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PubMed1991

Human recombinant macrophage colony-stimulating factor (M-CSF) increases Cl-esterase inhibitor (Cl-INH) synthesis by human monocytes.

The ability of macrophage colony-stimulating factor (M-CSF) to influence production of complement proteins by cultured human monocytes was studied. Three-day-old cultures of human monocytes were treated with 250-1000 U/ml recombinant human M-CSF (Cetus Corporation, Emeryville, CA). After 3 days the M-CSF containing medium was replaced by the same medium without M-CSF, and the cells were cultured for 3 more days. Samples taken at the removal of M-CSF and 3 days later were tested for the concentration of factor B and Cl-esterase inhibitor (Cl-INH) using ELISA methods, and C2 by using an immunohaemolytic assay. M-CSF induced a marked dose-dependent increase in the synthesis of Cl-INH, but did not significantly change Bf and C2 production. The findings suggest that M-CSF is able to influence selectively the complement protein-producing ability of cultured human monocytes.

Cells, Cultured↗
PubMed1975

[The complement system].

The complement system may be activated by at least two different pathways: the clinical pathway involving C1, C4 and C2 and the alternative pathway involving properdin, C3, factor B and factor D. The classical pathway can be activated by antigen antibody complexes, while the alternative pathway can be activated by other substances such as natural polysaccharides. Both pathways lead to an activation of C3 and of the last complement components (C5 to C9). Congenital defects of the complement system have been described for several components. Some of these defects are relatively well tolerated, but others, such as C3 deficiency, lead to increased susceptibility to bacterial infections. Acquired complement defects are frequently observed in association with several diseases. Usually they are characterized by an increased level of complement components involved in the classical pathway and therefore reflect activation by antigen antibody complexes. Such changes may be systematic, as in lupus erythematodes, or localized to some biological fluids such as synovial fluid in rheumatoid arthritis. In some renal diseases the complement profile suggests activation of the complement system by the alternative pathway, and this may reflect a different pathogenesis.

Angioedema↗
PubMed1982

Requirement for an additional serum factor essential for the antibody-independent activation of the classical complement sequence by Gram-negative bacteria.

Killing of Salmonella minnesota and Salmonella typhimurium S and R strains in serum of nonimmune humans and guinea pigs was drastically reduced in the selective absence of C1q, C1r, Ca2+, C4, or C2, the components of the classical complement pathway. Binding of C1 and C1q to the S form and six different core-deficient R mutant strains became stronger the shorter the lipopolysaccharide molecule. C1 and C1q had, under physiological conditions, no affinity to the serum-resistant S forms, whereas these components were bound by the serum-sensitive R forms with high affinity. However, a mixture of the individual complement components C1-C9, which rapidly lysed sensitized erythrocytes, did not kill the serum-sensitive bacteria. Isolated C1 bound to these bacteria cleaved fluid-phase C4 but did not convert C2. C2 turnover could be detected only when serum was used as a source of C1 or C4, indicating that an additional serum component is necessary for the antibody-independent bactericidal effect. Functional tests indicated that this factor is a euglobulin which mediates binding of C4 to the bacteria even in the absence of C1 or after treatment with EDTA. Binding of C4 followed by the generation of C4b sites as acceptors for C2 was a prerequisite for the killing of the bacteria. The factor could not be replaced by immunoglobulin G or immunoglobulin M, nor was it blocked by preincubation with anti-immunoglobulin G or anti-immunoglobulin M.

Animals↗
PubMed1992

Assessment of complement activation in clinical samples. Comparison of immunochemical and functional measurements of complement components with quantitation of activation fragments.

