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PubMed1972

C1r deficiency: an inborn error associated with cutaneous and renal disease.

The studies of sera from two siblings with C1r deficiency are described. The brother (18 yr old) has shown clinical manifestations resembling lupus erythematosus for 5 yr, and the sister (24 yr old) has had arthralgia and recurrent episodes of rhinobronchitis since early childhood. Three siblings have died: one brother died at age 12 with symptoms similar to the disease of the male patient studied here, and two other siblings died in infancy, probably from infection. The low hemolytic C1 activity of the patients could be restored by the addition of purified C1r to their sera. Bactericidal activity and immune adherence were found to be impaired. When alternate pathways of the complement system were studied, both sera permitted activation of terminal components with endotoxin and cobra venom factor. These findings support the view that an alternate pathway for activation of the terminal portion of the complement cascade exists which does not utilize the conventional pathway operating through the usual early components.

Adolescent↗
PubMed1993

Regulation of synthesis of complement proteins in HEp2 cells.

We investigated the synthesis of complement proteins in HEp2 cells and its regulation. Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-PAGE, we demonstrated that HEp2 cells synthesized C1r, C1s, C1 inhibitor, C3, C4, factor B, and factor H. The constitutive synthesis of C1r and C1s were the highest among these proteins, whereas the synthesis of C4 was observed only when the cells were stimulated with IFN-gamma. C1r and C1s were secreted readily, whereas the rate of the secretion of C4 and C1 inhibitor was much slower. Activated forms of C1r, C1s, and complexes of C1 inhibitor--C1s were found. IL-1 and TNF induced 6- and 7-fold increases in the synthesis of C3 and factor B. IFN-gamma induced increases in the synthesis of all seven proteins, the most pronounced effects being on the synthesis of C4 and C1 inhibitor--15- and 44-fold, respectively.

Complement System Proteins↗
PubMed1980

Complement activation, circulating C1q binding substances and inflammatory activity in rheumatoid arthritis: relations and changes on suppression of inflammation.

Patients with rheumatoid arthritis were treated with podophyllotoxin derivatives (PTD) or with cyclophosphamide. Increased concentrations of C1r-C1s-C1 inactivator complexes (C1r-C1s-C1 IA) in serum provided evidence for C1 activation, which was most pronounced before treatment. During treatment the levels of C1r-C1s-C1 IA clearly decreased, while the levels of C4 increased. This rise in C4 was contrasted to the decrease in other acute phase reactants as C-reactive protein. Circulating immune complexes were assessed by the C1q deviation test (C1q DV) and the C1 binding assay (C1q BA). Discrepancies were noted in the outcome of the two assays. Of parameters reflecting C1 inactivation C1r-C1s-C1 IA complexes were positively and C4 negatively correlated with the inflammatory activity as measured by synovitis index (SI). The values in C1q DV correlated with the C1r-C1s-C1 IA values and with SI. In contrast, C1q BA correlated with CRP but not with C1r-C1s-C1 IA or SI. The study gave evidence for a relationship between C1 activation as detected in serum and the extent of synovial inflammation in RA. The possibility is discussed that substances other than immune complexes may be involved in C1 activation and contribute to the synovial inflammation.

Adult↗
PubMed1991

Identification of the disulfide bonds of human complement C1s.

C1s, one of the three subcomponents of C1, the first component of the complement system, is a complex serine protease. To determine the disulfide-bonding pattern, fragments of C1s were generated by cleavage with pepsin, thermolysin, or subtilisin. Disulfide bonds have been identified by several methods, for example, direct observation of the phenylthiohydantoin derivative of cystine during Edman degradation of isolated peptides and placement in the known cDNA sequence. All of the 26 half-cystines are linked in disulfide bonds occurring at positions 50-68, 120-132, 128-141, 143-156, 160-187, 219-236, 279-326, 306-339, 344-388, 371-406, 410-534, 580-603, and 613-644. All of the disulfide bonds of the earlier described substructures of C1s, the EGF-homologous part, the two SCR units, and the two domains typical for C1s and C1r are localized within these domains.

Amino Acid Sequence↗
PubMed1996

Synthesis of classical pathway complement components by chondrocytes.

