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PubMed1983

[B, C2 and C4 complement factors, the HLA system and diseases. Genetic relation].

Close linkage of the complement factor loci C2, C4 and Bf to HLA loci has been firmly documented. A review of the literature was made about genetic defects of these components associated with a variety of disorders, especially immunologic diseases. Some allotypes of these factors are also closely linked to several diseases. Relationship between these diseases and the genes controlling the synthesis of C2, C4 and Bf and their allelic variants is not yet known but this association suggested several pathogenic hypotheses.

Complement C2↗
PubMed1989

Isolation and characterization of a novel plasma protein which binds to activated C4 of the classical complement pathway.

We report here the isolation and partial characterization of a previously unrecognized protease-sensitive plasma protein identified during the development of a novel protocol for the purification of the second component of human complement (C2). This new protein is physicochemically similar to C2. It coprecipitates with C2 on polyethylene glycol fractionation and specifically binds, like C2, to Sepharose-bound iC4/C4b. Binding occurs both in the presence and absence of C2. The purified protein has a chain structure similar to C2 as determined by sodium dodecyl sulfate-gel electrophoresis in the presence or absence of reducing agent and has a molecular mass of 120 kDa, only somewhat greater than C2 at 95 kDa. Both proteins radioiodinate under similar conditions to the same specific activities with each of two different methods that yield 10-fold disparate results. Quantitative Mancini analysis identifies 300 micrograms/ml of the 120-kDa protein in plasma and serum. The protein is present at normal concentrations in serum from individuals genetically deficient in C2, has no C2 functional activity, and is not cleaved as is C2 when serum complement is activated. Potent monospecific polyclonal anti-serum to each do not cross-immunoprecipitate using standard gel techniques. However, these anti-sera identify epitopes in common by Western blotting. The data presented indicate that the 120-kDa protein is a distinct plasma component and suggest that the protein is not an "immature" form of C2. Initial experiments to delineate a functional role for the 120-kDa protein have demonstrated a consistent inhibition of C1 site generation on EAC4b which is dose-dependent and reversible. Thus, this protein appears to be a new complement regulatory factor.

Blood Proteins↗
PubMed1977

Influence of a deficiency of the second component of complement on the bactericidal activity of neutrophils in vitro.

Serum from three patients with a complete, selective deficiency of the second component of complement (C2) did not promote optimal killing of Staphylococcus aureus, 502A by neutrophilic polymorphonuclear leukocytes (PMN) in vitro. The addition of C2 reagent or the presence of heat-stable opsonin in the C2-deficient serum corrected the defective killing of S. aureus that was observed with patient or control PMN. PMN from the patients or control subjects killed bacteria with equal efficiency under conditions of optimal opsonization (normal pooled serum). However, twice-washed control PMN were better than patient PMN in killing S. aureus under circumstances of suboptimal opsonization (C2-deficient serum, heated C2-deficient serum, heated normal pooled serum, or no replacement of serum). The latter finding was due to residual C2 on the surface of twice-washed control cells. As repeated washing of control PMN progressively removed cell-associated C2, the staphylocidal effectiveness of the control RMN decreased to the level of patient PMN. In contrast to the findings with S. aureus, triply-washed PMN from patients or controls killed normal numbers of Escherichia coli, ON2, in C2-deficient serum.

Animals↗
PubMed1984

HLA-B27 and allotypes of complement components in ankylosing spondylitis.

Thirteen families were studied for the frequency of HLA-B27 and allotypes of the components of complement, C2, C4 and Bf. The 13 probands all suffered from definite ankylosing spondylitis (AS) as defined by the New York criteria. The results showed that HLA-B27 positive haplotypes in AS patients possessed different complement allotypes. Thus, it is postulated that the gene conferring predisposition to the development of AS is either HLA-B27 itself or another gene in very close proximity to the HLA-B locus.

Alleles↗
PubMed1989

Chronic immune thrombocytopenic purpura--immunological analyses of a patient pre- and post-HIV seroconversion.