We have compared functional and immunochemical measurements of complement components with assays measuring the generation of activation fragments, for the assessment of classical pathway activation in vitro and in vivo. The generation of the C3a, C3b/C3bi cleavage fragments of C3, and of the C4d cleavage fragment of C4 measured by ELISA and RIA, was correlated with the decrease in total complement hemolytic activity (CH50) and in functional activity of C3 and C4 in normal human serum in which the classical pathway had been activated with aggregated IgG. The decrease in CH50 in in vitro activated serum was also correlated with the generation of C5a and soluble SC5b-9 complexes. In contrast, no or little increase in the concentration of C3a, C3b/C3bi and C4d was observed in plasma samples from patients with low CH50 and with low levels of immunochemical C3 and C4, indicating that fragment quantitation assays provide no information on the presence and extent of complement activation in vivo. Analysis of samples from patients expressing the four C4 genes and patients having one or two C4 null alleles indicated that a ratio of hemolytic C4 to C2 > or = 1 was indicative of complement activation without C4 deficiency, whereas a ratio below 1 was indicative of C4 deficiency with or without classical pathway consumption. Classical pathway activation and C4 deficiency in clinical samples are best predicted by the concomitant assessment of immunochemical levels of C3 and C4 and hemolytic levels of C4, C2 and C3.

Complement Activation↗
PubMedDate not supplied

Polymorphism of the complement components in human pathology.

The complement system is an important part of non clonal or innate immunity that collaborates with acquired immunity to kill pathogens and to facilitate the clearance of immune complexes. The complement is made up of 20 distinct plasma proteins and 9 different membrane proteins. Three components, factor B, C2 and C4 (with 2 isotypes), are coded by polymorphic HLA-linked genes and are sometimes referred to as class III antigens, inherited as compact units called complotypes. The C4 genes are the most polymorphic, including a common null allele (Q0) at both the C4A and C4B loci. Other polymorphic complement factors (not linked to HLA) are C3 (2 common alleles), C6 and C7 (closely linked, with 3 and 2 alleles, respectively). A certain degree of polymorphism has also been described for complement receptors and membrane control proteins. No differences in functional activity are usually detected among different alleles. Immune-mediated diseases are associated with C4Q0, in particular: systemic lupus erythematosus and discoid-systemic lupus erythematosus, insulin-dependent diabetes mellitus, liver cirrhosis, celiac disease and IgA/IgG4 deficiency. Even if optimal HLA markers do become available, genetic counselling is usually not the ultimate goal for dealing with most of the HLA-associated common diseases, although their study could help to better delineate disease pathogenesis.

Adrenal Hyperplasia, Congenital↗
PubMed1987

Subacute cutaneous lupus erythematosus in multiple members of a family with C2 deficiency.

Deficiency of the second component of complement (C2d) has been associated with systemic lupus erythematosus (LE)-like syndromes as well as recurrent infections. In particular, C2d has been associated with the LE subset of subacute cutaneous LE (SCLE), the presence of anti-Ro antibodies (anti-Ro or SS-A), and the human leukocyte antigen (HLA) types A25, B18, and DR2. A family with C2d in which three members have developed SCLE was observed and studied clinically, serologically, and immunogenetically. Deficiency of the second component of complement was present in all six family members, while anti-Ro was present in only two. There was a strong but incomplete association of C2d and SCLE with HLA-DR2, but the association was not complete with positivity of anti-Ro or antinuclear antibodies. Study of this family reconfirmed the close association of HLA-A25, -B18 and -DR2 with the C2 gene, but indicated a less close association of these loci with serologic markers.

Adult↗
PubMed1986

Regulation of complement protein biosynthesis in mononuclear phagocytes.

