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PubMed1989

Low incidence of null alleles of the fourth component of complement (C4) in elderly people.

Allotype frequencies of three complement proteins (C2, factor B, and C4) encoded on the sixth chromosome were tested in 150 "young" (under 53 yrs) and 131 "old" (over 62 yrs) healthy Hungarian individuals. In women, we found significant differences in BF*F allotype frequencies between the two age groups. A marked decrease of null alleles for C4 was observed especially in men. In the "old" age group, the total frequency of the non-expressed, "null" (Q0) alleles of the C4 protein dropped to almost one third of the "young" ones. The decrease was even larger (a 5.5-fold decrease in the incidence) among men. The relative risk of those having C4B*Q0 allele not to survive a "critical age period" of 53-62 yrs for males and 58-62 yrs for females was calculated to be 12.4 and 2.85, respectively. Our data substantiate the view that the expected life time is genetically determined and it can be forecast partly by the analysis of the antigens encoded on the sixth chromosome.

Adult↗
PubMed1998

Molecular heterogeneity of second and fourth components of complement and their genes in systemic sclerosis and association of HLA alleles A1, B8 and DR3 with limited and DR5 with diffuse systemic sclerosis.

Deficiency of the complement component C4 at the functional, protein and gene level and deficiency of complement component C2 at the functional level were investigated and HLA analysis was performed on patients with limited and diffuse systemic sclerosis (SSc). One of the patients with limited SSc (n = 15) had subnormal C4, 1 subnormal C2 and 1 subnormal C4 and C2 activities; the latter patient had HLA alleles A11;B35;Dw1 associated with type II C2 deficiency and therefore most likely had a defect at the C2 locus. One of the patients with diffuse SSC (n = 12) had subnormal C4 and 1 subnormal C4 and C2 activities. C2 deficiencies in patients other than the one with the haplotype associated with C2 deficiency appeared not to be determined by the gene at the C2 locus. The incidence of partial C2 deficiency in a normal Caucasian population is reported to be 16 in 10,000, and that of partial C4 deficiency also appears to be very low. The percentages of C4A*Q0 and C4B*Q0 alleles in normal controls (n = 45) were within the reported range. Seven patients with limited SSc (n = 14) had one or two C4A*Q0 alleles and 2 with diffuse SSc (n = 13) had one C4A*Q0 allele. Thus, the incidence of C4A*Q0 was higher than normal in limited SSc and within the normal range in diffuse SSc. The two-sided Fisher's exact test applied on these data revealed that the association of C4A*Q0 with limited SSc did not reach a significant level (p = 0.10). Two of the 3 patients with limited SSc, who had two C4A*Q0 alleles, carried a heterozygous C4A-21-hydroxylase A (OHA) gene segment deletion as detected by Southern blotting. There was no correlation between the subnormal activity of C4 and the occurrence of one or two C4A*Q0 (and C4A-21-OHA segment deletion). HLA alleles A1, B8 and DR3 (p = 0.002) were associated with limited SSc (n = 23) and DR5(w11) (p = 0.018) with diffuse SSc (n = 17).

Alleles↗
PubMed1980

Effects of histamine on monocyte complement production. I. Inhibition of C2 production mediated by its action on H2 receptors.

Histamine produced dose-dependent inhibition of the production of the second complement component (C2) by monocytes in tissue culture. The effect was not associated with either cell death, as ascertained by trypan blue exclusion, or loss of cells from the monolayer, as determined by measuring their DNA content. The specificity of the response was shown by the failure of histidine or histamine metabolites to inhibit C2 production. Preincubation of histamine with histaminase also abrogated the histamine effect. The kinetics of the effect were extremely rapid and irreversible, most of the reduction being achieved during a 5-min exposure to histamine. The H2 receptor antagonist cimetidine was able to prevent the histamine response, whereas chlorpheniramine, the H1 receptor antagonist, had no effect. Dimaprit and 4-methyl histamine, H2 receptor agonists, simulated the effect of histamine whereas the H1 receptor agonist 2-(2-aminoethylthiazole) was ineffective, confirming that the effect of histamine on C2 production by monocytes is mediated by the H2 receptors. Thus histamine, released from basophils or mast cells by the C3 and C5 cleavage products C3a and C5a respectively, may exert a negative feedback on further C3 and C5 cleavage by limiting the formation of the C3 (C42) and C5 (C423b) convertases.

Cells, Cultured↗
PubMed1985

The structure and genetics of the C2 and factor B genes.