A seven year follow-up of immune parameters is reported for a patient with chronic immune thrombocytopenic purpura (ITP) pre and post human immunodeficiency virus (HIV) seroconversion. Therapies such as intravenous IgG, prednisone, vincristine, or Ciclosporin A had no clear-cut beneficial effect on platelet counts. A long-term normalization of platelet counts was achieved by splenectomy. At splenectomy the patient was seropositive for HIV, most likely transmitted by blood products received half a year prior to laparatomy. Mean plasma levels of the second component of complement, C2, were half of the normal values prior to and within the lowest normal range post HIV seroconversion. Nevertheless, the T cell-dependent B cell response to HIV, which is dependent on the activation of C3 via the classical pathway of complement, was normal: Western blot analysis of total IgG and of IgG subclass responses to individual HIV antigens proved to be unimpaired.

Antigen-Antibody Complex↗
PubMed1987

Pedigree of the major histocompatibility complex in a family with a neonatal alloimmune thrombocytopenia.

Immunization of a mother negative for the platelet-specific antigen P1A1 against the P1A1 antigen of her child induced neonatal alloimmune thrombocytopenia. This prompt immune response occurred in her first pregnancy and we were therefore interested to study whether there is an association with genes located within the major histocompatibility complex. We deduced haplotypes of HLA-A, B, C and DR as well as of complement C2, C4 and Bf in the maternal family members.

Adult↗
PubMed1976

Inherited deficiency of the second component of complement. Rheumatic disease associations.

The prevalence of homozygous and heterozygous deficiency of the second component of complement (C2) was determined in patients with rheumatic disease including 137 with systemic lupus erythematosus (SLE), 274 with juvenile rheumatoid arthritis, and 134 with rheumatoid arthritis. 1 C2 homozygous deficient and 19 possible heterozygous deficient individuals were identified by using both immunochemical and functional assays to determine C2 levels. Of the 20, 8 had SLE (5.9%), 10 had juvenile rheumatoid arthritis (3.7%), and 2 had rheumatoid arthritis (1.4%), the homozygous deficient individual having SLE. The prevalence of C2 deficiency in the SLE and juvenile rheumatoid arthritis patients was significantly increased (P = 0.0009 and P = 0.02, respectively) when compared with controls, 6 (1.2%) of 509 blood donors having C2 levels consistent with heterozygous deficiency. 15 of the 20 C2 deficient patients were HLA typed and found to have antigens A10(Aw25), B18, or both. The patients with C2 deficiency and SLE had earlier age of onset of disease and less antinuclear antibody when compared with the C2 normal SLE patients. 11 families of the propositi were studied and found to have one or more C2 heterozygous deficient individuals. The family members had an equal distribution of rheumatic disease and antinuclear antibody in the C2 deficient and C2 normal groups. C2 deficient individuals were found to have significantly lower levels of properdin Factor B (242 mug/ml+/-54) when compared with the non-C2 deficient family members (282 mug/ml+/-73). These data support the concept that inherited deficiency of C2 is significantly associated with both SLE and juvenile rheumatoid arthritis.

Adult↗
PubMed1976

The chromosomal order of genes controlling the major histocompatibility complex, properdin factor B, and deficiency of the second component of complement.

The relationship of the genes coding for HLA to those coding for properdin Factor B allotypes and for deficiency of the second component of complement (C2) was studied in families of patients with connective tissue disorders. Patients were selected because they were heterozygous or homozygous for C2 deficiency. 12 families with 15 matings informative for C2 deficiency were found. Of 57 informative meioses, two crossovers were noted between the C2 deficiency gene and the HLA-B gene, with a recombinant fraction of 0.035. A lod score of 13 was calculated for linkage between C2 deficiency and HLA-B at a maximum likelihood value of the recombinant fraction of 0.04. 18 families with 21 informative matings for both properdin Factor B allotype and HLA-B were found. Of 72 informative meioses, three recombinants were found, giving a recombinant fraction of 0.042. A lod score of 16 between HLA-B and Factor B allotypes was calculated at a maximum likelihood value of the recombinant fraction of 0.04. A crossover was shown to have occurred between genes for Factor B and HLA-D, in which HLA-D segregared with HLA-A and B. These studies suggest that the genes for Factor B and C2 deficiency are located outside those for HLA, that the order of genese is HLA-A, -B, -D, Factor B allotype, C2 deficiency, that the genes coding for C2 deficiency and Factor B allotypes are approximately 3--5 centimorgans from the HLA-A and HLA-B loci, and that the apparent lack of recombinants between the Factor B gene and C2 deficiency gene suggests that these two genes lie in close proximity to one another.

Chromosome Mapping↗
PubMed1982

Antibody-independent activation of C1 by type Ia group B streptococci.