Proteins of the complement system (with the exception of the terminal components C6-9) are synthesized in mononuclear phagocytes. The extrahepatic macrophage is therefore an important local source of the complement proteins which may serve as a first-line host defence mechanism. Net synthesis and secretion of complement by these cells is a function of maturation of the mononuclear phagocytic series, the tissue from which the cells are isolated, and the state of macrophage activation. To define some of the mechanisms for regulation of complement gene expression in mononuclear phagocytes, the major histocompatibility complex class III genes and C3 have been investigated. These genes are expressed constitutively in hepatocytes and monocytes/macrophages. In the mononuclear phagocyte, interferon-gamma, at physiological concentrations, effects a dose- and time-dependent increase in factor B and C2 mRNA and a corresponding increase in factor B and C2 biosynthesis. This effect is specific inasmuch as the expression of other genes (e.g. C3) is decreased by interferon-gamma, and interferon-alpha and beta at concentrations one to two logs greater have only a minimal effect on C2 and factor B gene expression. Endotoxin acting directly on monocytes has qualitatively different effects on expression of the complement genes. These complex regulatory mechanisms are being investigated with the use of murine fibroblasts transfected with human DNA bearing the relevent complement genes.

Animals↗
PubMed1993

Classical pathway of complement activation in mammalian kidneys.

Two monoclonal antibodies (mAb M4d2 and M4d3) specific for the alpha 2-fragment (C4d), and one antibody (mAb M4c3) specific for the gamma-chain of human complement protein C4, have been tested for cross-reactivity against mammalian complement. These mAb have also been found to react with C4 from guinea-pig (mAb M4d2 and M4c3) as well as from cattle, baboon and rhesus monkey (mAb M4d3 and M4c3) in an activation ELISA. Since reactivity of mAb M4d2 and M4c3 included guinea-pig complement, the specific recognition of mammalian C4 could be confirmed with sera from C4-deficient (def') guinea-pigs. mAb M4d2 or M4d3, but not mAb M4c3, stained glomerular deposits within renal tissue sections from pig, cattle and guinea-pig. In the case of mAb M4d2, specificity of that staining could also be demonstrated in kidney specimens from C4-def' guinea-pigs. It can be concluded that, as in humans, the C4d fragment is also present in mammalian glomeruli. Compared with normal guinea-pigs, the C4-def' and C2-def' animals showed markedly increased glomerular deposits of IgM. It appears that glomerular deposition of complement C4d in mammals: (1) indicates activation via the classical pathway; (2) represents a general phenomenon of renal homeostasis; and (3) seems to be involved in the physiological clearance of immune complexes.

Animals↗
PubMed1978

Argentine hemorrhagic fever. Alterations of the complement system and anti-Junin-virus humoral response.

We investigated immunologic mechanisms and the role of complement in the pathogenesis of Argentine hemorrhagic fever, a disease caused by the Junin virus, a member of the arenavirus group. Total serum complement activity was reduced to 68 per cent of control values in patients with severe or moderate disease (P less than 0.001). C2, C3 and C5 values were also low (12 to 60 per cent) during the early acute period of the disease. However, serum C4 content was increased to 160 per cent of the control values in the same patients. Total complement activity returned to normal with clinical and laboratory recovery, at the time of detection of antibodies against Junin virus. C1q reactive material was found in four of 19 cases and no relation to the evolution of the disease could be established. These results suggest that immune complexes are not important in the pathogenesis of Argentine hemorrhagic fever, but that activation of the complement system has a role.

Antibodies, Viral↗
PubMed1975

Function of the classical and alternate pathways of human complement in serum treated with ethylene glycol tetraacetic acid and MgCl2-ethylene glycol tetraacetic acid.

