneal macrophages. It is demonstrated that the binding of IgG2a and IgG2b but not IgG1 and IgG3 augments the biosynthesis of C3 both in the presence and in the absence of the phorbol ester, phorbol myristate acetate in the case of both cell types. The multifunctional cytokine interleukin-6 (IL-6) alone reveals no effect on the gene expression of C3, but increases the effectiveness of mouse IgG2a and IgG2b. Confirming the role of Fc gamma RII, a strong up-regulation of C3 gene expression and C3 secretion was found when macrophages were cultured with the F(ab')2 fragment of the Fc gamma RII-specific monoclonal antibody 2.4G2.

Animals↗