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PubMed1985

Normal macrophage function in infants receiving Intralipid by low-dose intermittent administration.

The effect of soybean oil emulsion (Intralipid) therapy on serum complement levels was determined in infants who received Intralipid therapeutically (1 gm/kg over 12 hours, every other day). The effect of Intralipid on macrophage priming for increased superoxide anion production was studied in a mouse model. Intralipid administration did not affect either macrophage function. Serum levels of C2 and C4, complement components synthesized and secreted exclusively in macrophages, were not decreased either during the week the infants received Intralipid or in the week following administration. Macrophages from mice that had received Intralipid produced similar amounts of superoxide anion, as did macrophages from mice that had received saline solution. Our data suggest that macrophages in infants receiving Intralipid in this regimen will function normally.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Possible association between HLA-DR5 and superficial spreading melanoma (SSM).

Previous analyses of possible associations between MHC determinants and cutaneous malignant melanoma (MM) have been inconclusive. We have investigated 98 patients with special emphasis on histologically determined subtypes of MM, and 5 multiple-case families. In addition to HLA-ABC and DR typing, complement allotypes of C2, C4A, C4B, BF were determined. Among the unrelated patients HLA-DR5 and, secondarily, B49 were observed to be associated with superficial spreading (SSM) but not with nodular (NM) or lentigo maligna melanoma (LMM). In families with MM, no definite segregation of the disease according to HLA and complement haplotypes was discernible. Moreover, no coincidence of haplotypes occurred in patients of the different families. HLA region recombinations including B/DR and/or DR/GLO were found in all the families investigated.

Adolescent↗
PubMed2005

Kinetic studies on the interactions of heparin and complement proteins using surface plasmon resonance.

Heparin is a naturally occurring polysaccharide known to interact with complement proteins and regulate multiple steps in the complement cascade. Quantitative information, in the form of affinity constants for heparin-complement interactions, is not generally available and there are no reports of a comprehensive analysis using the same interaction method. Such information should improve our understanding of how exogenously administered pharmaceutical heparin and the related endogenous polysaccharide, heparan sulfate, regulate complement activation. The current study provides the first comprehensively analysis of the binding of various complement proteins to heparin using surface plasmon resonance (SPR). Complement proteins C1, C2, C3, C4, C5, C6, C7, C8, C9, C1INH, factor I, factor H, factor B and factor P all bind heparin but exhibit different binding kinetics and dissociation constants (Kd) ranging from 2 to 320 nM. By taking into account these Kd values and the serum concentrations of these complement proteins, the percentage of each binding to exogenously administered heparin was calculated and found to range from 2% to 41%. This study provides essential information required for the rational design of new therapeutic agents capable of regulating the complement activation.

Complement Activation↗
PubMed1984

Interactions of complement with an extract of airborne spring wheat dust.

The inhalation, by grain elevator workers, of airborne grain dusts can lead to pulmonary problems. Complement, which is present in human airways, can interact with various grain dusts, producing activation products that have been shown to participate in the inflammatory reaction. Because of this apparent connection between grain-dust inhalation, complement activation, and respiratory difficulties, we are studying the reaction of an aqueous extract of spring wheat dust (swd) with human complement. The swd extract activates both the classical and alternative pathways; it acts on purified C2 to inhibit it, and it reacts with undiluted serum to consume C4 with kinetics significantly different from those shown by a "typical" antigen-antibody complex (sensitized sheep erythrocytes). Enzyme susceptibility experiments suggest that the alternative and classical pathway activators of swd extract are neither protein nor nucleic acid; periodate oxidation indicates these substances are carbohydrate, and gel filtration suggests they are macromolecular. Enzyme vulnerability also indicates that the C2 inhibitor of swd extract is ribonucleic acid. Although endotoxin is present in swd extract, a gel-filtration experiment showed that a major fraction of the complement reactivity was not associated with this substance.

Complement Activation↗
PubMed1975

Activation of the complement and properdin systems in rheumatoid arthritis.

The classic (C1, C4, and C2) and properdin factors (D, C3b, and B) of complement generate C3 convertases that are capable of cleaving C3 and subsequently activating C5-C9. Both C1 and factor D are serine esterases, and both convertases undergo decay and regeneration. In seropositive rheumatoid arthritis, where intraarticular activation of the classic early components (C1, C4, and C2) by immunoglobulin complexes appears to predominate, findings of relative depressions in synovial fluid levels of factor B indicate recruitment of the amplification loop (D, C3b, and B), and relative declines in properdin levels suggest activation of the properdin pathway as well. Quantitative analysis of the complement system in disease states requires several different approaches: measurement of function and antigenic concentration to assess the functional integrity of the protein; determination of component metabolism to appreciate the relative contributions of hypercatabolism and hyper- or hyposynthesis to the plasma level; and for compartmentalized disease, measurement of the component in the appropriate biologic fluid and determination of local tissue synthesis.