This review summarises our current knowledge of the genetic organisation, structure and polymorphism of the loci for the complement proteins, C2 and Factor B--class III gene products of the major histocompatibility complex. cDNA probes specific for C2 and Factor B have been used to screen cosmid libraries of human genomic DNA, and this has allowed isolation and characterisation of the corresponding genes. Southern blot analysis of the cosmid clones and of uncloned genomic DNA has shown that there are single C2 and Factor B loci that are less than 500 bp apart. Molecular mapping has revealed that the C2 gene spans approximately 18 kb of DNA. This is in marked contrast to the Factor B gene which is 6 kb in length. The entire gene structure of the Factor B gene has been determined and the interesting features of this gene which have emerged from an examination of the intron-exon boundaries are discussed. C2 and Factor B are polymorphic and structural variants have been detected by differences in charge. The degree of polymorphism at the C2 and Factor B loci has been examined by Southern blot analysis of restriction digests of genomic DNA. Three DNA polymorphisms have been identified in the C2 gene. These polymorphisms subdivide the common allelic variant of C2 (C2C) and reveal that there is much greater variability at the C2 locus than that detected by protein typing. It is suggested that these DNA polymorphisms may serve as useful markers in the genetic analysis of diseases that are related to the major histocompatibility complex.

Amino Acid Sequence↗
PubMed1984

Role of C3 in the control of monocyte C2 production.

Serum-treated antigen-antibody complexes (IC) and DTSP-polymerized C3b and C3c inhibited the production of the second complement component (C2) by monocytes in culture, whereas monomeric C3, C3b, C3bi, C3c or C3d had no effect. The degree of inhibition of dithiobissuccinimidyl propionate (DTSP)-polymerized C3 was proportional to the degree of polymerization, dimer exhibiting less inhibitory activity than larger molecular weight polymers. The inhibitory effect of serum-treated IC and DTSP-polymerized C3b was abrogated by their pretreatment with Fab fragments of anti-C3, or pretreatment of monocytes with Fab fragments of antiserum to the C3b receptor (CR1). We have concluded that the inhibition of C2 production produced by serum-treated IC is due to bound C3b or C3bi, and is mediated by CR1. Furthermore cross linking of receptors is required for this effect; two or more than two receptors must be cross-linked for a significant effect to be observed.

Antigen-Antibody Complex↗
PubMed1985

Tissue-specific pretranslational regulation of complement production in human mononuclear phagocytes.

The net production of the complement protein C2, C4, and factor B differ among mononuclear phagocytes from peripheral blood and different tissues in experimental animals and in humans. To examine the mechanisms that regulate these differences in humans, the proportions of C2-producing cells, the average single-cell production rate of C2, the posttranslational glycosylation and kinetics of secretion of C2 and factor B, and the amounts of C2 and factor B mRNA were examined in freshly isolated peripheral blood monocytes, monocytes maintained up to 2 wk in culture, and freshly isolated tissue macrophages from breast milk and bronchoalveolar lavage. In addition, the biosynthesis of two other proteins synthesized and secreted by mononuclear phagocytes, C3 and lysozyme, were examined. We report that despite comparable rates of C3 and lysozyme synthesis and similar processing and kinetics of secretion of C2 and factor B, the freshly isolated tissue macrophage differs from the monocyte-derived macrophage in the proportion of C2-producing cells, in the average single-cell production rate of complement, and in the amounts of specific C2 and factor B mRNA. These differences are tissue specific, because C2-specific mRNA content in bronchoalveolar macrophages is considerably greater than in breast milk macrophages, although the amounts of factor B mRNA are comparable. These data suggest that tissue-specific regulation of complement production in human mononuclear phagocytes occurs at a pretranslational level. These studies now provide a basis for investigation of the molecular effects of agents that modulate the biologic functions of monocytes and macrophages.

Cell Differentiation↗
PubMed2005

Complementing the patient: a complement component deficiency in a patient with recurrent infections and glomerulonephritis.

We present a case showing the investigation of a 7-year-old girl with empyema and glomerulonephritis whose "immunological" defect was a single complement component (C2) deficiency which prevented her from activating her classical complement pathway. A defect in complement function should be suspected in any patient with severe or recurring pyogenic infections. Investigations of "? immune deficiency" should always include tests to assess the patency of the patient's complement system.

Child↗
PubMed1991

[Systemic lupus erythematosus associated with homozygous C2 deficiency. Apropos of a case report and literature review].

Inherited deficiencies of classical pathway complement components are rare and associated with autoimmune diseases and with increased susceptibility to bacterial infections. We report the clinical evolution and studies of the complement system in a 17-year-old female patient of Swiss origin presenting with systemic lupus erythematosus (malar rash, photosensitivity, leukopenia and antinuclear antibodies), in whom the hemolytically active second complement component (C2) was less than 10% of the normal value and antigenic C2 was not detectable. Linkage studies showed that the patient is HLA-A25, B18 positive and has the slow factor B allotype BfS. Further immunological assessment revealed low IgG4 concentrations in the patient, who had the G2M(23) allotype. The asymptomatic first degree family members had half-normal C2 levels compatible with a heterozygous state of C2 deficiency. Therapy with hydroxychloroquine for 17 months and topical sunscreen preparations produced marked clinical improvement. During the 4 years of follow-up, the patient has been well and shown only an abnormal titer of antinuclear antibodies. No infections were observed. To the best of our knowledge, 99 cases of homozygous C2 deficiency have been described so far and are discussed here.

