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PubMed1975

Phagocytes and C4 in paraproteinaemia.

Immunological studies were performed on patients with multiple myeloma. A defect in polymorphonuclear leucocyte (PMN) function as evidenced by diminished adherence of these cells to nylon fibre columns was detected in 16, and low levels of the fourth component of complement (C4) were observed in 14, of the 26 patients studied. Twelve of the patients with low C4 exhibited the defect in PMN adhesiveness whereas only four of the 12 patients with normal C4 showed the defect. The PMN defect was not caused solely by the low C4, since PMNs from seven patients with hereditary angioedema, which is associated with low levels of C4, did not show the defect. The low C4 and defect in PMN adhesiveness occurred primarily in patients with IgG myeloma; all but one of the patients with IgA myeloma, macroglobulinaemia, or light chain disease were normal in both parameters. Results of skin window studies indicated that patients with the PMN defect also had a defect in the early PMN inflammatory response. The defect in PMN adhesiveness could be completely corrected by incubating the cells in normal plasma. Binding of the C4 to paraprotein could not be demonstrated, and C1 activation was found to be caused only by one of 10 isolated paraproteins studied. These studies indicate that patients with paraproteinaemia have immunological abnormalities in addition to low immunoglobulin levels and suggest that these abnormalities may be involved in the pathogenesis of the recurrent infections commonly associated with this disease.

Adult↗

PubMedDate not supplied

[Elevated C3-proactivator serum levels in patients with chronic polyarthritis].

The C3-Proactivator (C3-PA) and the C3 and C4 complements were determined by radio-immuno diffusion in the serum of 72 patients with definite or classical rheumatoid arthritis, 51 patients with osteoarthrosis and 42 healthy subjects. C3-PA and C4 levles were significantly higher in the serum of patients with rheumatoid arthritis than in the control group (C3-PA in 72%, C4 in 37% of the RA patients). There was also a significant difference between seropositive und seronegative cases. Elevation of both components was more frequently found in patients with seronegative rheumatoid arthritis than in the seropositive cases. However, the C3-PA serum level is not correlated with the ESR. Also an elevation of the C3-PA serum level is not specific for rheumatoid arthritis, it is also found in other inflammatory diseases as well as after surgery.

Arthritis, Rheumatoid↗

PubMed1988

The susceptibility to insulin-dependent diabetes mellitus is associated with C4 allotypes independently of the association with HLA-DQ alleles in HLA-DR3,4 heterozygotes.

In the genetically homogeneous Danish population, 27 HLA-DR3,4 heterozygous patients with insulin-dependent diabetes mellitus (IDDM) and 19 DR3,4 heterozygous controls without family history of IDDM were investigated for HLA-region markers and Gm and Km immunoglobulin allotypes. The aim was to define susceptibility factors for IDDM development other than HLA-DR using a number of techniques: lymphocytotoxicity (HLA-DR and DQ antigens), cellular methods (Dw and DP typing), restriction fragment length polymorphism (DQ alleles), electrophoresis and immunofixation (BF and C4 allotypes), and passive hemagglutination inhibition (Gm and Km immunoglobulin allotypes). The complement allotype C4A3 and the HLA-DQw8 (DQw3.2) antigen were found in all of the patients, whereas this was the case for only 8 of the 19 controls (P = 6 x 10(-6)): five lacked C4A3, five others lacked DQw8, and one of the controls lacked both of these factors. Fourteen of the patients had the complement allotype C4B3 versus three of the controls (P = 0.01). Previously reported family studies suggest that these alleles are part of the following haplotype: B15, BFS, C4A3, C4B3, DR4, Dw4, DQw8, and these factors were found together in ten of the patients versus one of the controls (P = 0.01). The markers usually associated with DR3 did not show significant differences between IDDM patients and controls, and the non-HLA markers studied showed no significant deviation from what was expected. In addition to the susceptibility factor DQw8, the study suggests the existence of susceptibility genes for IDDM near the complement C4 genes on DR4-carrying haplotypes.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement C4↗

PubMed1999

Homozygous deletion of the CYP21A-TNXA-RP2-C4B gene region conferring C4B deficiency associated with recurrent respiratory infections.

The central class III region of the human major histocompatibility complex contains highly polymorphic genes that are associated with immune disorders and may serve as susceptibility factors for viral infections. Many HLA haplotype specific rearrangements, duplications, conversions and deletions, occur frequently in the C4 gene region. Genetic deficiencies of complement components are associated with recurrent occurrence of bacterial infections. We have studied the complement profile and the class III genes 5'-RP1-C4A-CYP21A-TNXA-RP2-C4B-CYP21B-TNXB -3' in a 4-year-old Caucasian patient. He has suffered from several pneumonias caused by respiratory viruses, eight acute otitis media, prolonged respiratory infections and urinary tract infection. Complement C4 was constantly low, but the other complement components, from C1 to C9, C1INH, factor B and properdin, were within normal limits. Immunological evaluation gave normal lymphocyte numbers and functions with the exception of subnormal T cell response to pokeweed mitogen. Molecular studies of the C4 gene region in the patient revealed homozygous deletion of CYP21A-TNXA-RP2-C4B generating total deficiency of C4B and the flanking 5' region up to C4A, and in the father a missing CYP21A gene. Further investigations are needed to elucidate the relationship between C4B deficiency and susceptibility to infections.

Adult↗

PubMed1991

Detection and cellular localization of human C4 gene expression in the renal tubular epithelial cells and other extrahepatic epithelial sources.

