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PubMed1983

Extended HLA/complement allele haplotypes: evidence for T/t-like complex in man.

The chromosomal distribution of alleles for HLA-A,-B,-C, and -DR and the serum complement protein alleles of factor B and C2 and C4 was studied in normal Caucasian families. Eight combinations of HLA-B, DR, BF, C2, C4A, and C4B markers were found to occur in haplotypes at frequencies significantly higher than expected. In these combinations, which were defined as extended major histocompatibility complex haplotypes, HLA-A showed limited variation. A possible mechanism for the maintenance of extended haplotypes are human analogs of murine t mutants which are characterized by crossover suppression and male transmission bias. One human 6p haplotype, HLA-B8, DR3, SCO1, GLO 2, was found to be transmitted from males to 83% of their offspring. The same haplotype with GLO 1 had no transmission bias. It is suggested that this GLO 2-marked chromosome is a human analog of a murine t mutant.

Alleles↗
PubMed1986

[Inhibition of the binding and activation of the first component of human complement. The effect of synthetic peptides, immunoglobulin fragments and various proteins].

A study has been carried out on the inhibition of the subcomponent Clq binding to sensitized sheep erythrocytes (EA) by the following synthetic peptides mimicking the structure of a putative complement binding site of immunoglobulin G: Boc-Trp-Tyr, Boc-Tyr-Trp, Trp-Tyr, Boc-Trp-Phe, Boc-D-Trp-D-Tyr, Boc-D-Tyr-D-Trp, Boc-Leu-Leu, Ac-Phe-Tyr, and commercial Thr-Lys-Pro-Arg (tuftsin). Boc-Trp-Tyr was found to be the most potent inhibitor of Clq binding to EA (Ki 2.86 X 10(-4) M), tuftsin ranking second with Ki 6 X 10(-4) M. The D,D-dipeptides failed to inhibit the Clq binding at the investigated concentrations. Insoluble Z-Trp-Tyr-OMe activated a classical pathway of complement system, as monitored by consumption of C4, C2 and C3 components. Synthetic octapeptide Boc-Glu-Val-Asp-Leu-Leu-Lys-Asp-Glu-OMe (corresponding to the sequence 36-43 of beta 2-microglobulin) inhibited the Clq binding with Ki 4.7 X 10(-4) M, which gave grounds for localizing the complement binding site in beta 2-microglobulin. The finding in the Clq structure of the peptide sequence homologous to than of the pepsin active site, as well as the close similarity in the specificity of these proteins towards hydrophobic amino acid residues justified the assumption on the same structural bases of their specificity. The results of the present study, along with the literature data, underlie the hypothesis on the involvement in the complement binding of the following IgG residues: Trp277, Tyr278, Lys320, Lys322, Glu318 and Lys290. The enlisted residues are closely located in the three-dimensional structure of the CH2 domain of IgG. Lysozyme and lactalbumin having the sequences homologous to Trp277-Tyr278 of IgG inhibited Clq binding to EA with Ki 3 and 1.5 microM respectively.

Amino Acid Sequence↗
PubMed1997

Two parallel routes of the complement-mediated antibody-dependent enhancement of HIV-1 infection.

OBJECTIVE: To study the mechanism of the complement-mediated antibody-dependent enhancement (C'-ADE) of HIV infection which may play a significant role in the progression of HIV-disease. METHODS: In vitro complement activating and complement-mediated HIV-infection enhancing abilities of three human anti-gp41 monoclonal antibodies (MAb) were tested. C'-ADE was estimated using HIV-1IIIB and CR2 (CD21)-carrying MT-4 target cells. Normal human serum (NHS), purified C1q, C1q-deficient (C1qD) and C2-deficient (C2D) human sera were applied as complement sources. RESULTS: All MAb mediated increased C1q binding to solid-phase gp41. All MAb had a marked dose-dependent and strictly complement-mediated HIV-infection enhancing effect. Mixtures of the MAb with purified C1q also significantly increased HIV-1 infection. C1qD serum had a markedly lower enhancing effect than NHS, which could be raised to normal level by addition of purified C1q. Pretreatment of the target cells with anti-CR2 antibodies only partially inhibited the enhancing effect of the MAb plus normal human serum. CONCLUSION: These novel findings indicate that besides the well-known facilitation of entry of HIV-1 by the interaction between virus-bound C3 fragments and CR2 present on the target cells, fixation of C1q to intact virions also results in an enhanced productive HIV-1 infection in the MT-4 cell cultures.