An immunochemical and functional analysis of the classical and alternate complement pathways in human serum was performed in the presence of 10 mM ethylene glycol tetraacetic acid (EGTA) and MgCl(2)-EGTA (MgEGTA), chelating agents which have been recently utilized as a means of distinguishing between these two complement pathways. Total hemolytic activity, integrity of the C1 complex, hemolytic activity of C2, conversion of factor B (C3 proactivator), and complement-dependent bactericidal activity were studied. The effect of these chelators on activation of complement pathways by Escherichia coli, by sensitized erythrocytes as a prototype of activators of the classical pathway, and by zymosan as a prototype of alternate (properdin) pathway activators was studied. Human serum containing 10 mM EGTA, which provides almost no ionized calcium and considerably less ionized magnesium than unchelated serum, allowed consumption of complement via the alternate (properdin) pathway, but blocked the classical pathway as judged by disintegration of the C1 complex and lack of utilization of C2. However, activity of the alternate complement pathway in EGTA serum, as judged by conversion of factor B and bactericidal activity against gram-negative bacteria, was distinctly suboptimal. Addition of magnesium ion in a concentration equimolar to EGTA (MgEGTA serum), while still providing conditions in which the C1 complex dissociated, significantly enhanced alternate complement pathway-mediated bactericidal activity. However, in MgEGTA serum considerable fluid-phase activation of the alternate pathway, as indicated by decrease in 50% hemolytic complement (CH(5 0)) titers and conversion of factor B to its active form in the absence of any activating challenge, was observed. Moreover, some fluid-phase consumption of C2 was observed in MgEGTA serum, even though, as mentioned, the C1 complex was shown to be dissociated under these conditions. MgEGTA-related activation of C2 and of the alternate (properdin) pathway of complement was significantly enhanced by the presence of zymosan and E. coli. These results indicate that use of the chelating agents EGTA and MgEGTA to differentiate between classical and alternate pathway activation of human complement is more complex than has hitherto been suggested. In EGTA serum, spontaneous activation of either pathway does not occur but bactericidal activity, as a measure of biologic function of complement, is suboptimal. In MgEGTA serum, bactericidal activity is fully expressed, but there is considerable instability, in terms of fluid-phase activation, in Mg(2+)-dependent components of both pathways. Thus, caution is indicated in the use and interpretation of the effects of these chelating agents on biologic functions mediated by either pathway of human complement.

Blood Bactericidal Activity↗
PubMed1994

Partial complement deficiencies in idiopathic thrombocytopenia of childhood.

We have examined the classical complement activation pathway in 36 children with idiopathic thrombocytopenia (ITP) in a retrospective study. An increased prevalence of congenital, partial complement deficiencies is found in ITP. Homozygous C4A deficiency was found in 5 patients (p < 0.05) and heterozygous C2 deficiency in 2 other patients (p = 0.05). We suggest that some cases of childhood ITP belong to the immune complex mediated diseases, such as systemic lupus erythematosus and that abnormal immune complex formation and clearance may lead to ITP.

Adolescent↗
PubMed1979

Complement activation by pneumococci associated with acute otitis media.

Pneumococci (types, I, III, VI, XIV, XVIII, XIX and XXIII) associated with acute otitis media were shown to activate complement in normal human serum by the classical as well as by the alternative pathway. In serum incubated with pneumococci classical pathway activation was demonstrated by decreased C4 values and the appearance of C1r-C1s-C1 IA complexes. Pneumococci caused C3 conversion in C2-deficient serum and in serum chelated with Mg++ EGTA showing activation of the alternative pathway without participation of the C42 convertase. Complement activation was more efficient when both pathways were intact. This was evident from a more pronounced C3 conversion and a greater reduction of the values for properdin and factor B in non-chelated serum as compared to Mg++ EGTA chelated serum.

Acute Disease↗
PubMed1979

Simultaneous occurrence of hereditary C6 and C2 deficiency in a French-Canadian family.

The sera of four sisters were found to lack the sixth component of complement (C6) and the serum of one was also partially deficient in the second component (C2). Two other blood relatives were found to be heterozygous for both deficiencies, while only one sibling had normal values. The father of these eight siblings was heterozygous for C2D and C6D and in the third generation, six children were heterozygous for C6 deficiency was treated for chronic active brucel-transmitted; the C6 deficiency was not linked to the HLA system, while the C2-deficiency segregated with the haplotype A10,B18. The proband, homozygous for C6 deficiency was treated for chronic active Brucellosis and in another sibling with C6 deficiency, toxoplasmosis was diagnosed. Neither bleeding disorders nor a tendency to collagen diseases have been observed and the opsonic activity was normal in the sera of all family members.