Using immunohistochemical studies, C1q, C1s, C4 and C2 were detected in chondrocytes in normal human articular cartilage and macroscopically normal articular cartilage from the inferior surfaces of hip joints of patients with osteoarthritis. Using reverse-transcribed polymerase chain reaction (RT-PCR), mRNA for C1q, C1s, C4 and C2 was also detected in RNA extracted from articular cartilage. C1r, C3, C1-inhibitor, C4-binding protein and factor I were not detected by either technique. Articular chondrocytes cultured in vitro synthesized C1r, C1s, C4, C2, C3 and C1-inhibitor but not C1q, C4-binding protein or factor I, as assessed by enzyme-linked immunosorbent assay (ELISA) and Northern blot analysis. Thus cultured articular chondrocytes have a complement profile that is similar to that of cultured human fibroblasts rather than that of articular chondrocytes in vivo. Complement synthesis in cultured chondrocytes was modulated by the cytokines interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), showing that cytokines can probably regulate complement synthesis in intact cartilage. The possible roles of local synthesis of complement components by chondrocytes in matrix turnover and the regulation chondrocyte function are discussed.

Base Sequence↗
PubMed1981

Stoichiometry and sedimentation properties of the complex formed between the C1q and C1r2C1s2 subcomponents of the first component of complement.

We have examined the functional and hydrodynamic properties of the first component of human complement, C1, and the activated first component, C1-, reassembled in the presence of Ca++ from C1q and either the C1r2C1s2 or the C1r-2C1s-2 tetramer. Reconstituted C1 has hemolytic activity similar to C1 in serum. As long as either tetramer is in excess and the total concentration is low, we find that only a 1:1 complex is formed between C1q and either the unactivated or activated tetramer. This complex sediments at 15.9 +/- 0.2 Svedbergs and has a complex sediments at 15.9 +/- 0.2 Svedbergs and has a m.w. of 739,000 +/- 37,000. The boundary shape of the sedimenting C1- preparation was broader than that of C1 suggesting the association constant between C1r2C1s2 and C1q may have decreased upon activation. At elevated concentrations, with more than a molar excess of C1q, C1 aggregated to form both 16S and 23S species.

Animals↗
PubMed1989

Monoclonal antibodies against components of the classical pathway of complement.

Activation of the classical pathway of complement involves several binding and enzymatic cleavage processes. Binding and enzymatic activation results in the appearance of new structures in the individual components. This report describes the different activation steps for C1q, C1r, C1s, C4 and C2 and summarizes monoclonal antibodies reported so far which recognize either conserved epitopes or activation-dependent epitopes with particular emphasis on neoepitopes occurring during the activation cascade.

Antibodies, Monoclonal↗
PubMed1977

Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, C1r-, and C1 esterase.

p-Carbethoxyphenyl episol-guanidinocaproate and p-(p'-guanidinobenzoyloxy)-phenyl derivatives were prepared, and their inhibitory effects on trypsin, plasmin, plasma kallikrein, thrombin, C1r- and C1 esterase were examined. Among the various inhibitors tested, p-nitrophenyl p'-guanidinobenzoate, N,N-dimethylamino p-(p'-guanidinobenzoyloxy)-benzoyl glycolate and N,N-dimethylamino p-(p'-guanidinobenzoyloxy)-benzilcarbonyloxy glycolate were the most effective inhibitors of trypsin, plasmin, plasma kallikrien and thrombin, and they strongly inhibited the esterolytic activities of C1r- and C1 esterase.

Complement Activating Enzymes↗
PubMed1997

Differential cytokine regulation of complement proteins in human glomerular epithelial cells.

We have previously shown in inbred strains of mice which naturally develop systemic lupus erythematosus that kidney C3, C2, C4 and factor B gene expression increases coincidently with the occurrence of glomerulonephritis, suggesting that local tissue complement gene expression could contribute to the pathogenesis of immune complex injury. In this study, we investigated the synthesis of complement proteins in glomerular epithelial cells (GECs) and its regulation. Using biosynthetic labelling, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we demonstrated that GECs synthesized C1r, C1s, C1 inhibitor, C3, C2 and factor B. Interferon-gamma induced increases in the synthesis of all these proteins. Both factor B and C3 proteins were increased following addition of either IL-1beta, IL-6 or TNF-alpha to GEC cultures; however, these cytokines did not increase either C2, C1r, C1s or C1-inhibitor biosynthesis. Lipopolysaccharide affected the biosynthesis of these proteins in a similar way. A semiquantitative analysis of the mRNA expression of some of these proteins by reverse-transcriptase polymerase chain reaction showed that these cytokine effects were pretranslational as there was enhancement of factor B mRNA expression by IL-1, TNF-alpha, IFN-gamma, IL-6 and endotoxin, but only IFN-gamma enhanced C1-inhibitor and C4 mRNA expression. These results may be of significance in the immunopathogenesis of glomerulonephritis, where it is likely that local complement production in GECs is independently regulated by cytokines, derived from resident glomerular mesangial cells or infiltrating monocyte/macrophages and T cells.

Animals↗
PubMed1975

The macromolecular structure of the first component of complement.