Antibodies, Monoclonal↗
PubMed1975

Interaction of peptidoglycans with anti-IgGs and with complement.

This report describes the interaction of peptidoglycan (Streptococcus group A, Staphylococcus epidermidis and Micrococcus lysodeikticus) with 2 serum mediator systems, namely with the anti-IgG system and with complement. The observation that the majority of rabbits hyperimmunized with A-variant streptococcal vaccine produced anti-group carbohydrate antisera containing anti-IgGs and antibodies directed to peptidoglycan suggested that the production of these 2 latter antibodies was related. This view was supported by the finding of a monoclonal 7S anti-IgG with antibody specificity for the pentapeptide of peptidoglycan as evidenced by inhibition of the coprecipitation of 7S anti-IgG with antigen-antibody complexes by the pentapeptide. Inhibition of the anti-idiotype reaction by the pentapeptide provided further evidence for the antibody specificity of 7S anti-IgG for peptidoglycan. When added to normal human sera all peptidoglycan preparations inhibited the hemolytic activity of the sera. Consumption of C3 in C2 deficient serum and consumption of C2 in normal serum indicated the activation of both known complement pathways. Activation of the classical pathway of complement was more efficient since 50 mug of peptidoglycan consumed approximately 70% of C2 per ml normal serum whereas more than 2 mg of the same preparations was required to inactivate 17-24% of C3 in C2 deficient sera. Each of the different peptidoglycan preparations consumed similar amounts of complement in all 20 sera tested. This finding suggested that activation of the classical complement pathway by peptidoglycan was not mediated by anti-peptidoglycan antibodies present in only 20-40% of normal human sera.

Animals↗
PubMed1999

Mechanism of complement-dependent haemolysis via the lectin pathway: role of the complement regulatory proteins.

Mannan-binding lectin (MBL) is an acute phase protein which activates the classical complement pathway at the level of C4 and C2 via two novel serine proteases homologous to C1r and C1s. We recently reported that haemolysis via this lectin pathway requires alternative pathway amplification. The present experiments sought to establish the basis for this requirement, and hence focused on the activity and regulation of the C3 convertases. Complement activation was normalized between the lectin and classical pathways such that identical amounts of bound C4 and of haemolytically active C4,2 sites were present on the indicator cells. Under these conditions, there was markedly less haemolysis, associated with markedly less C3 and C5 deposited, via the lectin pathway than via the classical pathway, particularly when alternative pathway recruitment was blocked by depletion of factor D. Lectin pathway activation was associated with enhanced binding in the presence of MBL of complement control proteins C4bp and factor H to C4b and C3b, respectively, with decreased stability of the C3-converting enzyme C4b,2a attributable to C4bp. Immunodepletion of C4bp and/or factor H increased lectin pathway haemolysis and allowed lysis to occur in absence of the alternative pathway. Thus, the lectin pathway of humans is particularly susceptible to the regulatory effects of C4bp and factor H, due at least in part to MBL enhancement of C4bp binding to C4b and factor H binding to C3b.

Animals↗
PubMed1993

Expression of the complement classical pathway by human glioma in culture. A model for complement expression by nerve cells.