Antigen-Antibody Complex↗
PubMed1989

Biosynthesis of complement C4 messenger RNA in normal human kidney.

Complementary DNA (cDNA) probes were used to investigate the extrahepatic production of the major histocompatibility complex (MHC)-linked complement components C4, factor B and C2 in various normal human tissues. The presence of the corresponding messenger RNA (mRNA) was tested by Northern blot analysis. Complement C4 mRNA was found in liver, and with high intensity also in normal kidneys. In contrast, no C2 mRNA and only very low amounts of factor B mRNA could be detected in the kidney. Slot blot hybridization was performed to quantitate the amount of C4 mRNA, and the intensity of C4 mRNA hybridization in the kidney samples was about 25% compared with liver RNA. C4-specific transcripts were not present in isolated glomeruli but in the renal interstitium. Other human tissues, such as tonsil, spleen, thymus, brain, lung and peripheral mononuclear cells, contained no C4 mRNA. Low amounts of C4 mRNA were found in colon, thyroid gland, lymph node and breast carcinoma. The results obtained with lung, where C2 mRNA was found but no C4 mRNA, further indicate an independent, tissue-specific regulation of the class III gene expression. The results, showing that the complement C4 genes are transcribed very efficiently in normal human kidney, suggest a direct role of complement C4 in renal pathogenesis.

Adult↗
PubMed1981

Activation of the classical pathway of complement by Hageman factor fragment.

A fragment of activated Hageman factor (HFf) has been demonstrated to activate the classical pathway of complement in a manner that is analogous to complement activation by antigen-antibody complexes or aggregated IgG. Thus C1, C4, C2, C3, and C5 were found to be depleted on addition of HFf to serum. The reduction of serum hemolytic activity was maximal upon addition of 5 micrograms HFf and an incubation time of 60 min at 37 degrees C. Consumption of the total complement activity and of the individual components proceeded in a dose-dependent fashion. No comparable activity was observed when equimolar concentrations of either the native Hageman factor (HF) or two-chain activated form of Hageman factor (HFa) were incubated with serum. Further, the ability of HFf to convert serum C3 and C4 was similar to that of aggregated IgG as assessed by immunoelectrophoresis. This function of HFf appeared to be independent of plasminogen (or plasmin) since plasminogen-free serum was indistinguishable from normal serum. Radial double immunodiffusion experiments using antiserum to C1q, C1r, and C1s on HFf-treated serum demonstrated the dissociation of the C1 trimolecular complex, with concomitant reduction of C1r antigenicity that is indicative of C1 activation. Thus, HFf appears to lead to C1 activation upon incubation with serum or when incubated with partially purified C1. This may represent a control link between activation of the intrinsic coagulation-kinin pathway and the initiation of the classical complement cascade.

Animals↗
PubMedDate not supplied

Complexity in the major histocompatibility complex.

The human major histocompatibility complex (MHC) is one of the most intensively studied regions of the human genome, containing over 70 known genes and spanning about 4 million base pairs (4 Mbp) of DNA on chromosome 6p21.3 (Klein, 1986). It can be divided up into three regions: the class I region (telomeric), the class II region (centromeric), and the class III region (between class I and II), which includes the complement component genes C2, C4, and Bf (Trowsdale & Campbell, 1988). The MHC has been mapped in detail using pulse field gel electrophoresis (PFGE) and by cloning in yeast artificial chromosome (YAC) and cosmid vectors, revealing long stretches of DNA between the regions as well as between individual class I and class II genes. Novel genes, that have no sequence relationships with class I, class II or complement components, have recently been found in these areas, and we will present an update on these after reviewing the more established loci.

Chromosome Mapping↗
PubMed1987

Mechanism of killing of Giardia lamblia trophozoites by complement.