A prototype fresh clinical isolate of type Ia group B streptococci (strain 515) can be opsonized by serum containing low levels of antibody. This opsonizing process can also occur in hypogammaglobulinemic serum, confirming its antibody independence, but it does require Ca++ ions and the second component of complement (C2). When formalin-fixed organisms are reacted with whole serum, C4 and C3 are cleaved. These data are strong evidence that this organism can directly activate C1 in the absence of antibody and that this activation leads to the formation of a classical C3 convertase (C4b2a), which cleaves C3. The observation that opsonization can occur in hypogammaglobulinemic serum suggests that complement alone, presumably the fixation of C3b, is sufficient for phagocytes to ingest this pathogen.

Complement Activation↗
PubMed1985

Pretranslational regulation of the synthesis of the third component of complement in human mononuclear phagocytes by the lipid A portion of lipopolysaccharide.

The third component of complement (C3) is a plasma glycoprotein with a variety of biologic functions in the initiation and maintenance of host response to infectious agents. While the hepatocyte is the primary source of plasma C3, mononuclear phagocytes contribute to the regulation of tissue availability of C3. Lipopolysaccharide (LPS), a constituent of cell walls of gram-negative bacteria, consists of a polysaccharide moiety (core polysaccharide and O antigen) covalently linked to a lipid portion (lipid A). Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-polyacrylamide gel electrophoresis, we examined the effects of LPS on synthesis of C3 by human mononuclear phagocytes as well as synthesis of the second component of complement (C2), factor B, lysozyme, and total protein. LPS increased C3 synthesis 5-30-fold without affecting the kinetics of secretion of C3 or the synthesis of C2, lysozyme, or total protein. Factor B synthesis was consistently increased by LPS. Experiments with lipid A-inactivated LPS (alkaline treated), LPS from a polysaccharide mutant strain, and lipid X (a lipid A precursor) indicated that the lipid A portion is the structural element required for this effect. Northern blot analysis demonstrated at least a fivefold increase in C3 mRNA in LPS-treated monolayers, which suggests that the regulation of the increase in C3 synthesis is pretranslational. C2 mRNA and factor B mRNA were increased approximately twofold. The availability of specific gene products in human mononuclear phagocytes that respond to LPS should permit understanding of the molecular regulation of more complex functions of these cells elicited by LPS in which multiple gene products are coordinately expressed.

Complement C2↗
PubMed1987

Cell-specific expression of the human complement protein factor B gene: evidence for the role of two distinct 5'-flanking elements.

The human complement protein Factor B is encoded by a single gene in the major histocompatibility complex and is closely linked to the gene encoding the second component of complement C2. DNA sequencing, S1 mapping, and primer extension experiments have established that the transcription initiation site of the Factor B gene lies only 421 bp from the poly(A) site of the C2 gene. Deletion analysis of the Factor B 5'-flanking region has suggested the presence of cis-acting DNA elements that are essential for the cell-specific expression of the Factor B gene. These sequences extend into the 3' region of the C2 gene. We have defined an enhancer element in the 5'-flanking region in addition to the promoter element. Our results suggest that the cell-specific expression of the Factor B gene is dependent upon the combinatorial effect of both the promoter and the enhancer elements.

Base Sequence↗
PubMed1990

Interferon-mediated transcriptional and post-transcriptional modulation of complement gene expression in human monocytes.