In this paper we demonstrate the synthesis of the components of the classical complement pathway, namely C1q, C1r, C1s, C1-Inh, C2, C4, and C5, by human glioma cell lines (U118MG, T193, and T98G). All these components were structurally, antigenically, and functionally similar to their serum counterparts as determined by biosynthetic labeling experiments, Western blot analysis, and hemolytic assays. Northern blot analysis of mRNA demonstrated that, for each of these components, their specific mRNA had the same size as the equivalent mRNA from hepatic tissue. We could not detect the synthesis of C4bp by these cell lines, and the secretion of C1q was only detected after stimulation by interferon-gamma. All these syntheses were up-regulated by interferon-gamma and tumor necrosis factor. Interleukin-1 beta only increased C2 expression and reproducibly down-regulated C5 secretion when used at high doses. Glioma cell lines appear to be an efficient and convenient model for the analysis of complement expression in human astrocytic cells.

Astrocytes↗
PubMed1985

Synthesis of C1 inhibitor (C1-INA) by a human monocyte-like cell line, U937.

Human monocytes are known to synthesize many of the components of complement, including C1-INA. In this report we demonstrate that the human monocyte-like cell line U937 is also capable of synthesizing functional C1-INA. This was shown in several ways, including 1) incorporation of tritiated amino acids into antigenic C1-INA, immunoprecipitation, and detection by fluorography; 2) a sensitive ELISA, which allowed quantitation of antigenic C1-INA in cell lysates, and 3) a C2-dependent hemolytic assay in which the functional activity of U937 C1-INA was assayed. Data from the ELISA indicate that U937 cells contain between 2.1 to 12.8 ng of C1-INA per 1 X 10(6) cells. Furthermore, fluorescence-activated cell sorter analysis revealed that approximately 16% of U937 cells carry C1-INA as a surface bound antigen. Other proteins found to be synthesized by U937 cells include C1r, C8, and possibly alpha-2-macroglobulin. These results suggest that the U937 cell line could be a convenient and valuable model for the study of monocyte C1-INA synthesis and physiology.

Amino Acids↗
PubMed2000

Serine proteases of the complement system.

The complement system in blood plasma is a major mediator of innate immune defence. The function of complement is to recognize, then opsonize or lyse, particulate materials, including bacteria, yeasts and other microrganisms, host cell debris and altered host cells. Recognition occurs by binding of complement proteins to charge or saccharide arrays. After recognition, a series of serine proteases is activated, culminating in the assembly of complex unstable proteases called C3/C5 convertases. These activate the complement protein C3, which acts as an opsonin. The complement serine proteases include the closely related C1r, C1s, MASPs 1-3 (80-90 kDa), C2 and Factor B (100 kDa), Factor D (25 kDa) and Factor I (85 kDa). Each of these has unusually restricted specificity and low enzymic activity. The C1r, C1s and MASP group occur as proenzymes. When activated, they are regulated, like many plasma serine proteases, by a serpin, C1-inhibitor. C2 and Factor B, however, have complex multiple regulation by a group of complement proteins called the Regulation of Complement Activation (or RCA) proteins, whereas Factors I and D appear to have no natural inhibitors. Advances in structure determination and protein-protein interaction properties are leading to a more detailed understanding of the complement-system proteases, and are indicating possible new routes for potential therapeutic control of complement.

Animals↗
PubMed1984

Ehrlich ascites cells activate the alternative pathway of the human complement system.

Incubation of Ehrlich ascites cells with normal or C1q or C2 deficient human sera results in killing of the cells. Killing occurred also in the absence of free Ca++, which supported by the fact that factor B and C3 were cleaved, leads to the conclusion that the alternative pathway of the complement system is activated on the surface of the Ehrlich ascites cells.

Animals↗
PubMed1986

Cloning of cDNA and genomic DNA for human von Willebrand factor.