Only antibodies of the IgM class support the lytic effect of complement on Giardia lamblia (GL). We sensitized GL trophozoites (SGL) at 4 degrees C with serum containing anti-GL antibodies or IgM purified from this serum, and either normal human serum (NHS), complement 2-deficient human serum (C2d-HS), or C4-deficient guinea pig serum was used as source of complement. SGL were killed by NHS (86%) and by the deficient sera (50 and 40%, respectively), suggesting activation of the alternative pathway. However, the reaction was inhibited by Mg-EGTA. These observations led to studies of the role of C1. The lytic effect of NHS and C2d-HS on SGL was abolished by immunochemically depleting C1 from these sera, and reconstituted by adding purified C1q plus C1r and C1s. Factor B-depleted C2d-HS also lost its capacity to mediate killing, but reconstitution with factor B led to a dose-dependent increase in the killing of SGL. We next investigated the participation of the membrane attack complex in this system. SGL carrying C5b to C7 were lysed when incubated with C8 alone (56%); the addition of C9 further increased killing (98%), while C9 in the absence of C8 had no effect. We concluded that although activation of the classical pathway produces lysis of SGL, lysis may also proceed through a unique pathway of complement activation that requires C1 and factor B, but is independent of C4 and C2. Lysis of SGL can be accomplished by C5b to C8 in the absence of C9.

Animals↗
PubMed1980

Control of complement synthesis and secretion in bronchoalveolar and peritoneal macrophages.

The effect of inflammation on C (C2 and C4) biosynthesis by bronchoalveolar and peritoneal cells was studied with methods that detect changes in synthesis rates and qualitative changes in cell populations. Adherent bronchoalveolar macrophages produced less C2 and C4 than adherent peritoneal macrophages. However, the subset of cells capable of producing C was more than 20-fold greater in the peritoneal cell population than in the population of bronchoalveolar cells. The rate of synthesis per C producing bronchoalveolar macrophage was 5 to 10 times the rate by C producing peritoneal macrophages. In contrast, the effect of an inflammatory stimulus on C production was the result of a change in rate of synthesis per cell, not a change in the proportion of C producing cells. This stimulatory effect was exerted locally, not on a cell population harvested from a distant site. At least two mechanisms for local control of C levels in tissues have been identified--that is, a change in synthesis rate and a qualitative change in macrophage cell population. The capacity to alter C levels at a site of inflammation may be important for C dependent functions in host defenses.

Animals↗
PubMed1984

C4 allotyping distinguishes HLA-B14.1 and B14.2 subgroups.

Complement allotyping (C4, C2, and BF) was performed in 60 unrelated individuals and 15 families characterized for the subtypes (14.1 and 14.2) within HLA-B14. Eighty-seven percent of B14.2 individuals typed positive for the rare C4A2 variant. In contrast, less than 7% of B14.1 individuals were positive for this C4 allotype which is in keeping with a control background frequency. Family studies revealed that three distinct complotypes (complement haplotypes) are characteristic for the two HLA-B14 subgroups. The SC22 and FC31 complotypes characterize the B14.2 subtype, whereas SC31 appears to define B14.1.

Complement C4↗
PubMed1988

Molecular mapping of the HLA-linked complement genes and the RCA linkage group.

Phenotypic genetics have established linkage of the genes encoding proteins involved in the activation of the complement component C3. C2, factor B and C4, three of the structural components of the classical and alternative pathway C3 convertases, are encoded by genes which have been mapped to the class III region of the major histocompatibility complex (MHC) on human chromosome 6. The regulatory proteins factor H, C4BP, CR1, CR2 and DAF, which are involved in the control of C3 convertase activity, are encoded by closely linked genes, termed the regulators of complement activation (RCA) linkage group, that have been mapped to human chromosome 1. cDNA clones for all these proteins have been isolated, and this has made it possible to investigate the organization and structure of the MHC class III genes and the genes in the RCA linkage group. This short review summarizes some of the main features which have emerged from recent cloning work.

Animals↗
PubMed1983

A hemolytic assay for clinical investigation of human C2.

The heat lability of early acting components of human complement was studied in detail. Kinetic disappearance of individual components was monitored by hemolytic assay. C2 and factor B were the most heat labile components. We took advantage of the difference in heat stability between C2 and C1 to develop a hemolytic assay for human C2.

Animals↗
PubMed1981

Enzymatic treatment transforms trypomastigotes of Trypanosoma cruzi into activators of alternative complement pathway and potentiates their uptake by macrophages.