The binding of C1 to IgG and the interactions between C1 subcomponents have been studied by affinity chromatography of serum C1 and purified C1 proteins on Sepharose-IgG. Affinity chromatography of serum on Sepharose-IgG resulted in the binding of C1; subsequent washing with EDTA removed only C1s and C1t. Affinity chromatography of serum-EDTA on Sepharose-IgG resulted in binding of only C1q and C1r. Affinity chromatography of serum on Sepharose-tryptophan-modified-IgG resulted in the binding of only C1r and C1s. By the use of purified C1 proteins and Sepharose-IgG in binding studies it was confirmed that both C1q and C1r bind independently to sites on IgG and hold C1s and C1t by Ca++-dependent bonds. Measurements of the hemolytic activity of various combinations of C1 subcomponents confirmed the data obtained by the affinity binding studies. Both C1t and C1r independently enhanced the C1 activity of C1q-C1s mixtures; maximal activity required all four subcomponents. Sucrose gradient ultracentrifugation of mixtures of C1 proteins showed formation of the following complexes: C1qs (12S), C1qrs (15S), C1qst (18-23S), and C1qrst (19S). The evidence suggests that the spatial sequence of the components of the Sepharose-IgG-Serum C1 complex is: Sepharose-IgG: C1q: C1t: C1s: C1r: IgG-Sepharose. The probable physiologic significance of this model is discussed.

Blood Proteins↗
PubMed2004

Microglial activation and increased synthesis of complement component C1q precedes blood-brain barrier dysfunction in rats.

A reliable way to visualise the state of microglial activation is to monitor the microglial gene expression profile. Microglia are the only CNS resident cells that synthesise C1q, the recognition sub-component of the classical complement pathway, in vivo. C1q biosynthesis in resting ramified microglia is often low, but it increases dramatically in activated microglia. In this study, the expression of C1q was used to monitor microglial activation at all stages of 3-chloropropanediol-induced neurotoxicity, a new model of blood-brain barrier (BBB) breakdown. In rats, 3-chloropropanediol produces very focused lesions in the brain, characterised by early astrocyte swelling and loss, followed by neuronal death and barrier dysfunction. Using in situ hybridisation, immunohistochemistry, and real-time RT-PCR, we found that increased C1q biosynthesis and microglial activation precede BBB dysfunction by at least 18 and peak 48 h after injection of 3-chloropropanediol, which coincides with the onset of active haemorrhage. Microglial activation is biphasic; an early phase of global activation is followed by a later phase in which microglial activation becomes increasingly focused in the lesions. During the early phase, expression of the pro-inflammatory mediators interleukin-1beta (IL1beta), tumour necrosis factor alpha (TNFalpha) and early growth response-1 (Egr-1) increased in parallel with C1q, but was restricted to the lesions. Expression of C1q (but not IL1beta, TNFalpha or Egr-1) remains high after BBB function is restored, and is accompanied by late up-regulation of the C1q-associated serine proteases, C1r and C1s, suggesting that microglial biosynthesis of the activation complex of the classical pathway may support the removal of cell debris by activation of complement.

Animals↗
PubMed2001

Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases.

We have investigated the molecular basis of selective and complete C1s deficiency in 2-year-old girl with complex autoimmune diseases including lupus-like syndrome, Hashimoto's thyroiditis, and autoimmune hepatitis. This patient's complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, and undetectable levels of C1s Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of genomic DNA by PCR followed by direct sequence analysis revealed a homozygous nonsense mutation in the C1s gene exon XII at codon 534, caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction site for endonuclease Fok-1 created by the mutation to detect this mutation in the genomic DNA of seven healthy family members. Four additional heterozygotes for the mutation were identified in two generations. Our data characterize for the first time the genetic defect of a selective and complete C1s deficiency in a Caucasian patient.

Age of Onset↗
PubMed1983

Circulating immune complexes and C1 activation in patients with rapidly progressive glomerulonephritis, before and after treatment with immunosuppression and plasma exchange.

Well-known assays for detection of circulating immune complexes (CIC) (C1 q binding assay, C1q deviation test, solid-phase C1 q binding assay, solid-phase conglutinin binding assay, and the platelet aggregation test) were used in 30 patients with different kinds of rapidly progressive glomerulonephritis. In 89% of the patients evidence of CIC was found in at least one of the assays. 81% of the patients were positive in the C1q binding assay and/or the conglutinin binding assay with addition of complement. CIC were more often detected by several assays, and with higher values in patients with systemic disease than in patients with renal involvement alone. CIC were found in 2 patients with Goodpasture's syndrome. 15 patients were reexamined after treatment with plasma exchange, when the disease was clinically inactive. The patients were still on immunosuppressive treatment. In most of these, CIC were detectable, but with lower values than at the start of treatment. Before treatment, high levels of C1r-C1s-C1 inactivator complexes suggested increased C1 activation in 93% of the patients. C-reactive protein was raised, and the concentrations of C1 q, C1s, C4, C3 and factor B were normal or high in most of the patients. Pronounced hypocomplementemia was found only in 2 patients with systemic lupus erythematosus (SLE). After treatment, the levels of C-reactive protein, C1 q, C1s, C3 and factor B had decreased in the non-SLE patients, while the average levels of C4 and C1r-C1s-C1 inactivator complexes were essentially unchanged.