Adolescent↗
PubMed1993

Synthesis and regulation of complement components by human monocytes/macrophages and by acute monocytic leukemia.

Proteins of the complement system (C2, C3) are synthesized by human monocytes and macrophages, thus providing an important local source of these proteins in vivo which serve as a first-line host defense mechanism. In this study, we investigated the production of complement components C2, C4, and C9 by human monocytes/macrophages and by the pathologic cells of acute monocytic leukemia which represent a source of immature monocytic precursors. Human blood monocytes were collected and purified by cytapheresis and elutriation and leukemic cells by Ficoll gradient. Secretion of complement components was measured by a hemolytic assay. The evaluation of the mRNAs of the various complement components in the cells was performed by polymerase chain reaction (PCR) by adding 32P labeled deoxycytidinetriphosphate (dCTP) to the amplification step. Functional C2 was found to increase during in vitro maturation of macrophages up to the fourth week of culture. C2 mRNA was detected after amplification and increased during the maturation. Interferon-gamma (IFN-gamma) mediated a marked increase of the C2 mRNA. We found a decrease in synthesis of C4 mRNA during in vitro differentiation of human monocytes. The effect of IFN-gamma resulted in an increase in C4 mRNA. C9 mRNA was not detected although it was detected in the HepG2 hepatoma-derived cell line. Functional C2 was not detected by leukemic cells after 24 h of culture but little functional C4 was present in the cell supernatants. As they were by human monocytes and macrophages, C2 and C4 mRNAs were detected after amplification but C9 mRNAs were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1981

The location of C2, C4, and BF relative to HLA-B and HLA-D.

The loci for HLA-A,B,C,D, and DR are known to be closely linked to the structural loci for the complement components C2, BF, and the duplicated loci for C4, C4A and C4B. Conflicting evidence has been presented for the order of these genes. However, new techniques have made possible identification of markers in the HLA-D and C4 region for nearly all identified haplotypes. In our population we have confirmed five HLA-B-D crossovers and in each case informative allotypes of C2, BF, or C4A and C4B segregated with HLA-D or DR suggesting that the loci for these proteins lie close to HLA-D and DR. These findings may be of importance for resolving problems encountered in the assignment of HLA-D alleles.

Complement C2↗
PubMed2006

Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2.

Lectin pathway activation of C3 is known to involve target recognition by mannan-binding lectin (MBL) or ficolins and generation of classical pathway C3 convertase via cleavage of C4 and C2 by MBL-associated serine protease 2 (MASP-2). We investigated C3 activation in C2-deficient human sera and in sera with other defined defects of complement to assess other mechanisms through which MBL might recruit complement. The capacity of serum to support C3 deposition was examined by ELISA using microtiter plates coated with O antigen-specific oligosaccharides derived from Salmonella typhimurium, S. thompson, and S. enteritidis corresponding to serogroups B, C, and D (BO, CO, and DO). MBL bound to CO, but not to BO and DO, and efficiently supported C3 deposition in the absence of C2, C4, or MASP-2. The existence of an MBL-dependent C2 bypass mechanism for alternative pathway-mediated C3 activation was clearly demonstrated using CO, solid-phase mannan, and E. coli LPS. MASP-1 might contribute, but was not required for C3 deposition in the model used. Independent of MBL, specific antibodies to CO supported C3 deposition through classical and alternative pathways. MBL-dependent C2 bypass activation could be particularly important in various inherited and acquired complement deficiency states.

Complement Activation↗
PubMed1982

Gold inhibition of the production of the second complement component by lymphokine-stimulated human monocytes.

The ability of gold sodium thiomalate to inhibit production of the second complement component (C2) by monocytes stimulated by a lymphokine (monocyte complement stimulator is demonstrated. This gold salt inhibits C2 production irreversibly if monocytes are incubated with it before or during lymphokine stimulation. Thiomalic acid is not inhibitory. Monocytes already stimulated by lymphokine are resistant to inhibition of C2 production by gold sodium thiomalate. Gold salts do not reduce monocyte viability, phagocytic ability (latex heads) accessory cell function (as measured by the ability to present antigen to autologous lymphocytes), or capacity to act as stimulating cells in mixed leukocyte culture. Gold sodium thiomalate's inhibition of monocyte responsiveness to lymphokine may be significant in explaining the therapeutic benefit of gold salts in rheumatoid arthritis.