The addition of lymphoblastoid interferon alpha, fibroblast interferon beta and recombinant interferon gamma to in vitro monocyte cultures produced dose-dependent increases in transcription rates of the genes encoding the second component of complement (C2), factor B (B) and C1 inhibitor, and the abundance of their respective mRNA. Interferon gamma was the most effective at stimulating transcription of the C1-inhibitor gene whereas interferons alpha and beta were more effective at increasing the transcription of the C2 and B genes. Transcription of the C3 gene was reduced by interferon gamma. None of these cytokines altered the level of transcription of the actin gene. Interferon-induced changes in the levels of transcription of the C2, B and C1-inhibitor genes occurred rapidly, with significant changes occurring within 30 min of exposure to these cytokines. Within 4 h of removal of the interferons from the culture fluid, the level of transcription of the C1-inhibitor, C2, B and C3 genes returned to control values, as did abundance of C2, B and C3 mRNA. However, the abundance of C1-inhibitor mRNA remained elevated in interferon-gamma-treated monocytes. Combinations of interferons produced less than additive effects on the stimulation of the transcription of C2, B and C1-inhibitor genes, whereas measurements of C1-inhibitor mRNA and B mRNA showed that interferon gamma acted synergistically with interferon gamma to increase the abundance of the mRNA. Their effects on C2 mRNA abundance were less than additive. The half-lives of C1-inhibitor, C2, B and C3 mRNA were not altered by interferon alpha, whereas interferon gamma shortened the half-life of C2 mRNA by approximately 50%, and prolonged the half-lives of B and C1-inhibitor mRNA approximately twofold and fivefold, respectively. The half-life of C3 mRNA was unaltered by either interferon. These results show that the large increase in C1-inhibitor synthesis which occurs in interferon-gamma-treated monocytes, is due to a combination of increased transcription and increased C1-inhibitor mRNA stability. They also suggest that the synergistic effects of interferon alpha together with interferon gamma on C1-inhibitor and factor B synthesis is also dependent upon increased transcription and increased mRNA stability.

Complement C1 Inactivator Proteins↗
PubMed1981

Complement synthesis by guinea pig peritoneal macrophages: failure to detect chemical carcinogens.

In vitro production of the second and fourth components of complement (C2 and C4, respectively) by peritoneal macrophages from noninbred Hartley guinea pigs was tested after the animals had been inoculated with known carcinogens. The system demonstrated the capacity of N-nitrosodimethylamine to decrease C2 and C4 production. However, a similar decrease in C2 and C4 production was seen with only CCl4, 1 of the 10 chemical carcinogens studied. This system had little usefulness as a short-term screening procedure for the detection of carcinogenicity. The effect of the carcinogens on several other functions of peritoneal macrophages was also determined. The number of peritoneal exudate cells (PEC) was significantly lower in carcinogen-inoculated animals than in solvent-inoculated controls for three carcinogens: BeSO4, P < 0.005; CHCl3, P < 0.025; and CCl4, P < 0.01. However, the capacity of the PEC to adhere to plastic was decreased by only CHCl3 (P < 0.05), and adherent cells from all guinea pigs produced normal amounts of total secreted protein.

Animals↗
PubMed1985

Carbohydrate composition of the second, third and fifth components and factors B and D of human complement.

The carbohydrate composition of the second, third and fifth components of human complement (C2, C3 and C5) and of factors B and D was determined employing gas-chromatographic and mass-spectrometric methods. C2 was found to contain 15.9% carbohydrate composed of fucose, galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (approximate molar ratio 1:4:9:9:4). N-acetylglucosamine and mannose (approximate molar ratio 1:4), amounting to 1.7% of the mass of the molecule, were the only monosaccharides detected in C3. C5 contained 3.8% carbohydrate composed of galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (approximate molar ratio 2:4:4-5:2). The carbohydrate moiety of B consisted of fucose, galactose, mannose, N-acetylglucosamine and N-acetylneuraminate (molar ratio 1:2:3:4:2). The total carbohydrate content of B was estimated at 8.6%. In addition to these monosaccharides, glucose (0.4-0.9%) was also detected in all preparations analysed. Glucose was the only sugar detected in D.

Carbohydrates↗
PubMed1978

The purification and properties of the second component of human complement.

The second component of human complement (C2) was purified by a combination of euglobulin precipitation, ion-exchange chromatography, (NH4)2SO4 precipitation and affinity chromatography. The final product was homogeneous by the criterion of polyacrylamide-gel electrophoresis and represents a purification of about 4000-fold from serum with 15-20% yield. Component C2 comprises a single carbohydrate-containing polypeptide chain, with an apparent mol.wt. of 102000; alanine is the N-terminal amino acid. The molecule is rapidly cleaved by activated subcomponent C1s with the loss of haemolytic activity to yield two fragments with apparent mol.wts. of 74000 and 34000. These fragments are not linked by disulphide bonds and can be easily separated. A second protein isolated during the purification of component C2 was identified by its haemolytic and antigenic properties as complement Factor B, the protein serving an analogous function to component C2 in the alternative pathway. The protein, which is also a single carbohydrate-containing polypeptide chain, has an apparent mol.wt. of 95000 and threonine as N-terminal amino acid. The amino acid analyses of component C2 and Factor B are compared.

Chromatography, Agarose↗