Antigen-Antibody Complex↗
PubMed1992

Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease.

Serum mannose-binding protein (MBP) is a C-type lectin that binds to terminal mannose and N-acetylglucosamine moieties present on surfaces of certain pathogens and activates the classical complement pathway. In the present study, we describe the mechanism underlying the activation triggered by MBP. The human serum MBP fraction was obtained by sequential affinity chromatography on mannan-Sepharose, anti-IgM-Sepharose and anti-MBP-Sepharose in the presence of calcium ions. This fraction contained a C1s-like serine protease as assessed by C4 consumption. The C1s-like serine protease, designated MBP-associated serine protease (MASP), was separated from MBP by rechromatography on anti-MBP-Sepharose in the presence of ethylenediaminetetraacetic acid. MASP exhibited both C4- and C2-consuming activities. The molecular mass of MASP was estimated to be 83 kD with two polypeptides of heavy (66 kD) and light (L) (31 kD) chains linked by disulfide bonds. The serine residue responsible for protease activity is located on the L chain. Reconstitution experiments using MASP and MBP revealed that combination of the two components restores C4- and C2-activating capacity on mannan. Based on analyses of molecular size, antigenicity, and 11 NH2-terminal amino acid sequences of the L chain, we conclude that MASP is a novel protein different from C1r or C1s. Our findings are not in accord with a proposed mechanism by which MBP utilizes the C1r2-C1s2 complex to initiate the classical complement pathway.

Amino Acid Sequence↗
PubMed1983

Complement activation and impaired capacity to solubilize immune complexes or to prevent their formation in essential mixed cryoglobulinemia.

The complement profile, the immune complex solubilizing capacity (ICSC), the immune complex precipitation inhibition capacity (ICPIC), the presence of cryoprecipitable material, and the presence of immune-aggregate- and non-immune-aggregate mediated C1q-binding activity was assessed in serum samples from 23 patients suffering from essential mixed cryoglobulinemia (EMC). No correlation between the levels of cryoglobulins and the clinical activity of EMC was found. The mean C1q-binding activity in EMC serum samples was abnormally elevated 28 +/- 29% (mean +/- SD). In six out of eight serum samples that contained C1q-binding material, evidence was obtained that such material was of the complexed immunoglobulin G (IgG) type. Among the levels of C1q, C1r, C2, C4, C3, C5, C6, C1-inhibitor, C3d, B, I, H, as well as the total hemolytic activity and the activity of the alternative pathway of the complement, the mean serum concentrations of C1, C2, and C4 and in consequence the mean total hemolytic activity were significantly reduced, whereas the mean levels of C3d were significantly elevated in the EMC serum samples. The capacity of the 23 EMC serum samples to solubilize preformed immune precipitates from bovine serum albumin (BSA) and rabbit anti-BSA antibodies as well as their capacity to prevent the formation of the precipitable form of such complexes was analyzed. Compared to the ICSC and the ICPIC of 30 normal human sera, the ICSC and the ICPIC of EMC serum samples were reduced to 57 +/- 24% and 38 +/- 33%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Ancient origin of the complement lectin pathway revealed by molecular cloning of mannan binding protein-associated serine protease from a urochordate, the Japanese ascidian, Halocynthia roretzi.

Recent identification of a C3-like gene in sea urchins revealed the presence of a complement system in invertebrates. To elucidate further the components and function of the pre-vertebrate complement system, we attempted to isolate an ascidian (urochordata) C3 convertase. After identification of C3 cDNA from Halocynthia roretzi, a Japanese ascidian, reverse transcriptase-PCR amplification of hepatopancreas RNA was performed using primers encoding highly conserved amino acid sequences of the vertebrate Bf and C2 serine protease domain. Two candidate sequences were identified, and the corresponding cDNA clones were isolated from a hepatopancreas library. Surprisingly, neither clone is related to Bf/C2 but rather share the same domain structure of mammalian C1r/C1s/MASP (mannan binding protein-associated serine protease), and are more related evolutionarily to mammalian MASP than to mammalian C1r or C1s. The identification of the tunicate MASP clones, amplified with primers designed to amplify Bf or C2, suggests that the lectin pathway antedated the classical and alternative pathways of complement activation.

Amino Acid Sequence↗