The recent isolation of cDNA and genomic DNA clones for human vWF by ourselves and others has finally laid to rest the historical notion that factor VIII and vWF might have a precursor-product or other complex relationship. These two hemostatic activities are clearly present on two distinct proteins, each encoded by a separate gene. Whether ther is coordinate regulation of the factor VIII and vWF genes is still unknown. The structure and structure-function relationships of the vWF protein have been elucidated by many investigators, only some of whom can be cited in this short paper. Together, these molecular biology and protein chemistry studies have shown that vWAgII is the amino-terminal propeptide of vWF, explaining the proportional deficiency of these two plasma proteins in von Willebrand disease (type I). In addition, sites of proteolytic processing, glycosylation, and disulfide bond formation have been defined, and some of the binding functions of mature vWF have been identified with specific amino acid sequences. The protein has a highly repeated structure, suggesting a complex evolutionary history. The A domains of vWF appear to be homologous to complement factor B, and perhaps to component C2, although the biological meaning of this similarity is unknown. Genomic DNA clones have been isolated corresponding to approximately one third of the vWF gene on chromosome 12, and a fragment of the cDNA also hybridizes to uncharacterized sequences on chromosome 22. Preliminary studies in von Willebrand disease have revealed two patients with very large deletions in the vWF gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1978

Development of photosensitivity and an SLE-like syndrome in a patient with psoriasis.

An unusual case of photosensitive psoriasis and systemic lupus erythematosus-related syndrome was characterized by erythroderma, chronic urticaria, angioneurotic edema, intermittent low-grade fever, and polyarthralgias. Investigation revealed no measurable total hemolytic complement and markedly diminished levels of C4, C2, and C3. Microscopic examination of three skin biopsy sections of sun-exposed skin showed psoriasis. Skin biopsy sections of sun-exposed psoriatic plaques and of non-sun-exposed, uninvolved skin (which were stained with fluorescein-tagged anti-IgG, anti-IgM, anti-IgA, and anti-C3) showed granular deposits of IgM and C3 at the dermal-epidermal junction in the sun-exposed plaques, and IgM alone in a granular pattern at the dermal-epidermal junction in uninvolved skin. Antibodies to single-stranded but not double-stranded DNA were detected in the patient's serum. In addition, serum immune complex-like material was detected by sucrose density-gradient ultracentrifugation, standard anticomplementary assays, and radioimmunoassays using both C1q and monoclonal rheumatoid factor.

Adult↗
PubMed1983

Activation of the alternative pathway of complement by Acanthamoeba culbertsoni.

Normal human serum (NHS) contained an amoebicidal property for Acanthamoeba culbertsoni. Killing was quantitated by measuring the ability of the amoebae to undergo cell division subsequent to exposure to NHS, and also by microscopical examination. Plasma membrane disruption and extrusion of intracellular components occurred within 5-10 min following exposure to NHS. Adsorption of specific antibody did not remove the amoebicidal activity while heating serum at 56 degrees C/30 min or treatment with zymosan prevented the killing of A. culbertsoni. Haemolytic complement was consumed and C3 conversion occurred during the incubation of NHS with amoebae. Killing required the presence of the late complement components. The findings that (a) amoebae were killed in C2 deficient human serum and ethylene glycol tetra-acetic acid (EGTA), but not ethylenediamine tetra-acetic acid (EDTA) treated NHS; (b) haemolytic complement consumption, which occurred by incubating NHS with the amoebae, could be prevented by addition of EDTA, but not EGTA and (c) conversion of C3 occurred in the presence of EGTA, but not EDTA, indicated that activation of the alternative pathway of complement was involved. This may be of importance as a natural defence mechanism in humans against A. culbertsoni infections.

Amoeba↗
PubMed1993

The intracellular bacterium Rhodococcus equi requires Mac-1 to bind to mammalian cells.