Adult↗
PubMed1985

Molecular biology of the human and mouse MHC class III genes: phylogenetic conservation, genetics and regulation of expression.

The generation of complementary and genomic DNA clones for the human and mouse MHC class III genes has advanced the study of the organization, structure, genetics and expression of these loci. These clones have been useful in defining new polymorphic markers in each species and therefore permit a more complete genetic analysis of the complement cluster and the MHC as a whole. The coding sequences of the factor B and C4 genes are extensively conserved both within and between species, in contrast to the coding sequences of other MHC products. In human and mouse, the organization of the class III genes is similar with respect to order and position between the class II and class I regions of the MHC. However, these inter-species similarities in the organization and products of the class III genes does not extend to their regulation. In addition to complement gene expression being regulated differently between tissue sites within a species, expression is apparently regulated differently in analogous tissues between species. The considerable progress which has been made in the molecular analysis of C2, factor B and C4 using DNA clones forms the basis for the future study of the biology of the class III genes and the role of complement in inflammatory processes and in the immune system.

Animals↗
PubMed1984

Recurrent sepsis with deficiencies of C2 and galactokinase.

A 4-year-old girl with recurrent, severe bacterial infections and absence of both the second component of complement and galactokinase was investigated for immunodeficiency. The C2 deficiency (C2D) was diagnosed after four major pyogenic infections. Results of studies of cellular and humoral immunity were normal, as were polymorphonuclear leukocyte chemotaxis and bactericidal activities and alternative-pathway hemolytic activity. Serum chemotactic and opsonic activities were deficient in this patient and in an older, asymptomatic sibling with C2D. Fresh-frozen plasma, administered during an episode of Streptococcus pneumoniae meningitis, enhanced serum opsonic activity at 12 hours after infusion. To our knowledge, this is the first description of C2D in a patient with a documented second, unusual genetic defect.

Antibody Formation↗
PubMed1977

Comparison of ethyleneglycoltetraacetic acid and its magnesium salt as reagents for studying alternative complement pathway function.

The divalent cation chelators, ethyleneglycoltetraacetic acid (EGTA) and its magnesium salt, MgEGTA, were compared in studies of alternative complement pathway function. EGTA (0.01 M) inhibited both the rate and the amount of complement activation by zymosan whether compared to nonchelated serum or to serum chelated with MgEGTA (0.01 M). The rate of alternative pathway activation by zymosan was slightly slower in MgEGTA-chelated serum than in nonchelated serum, but the overall amount of complement consumed by a given amount of zymosan was not decreased. MgEGTA chelation spontaneously activated the alternative pathway, as reflected by lysis of erythrocytes from a patient with paroxysmal nocturnal hemoglobinuria. No evidence could be found that MgEGTA either spontaneously activated C2 or facilitated zymosan activation of C2. Suggested guidelines for the use of these chelators are advanced.

Adult↗
PubMed1976

The complement abnormalities of lipodystrophy.

Investigation of the serum complement system in 25 patients with various forms of lipodystrophy showed no abnormality in three patients with total lipodystrophy; a single patient with limb lipodystrophy had evidence of activation of the classical complement pathway. However, of the 21 patients with partial lipodystrophy, 17 had low serum C3, with normal C4 and C2, concentrations, accompanied in 14 by a serum C3 splitting factor indistinguishable from nephritic factor, suggesting activation of the alternative pathway. These abnormalities occurred in 10 patients without clinically overt renal disease. Seven patients had overt nephritis; renal biopsies obtained in six showed mesangiocapillary (membranoproliferative) nephritis in all. Thus, the majority of patients with partial lipodystrophy have hypocomplementemia. Although nephritis may not invariably develop, the high rate of mesangiocapillary nephritis in these patients suggests that complement activation via the alternative pathway predisposes to the development of this form of glomerular disease.

Adolescent↗