Cell Survival↗
PubMed1991

[Immunogenetic markers (BF, C2, C4, 21-OH, TNF alpha, TCR beta, Ig) and insulin-dependent diabetes in the Tunisian population: serological and molecular study].

48 Tunisian people suffering from the IDDM auto-immune disease were compared to 35 control healthy persons for the polymorphisms of the complement BF, C2 and C4 proteins and genes, of the IgG (Gm allotypes) as well as of the TNF alpha and TCR C beta genes. Our study shows that the BFF1-C4A3-C4BQO and BFS-C4AQ0-C4B1 complotypes are associated to IDDM (RR of 2.97 and 3.07 respectively), as previously reported for other circummediterranean populations. The frequency of the Gm 21.28; 1.17; .. haplotype is increased, but not significantly, among the patients. The RFLP analysis reveals that the 2.65 kb SacI allelic restriction fragment of the C2 gene may be considered as a genetic marker of susceptibility to IDDM because its frequency raises to 0.206 among the patients vs 0.021 in the healthy individuals (p less than 0.001). The frequencies of the C4AQ0 and C4BQ0 alleles are more important among the IDDM patients than within the control sample, but the only C4BQ0 allele frequency is significantly increased. Both C4AQ0 and C4BQO result mainly from deletions. The frequencies of the allelic restriction fragments of the TNF alpha and TCRC beta genes are not significantly different among the patients and the controls. But the small sample size don't allow us to conclude definitively. It would be very interesting to extend the RFLP analysis to the TCR V beta and V alpha gene regions on more numerous samples.

Adolescent↗
PubMed1993

Chronic neutropenia associated with C2 and C9 deficiency.

A Japanese male with a deficiency of the second and ninth components of complement associated with chronic idiopathic neutropenia is presented. In this case the second component of complement is totally deficient while the ninth component is approximately half that of normal control. Neutrophil granulocytes are constantly few, but this case shows no evidence of susceptibility to either viral or bacterial infections. His HLA type is different from that of Caucasians, suggesting that the genetic abnormality responsible for the complement deficiency of this Japanese case is different from that seen in Caucasian patients.

Adult↗
PubMed1988

Studies on the formation of a unique cellular intermediate (EAC14256) from EAC142 and C56.

The binding reaction of C56 to EAC142 was studied. The following was observed: (1) C56 can bind to EAC142, without participation of C3 or C7, to form EAC14256; (2) the efficiency of EAC14256 formation from EAC142 and C56 depends highly on the ionic strength of the buffer; (3) EAC14256, generated from EAC142 and C56, decays spontaneously by elution of C56 into the medium and thus the reaction between C56 and EAC142 is reversible; (4) the receptor on EAC142 for C56 is C2 or C42 on the cell surface, and (5) the binding of C56 to C2 or C42 on cells is independent of the usual (C3-dependent) complement cascade activation. These observations, together with the results of our previous report, indicate that the binding of C56, generated from the activation of C5 by C42 (without C3), to EAC142 may be the initial step of membrane attack complex formation in C3-independent immune hemolysis.

Antibodies↗
PubMed1989

Enhanced resolution of the SstI polymorphic variants of the C2 locus: description of a new size class.

Investigation of the SstI polymorphism at the 5' region of the gene encoding the serum complement component, C2, in unrelated individuals has been limited by inadequate resolution of the different size variants using conventional agarose gel electrophoresis. We have overcome this problem by the simple modification of electrophoretic conditions using both low current and temperature. With the technique described in this report it has been possible to assign the hetero- and homozygosities of the SstI polymorphism in unrelated individuals without the need for family studies. Using this approach we have investigated a population of 60 healthy, unrelated Caucasians. Five different variants of the SstI polymorphism, the 2.75-, 2.7-, 2.65-, 2.55-, and 2.4-kb fragments, were observed. The 2.7-kb SstI fragment is the most common variant, followed by the 2.65- and the less common 2.4-kb SstI fragments. These fragments occurred at frequencies of 53.3, 35.8, and 7.5%, respectively. We report here a new rare variant of the 2.75- and another rare variant of the 2.55-kb SstI fragments; both occurred at a frequency of 1.7%. The latter variant was previously described as the 2.6-kb SstI fragment but is reclassified in this report as 2.55-kb, based on the results of better resolution on electrophoresis. All the larger-size classes of the SstI polymorphic variants, the 2.75-, 2.7-, and 2.65-kb fragments, are associated with the 4.5-kb TaqI fragment, while the smaller-size classes of 2.55- and 2.4-kb fragments are associated with the 6.6-kb TaqI fragment at the 3' end of the C2 gene.

Blotting, Southern↗