Rhodococcus equi is a facultative intracellular bacterium of macrophages that causes disease in immunocompromised individuals, particularly those with AIDS. In this report, we demonstrate that R. equi binding to mammalian cells requires complement and is mediated primarily by the leukocyte complement receptor, Mac-1. Bacteria bind to macrophages poorly unless exogenous complement is added to the incubation medium. The addition of fresh nonimmune serum, which contains no detectable antibodies to R. equi, greatly enhances bacterial binding to macrophages, whereas heat inactivation of this serum or immunological depletion of C3 from the serum reduces binding to levels only slightly higher than those of binding under serum-free conditions. Human serum depleted of C2 or C4 is fully opsonic, indicating that complement activation and fixation occur by the alternative pathway. The serum-dependent binding of rhodococci to macrophages is mediated primarily by the macrophage complement receptor type 3, Mac-1 (CD11b/CD18). Bacteria do not bind to fibroblastoid or epithelial cells that lack this receptor. Most of the bacterial binding to macrophages is inhibited by a monoclonal antibody to Mac-1 but is unaffected by a monoclonal antibody to complement receptor type 1. Furthermore, opsonized, but not unopsonized, bacteria bind to purified Mac-1 immobilized on plastic. In addition, in the presence of opsonic complement, rhodococci bind efficiently to fibroblastoid cells transfected with cloned Mac-1 but relatively poorly to cells transfected with the complement receptor type 1. Hence, R. equi fixes complement by activating the alternative complement pathway, and this fixation is a requirement for bacterial adhesion and invasion. Furthermore, complement fixation defines rhodococcal host cell tropism, since R. equi binds specifically and exclusively to cells expressing Mac-1.

Animals↗
PubMed1978

Binding of activated properdin to untreated erythrocytes: a new function of activated properdin.

Activated human properdin was found to be capable of binding to rabbit and sheep erythrocytes to form new intermediate cells of the alternative pathway of the complement system. The intermediate cells, termed EP, can react with B, D and C3 to form other intermediate cells, tentatively termed EPB(D)C3, which can be lysed by the subsequent action of six late-acting complement components, C3 to C9. The possibility of participation of C3, B, D or immunoglobulin in the formation of EP cells was neglected by the experiments in which the inhibition of the reactivities of P or EP by antisera to P, C3, B, D or immunoglobulins were investigated. The reduction in reactivities of P to E, or of EP to B, D and C3 was observed only when pretreated with antiserum to P. Furthermore, EP cells were agglutinated only by anti-P, not by antisera to C3 or IgG. The other possibility of participation of the classical complement components such as antibody, C1, C4 and C2 in the formation of EPB(D)C3 was excluded by the non-reactivities of EP with C4 and C2 and of EAC1 with B, D and C3. Thus, activated properdin is likely to function not only as modulator of preformed enzyme such as C3bBb but also as one of early-acting components of the alternative pathway.

Agglutination↗
PubMed2006

Which complement assays and typings are necessary for the diagnosis of complement deficiency in patients with lupus erythematosus? A study of 25 patients.

INTRODUCTION: Deficiencies in components of the classical pathway of complement activation are strong risk factors for lupus erythematosus (LE).Yet, it has not been addressed whether the conventional measurements of the serum hemolytic CH50 activity and antigenic concentrations of C3 and C4 are sufficient to asses a deficiency in C4A, C4B or C2 components, the most common deficiencies associated with LE. PATIENTS AND METHODS: In a retrospective series, we performed complement analyses in 35 patients with LE who were systematically screened for a complement deficiency. The majority of patients had cutaneous LE with mild systemic involvement and no complement consumption. Of 25 patients (72%) with complement deficiency we found 13 with a partial C4A deficiency, 2 with a complete C4A deficiency, 6 with a partial C4B deficiency, 2 with a complete C4B deficiency and 2 with a combined partial C2 and C4A deficiency. RESULTS: The total complement activity (CH50) was decreased in only one out of two patients with complete C4B deficiency. CH50 level was found to be low-normal (35-38 U/ml(-1)) in one patient with partial C4B deficiency, one patient with complete C4B deficiency and both patients with combined partial C4A and C2 deficiency. Total C4 levels were normal in 9 out of 13 the patients with a partial C4A deficiency and in 2 out of 6 patients with a complete C4B deficiency. The antigenic concentration of C3 was low in only 1 patients with a complete C4B deficiency and within the normal range in all the others patients. Overall, 50% of the patients had normal or elevated C3, C4, and CH50 levels. DISCUSSION: This study emphasizes that the usual measurements of CH50, C3 and C4 levels are not adequate to detect a C4 and/or C2 deficiency in patients with LE. In epidemiologic or investigative studies addressing the prevalence of complement deficiency, more elaborated diagnostic tests, such as C4 protein allotyping, C2 level measurement and genetic screening for type I C2 deficiency should also be performed.