In the absence of bound antibody, trypomastigote bloodstream forms of Trypanosoma cruzi fail to activate the alternative complement pathway. We now demonstrate that treatment with trypsin and, to a lesser extent, with sialidase converts these protozoa into activators of the pathway, as judged by their lysis in normal sera or sera genetically deficient in fourth or second component of complement (C4 or C2) and their Mg2+-dependent consumption of C3 as measured by crossed immunoelectrophoresis. In addition, after pretreatment with enzyme and incubation in C5-deficient serum, trypomastigotes were shown to possess both C3 and properdin factor B (B) on their surface as judged by immunofluorescence. Requirement for the late components C5-C9 was suggested by the failure of C5-deficient sera to lyse trypsin-treated parasites. The inability to activate the alternative complement pathway was regained by these organisms after incubation in vitro. This restoration of insusceptibility was inhibited when puromycin was included in the culture medium. Treatment of the trypomastigotes with trypsin also potentiated their uptake by mouse peritoneal macrophages without apparent interference with their capacity to differentiate and multiply inside the cell. These findings suggest that untreated trypomastigotes normally escape recognition by the alternative pathway in vivo because of the presence on their surface of trypsin- and sialidase-sensitive regulatory molecules, the expression of which is dependent on protein synthesis.

Animals↗
PubMed1985

Biosynthesis of complement components by cultured rat hepatocytes.

Hepatocytes which had been isolated from the livers of Charles River rats were cultured in vitro. The cells were shown to synthesize albumin and the complement components C4, C2, C3 and B. Pulse-label studies with [35S]methionine showed that C4 and C3 were synthesized as single polypeptide chains. Pro-C4 did not appear to be converted into the plasma form of C4 intracellularly, whereas cell lysates contained the alpha- and beta-chains of plasma C3 as well as pro-C3. It is concluded that culture of rat hepatocytes in vitro provides a useful technique for studies of the synthesis of complement components.

Albumins↗
PubMed1984

Formation of EAC142 and EAC1423 with macrophage culture supernatant containing the secreted complement components C1 to C3.

Culture supernatants of thioglycollate-elicited guinea pig peritoneal macrophages contained hemolytic C1, C4, C2 and C3, whereas hemolytic C5, C6, C7, C8 or C9 were not detected. Activity of C1, C2 and C3 increased up to a 48 h culture period, whereas C4 activity already declined in 2 day old cultures. After secretion, the hemolytic activity of C1 was least stable in culture supernatant. Sensitized sheep erythrocytes (EA) when incubated with culture supernatant initiated activation and functional cooperation of secreted C1 to C3 as indicated by formation of EAC142 and EA1423 intermediates. Decay and regeneration with purified C2 was shown for EAC142 and deposition of C3 fragments on EAC1423 was demonstrated with anti-C3. On an average, supernatants of 2 day old macrophage cultures were most suitable for formation of EAC142 and EAC1423 . The rate of EAC142 and EAC1423 formation, and also of C2 and C3 inactivation, during incubation of EA with culture supernatant was slow; addition of purified C1 to culture supernatant, however, greatly enhanced the same reactions of EA with supernatant which indicated that C1 was the rate limiting factor. Local secretion of hemolytic C1, C4, C2 and C3 by macrophages may have an important role in antimicrobial defense mechanisms due to the well-known functional cooperation between macrophages and activated C3.

Animals↗
PubMed1990

Effect of sodium chloride concentration on fluid-phase assembly and stability of the C3 convertase of the classical pathway of the complement system.

The assembly of the classical-pathway C3 convertase from C4 and I2-treated C2 by the action of C1s is an Mg2(+)-dependent reaction. The Mg2+ concentration necessary for the assembly of C3 convertase in the fluid phase was found to be dependent on NaCl concentration. In the absence of NaCl more than 5 mM-MgCl2 was found to be required, whereas 0.5 mM-MgCl2 was adequate for the assembly of C3 convertase in the presence of 150 mM-NaCl. The C3 convertase assembled in a low-ionic-strength buffer was extremely labile compared with that assembled in buffer of physiological ionic strength, and the stability of C3 convertase was improved with the increase in NaCl concentration. It was found that the stabilizing effect of NaCl on C3 convertase was due to inhibition of the dissociating activity of C2b, which was formed during the assembly of C3 convertase. In addition to the dissociation-accelerating effect, C2b inhibited the assembly of C3 convertase in low-ionic-strength buffer, and this effect also was diminished with increase in NaCl concentration. An increase in NaCl concentration to more than 200 mM resulted in a decrease in the assembly of C3 convertase. This effect was not due to the lability of the assembled C3 convertase but due rather to the inhibition of C2 cleavage by C1s. Purified C3 convertase itself is stable in dilute medium or high-ionic-strength medium such as 500 mM-NaCl, suggesting that the interactions between C4b and C2a are hydrophobic. In these respects C2b seemed to be functionally similar to C4bp, but C2b failed to act as a cofactor for the Factor I-catalysed C4b cleavage.

Complement C2↗