Adult↗
PubMed1978

Host defense against opportunist microorganisms following trauma. II. Changes in complement and immunoglobulins in patients with abdominal trauma and in septic patients without trauma.

Total hemolytic complement (CH50), conversion of C3 by inulin and cobra venom factor (CoVF), and immunochemical levels of Clq, C4, C2, C3, C5, factor B, properdin, C3b inactivator (KAF), and immunoglobulins (Igs) G, A, and M were measured in the sera of ten patients with abdominal trauma and ten medical patients with septicemia without trauma. Reduction in C3 conversion by CoVF and decrease in the levels of properdin and KAF were demonstrated in the trauma sera. CH50 and the level of C5 were also decreased. Conversion of C3 by inulin and levels of factor B, Clq, C4, C2, and C3 were found to be normal in the patients' sera. Complement levels and activities were found to be normal in the sera of the septic non-trauma patients. A decrease in serum IgM was observed in both patient groups; levels of IgG and IgA were normal. These results indicated that abnormalities of immunoglobulin and of the alternative and classical complement pathways were associated with nonburn trauma. Moreover, the data suggested that consumption of the classical complement pathway associated with septicemia in the thermally injured patient resulted from synergism between the trauma and infection rather than from septicemia per se.

Abdominal Injuries↗
PubMed1981

Complement-derived chemotactic activity is generated in human serum containing uroporphyrin after irradiation with 405 nm light.

Patients with porphyrias have varying degrees of photosensitivity, associated with elevated levels of porphyrins in plasma, erythrocyte, urine and/or feces. To investigate the role of complement in the pathogenesis of cutaneous lesions, varying amounts of uroporphyrin were added to normal human serum (0.1-10 microgram/ml), and the mixtures were then exposed to 405 nm irradiation. Such treatments result in the diminution of total hemolytic complement activity and hemolytic titers of C1, C4, C2, C3, and C5; furthermore, cleavage products of C3 and C5 were detected. Chemotactic activity for human polymorphonuclear leukocytes was generated that was inhibitable by incubation with anti-C5, but not with anti-C3 antisera. No chemotactic activity was generated in Mg++-EGTA treated serum nor in C4-deficient guinea pig serum. These data indicate that irradiation with 405 nm light of normal human serum containing uroporphyrin results in activation of the complement system via the classical pathway, and the generation of complement (C5)-derived chemotactic activity for human polymorphonuclear leukocytes.

Adult↗
PubMed1982

Decreased chemotactic activity in activated newborn plasma.

The roles of complement levels and CFI activity in the regulation of chemotactic factor generation were evaluated in newborn and adult plasmas. Plasma samples were obtained from 19 healthy adults, 19 neonates, and 12 3-day-old infants. CFI levels were determined in all samples, chemotactic activity in 15 of the 19 adult and newborn samples, and complement levels in 10 of these 15. Compared to adult plasmas, CFI activity was higher in newborn and infant plasmas and chemotactic activity was lower. A close reciprocal relationship was shown between these two activities (r=-0.958). When corrected for the effects of CFI, the difference in chemotactic activity between newborns and adults disappeared. Mean levels of C1, C3, C4, C5, C3 to C9, CH50, factor B, and properdin were lower in newborn plasmas; however, C2 levels were higher. Partial correlations between these complement components and the chemotactic activity were of small magnitude and statistically not significant. These data suggest that higher CFI activity, rather than lower complement levels, accounts for most of the differences in chemotactic activity between newborn and adult plasma. (J Lab Clin Med 99:331, 1982.)

Adult↗