Although the liver is the major source of most complement proteins, recent reports have characterized extrahepatic expression of the genes for some of these components in a variety of tissues. In most cases, however, the specific cell type responsible for the extrahepatic complement expression has not been determined in situ. The authors studied expression of the fourth component of complement (C4) in a variety of human tissues by Northern analysis and by in situ hybridization. The C4 gene was found to be expressed at high levels in liver and both normal and diseased kidneys. In addition, evidence of C4 gene expression was found in the small intestine and brain. By in situ hybridization, the renal C4 gene expression was exclusively localized to tubular epithelial cells. C4 expression was also identified in hepatocytes, thyroid follicular epithelial cells, and ductal epithelial cells of the submandibular salivary gland. Although it is unlikely that local expression of the C4 gene contributes to glomerulonephritis, these results indicate that some components of complement may have a physiologic role in epithelial cell function.

Antigen-Antibody Complex↗

PubMed1984

Molecular mechanism for feedback regulation of C4 biosynthesis in guinea pig peritoneal macrophage.

Previous reports have shown that regulation of local extrahepatic production of complement may not reflect the regulation of plasma concentrations of the corresponding proteins and, further, that alteration of the tissue microenvironment can affect local macrophage protein synthesis. This report describes the molecular basis for control of the biosynthesis and secretion of a class III major histocompatibility complex gene product, the fourth component of complement (C4), from guinea pig macrophages by extracellular native C4 protein. The effect is specific for C4 synthesis, since production of C2 and total secreted protein was unaffected by fluid phase C4. C4 synthesis by extracellular C4 is regulated at a pretranslational level, without an effect on posttranslational proteolytic cleavage, glycosylation, or secretion. Specific C4 and factor B cDNA probes were used to demonstrate, by dot hybridization and Northern blot analysis, a decrease in messenger RNA coding for C4 that paralleled the inhibition of C4 biosynthesis, while the amount of total RNA and mRNA specific for factor B remained constant. Inhibition of C4 biosynthesis and the disappearance of mRNA encoding C4 occurred between 4 and 6 h after exposure of the macrophages to biologically active or methylamine-inactivated C4 protein. These data demonstrate that regulation of C4 biosynthesis by guinea pig macrophages serves as a model for the study of the molecular mechanisms of macrophage activation as well as the control of production of a component of the inflammatory response.

Animals↗

PubMed2004

Detection of retroviral antisense transcripts and promoter activity of the HERV-K(C4) insertion in the MHC class III region.

An insertion of 6.4 kb is present in intron 9 of 60% of the human complement C4 genes, as well as in the C4 genes of a number of Old World primates. This insertion has the typical genomic organization of endogenous retroviruses, with the three major genes gag, pol and env flanked by long terminal repeats (LTRs). This human endogenous retrovirus K [HERV-K(C4)] insertion is in reverse orientation to the C4 coding sequence. Using RT-PCR as well as RNase protection assays, retroviral transcripts could be detected in different human cell lines which were only present in the antisense orientation of the retrovirus. Furthermore, C4 expression as well as intermediate transcripts comprising both HERV-K(C4) and C4 coding sequences was observed in these cells. These findings were confirmed using real-time PCR to quantitate the number of specific mRNA transcripts. Using reporter gene assays, it could be demonstrated that only the 3'LTR exhibits promoter activity, but in the sense orientation of the retrovirus. It has been suggested earlier that expression of C4 could lead to the transcription of a retroviral antisense RNA, which might protect against exogenous retroviral infections. In a previous study, it was shown that the expression of retroviral-like constructs was significantly downregulated in mouse cells transfected with human C4 genes, and that this downregulation was further modulated after IFN-gamma stimulation of C4 expression. In a new series of experiments, we have now confirmed these observations, using human hepatoma cells constitutively expressing C4. A dose-dependent downregulation of up to 45% caused by hybridization of retroviral sense and genomic HERV-K(C4) antisense RNA was observed. The functional 3'LTR promoter, the presence of retroviral antisense RNA transcripts and the functional detection of HERV-K(C4)-specific antisense activity provide strong evidence for a major role of the HERV-K(C4) insertion in the control of gene expression, resulting in a selective advantage favouring the presence of this element in human and primate C4 genes.

Complement C4↗

PubMed1994

Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls.

Recently, several authors have reported that immunoglobulin IgM, complement C3c, complement C4, and positive acute phase proteins (e.g., haptoglobin, alpha 1-acid glycoprotein and alpha 1-antitrypsin) were significantly increased, while negative acute phase proteins (e.g., albumin and transferrin), were decreased in depressed patients. In the present study, the levels of the immunoglobulin IgM, complement C3c, C4, alpha 1-antitrypsin and haptoglobin were found to be significantly increased in 20 unipolar depressed patients compared to healthy controls. The concentrations of total protein and albumin were significantly reduced in these patients. The concentrations of alpha 1-protein, (which is related to alpha 1-antitrypsin), and alpha 2-protein (which related to haptoglobin), were also significantly elevated in unipolar depressed patients. The results suggest that unipolar depression is associated with an acute phase response, which is possibly caused by changes in cytokines and corticosteroid secretion in depressed patients.

Acute-Phase Proteins↗

PubMed1996

Effect of HLA type and hypocomplementaemia on the expression of parvovirus arthritis: one year follow up of an outbreak.

OBJECTIVES: To determine the effect of HLA type and hypocomplementaemia on the duration and severity of joint involvement in parvovirus infection (HPV). METHODS: Forty seven patients were selected on a geographical basis from 83 with proven HPV infection during an outbreak that occurred in Oxfordshire in 1993. They were contacted by questionnaire a year later. Thirty five patients were available for examination and blood sampling. Subjects were typed for HLA-DRB1 alleles and HLA-B27 status. Immunological profiles, including C3 and C4 complement components, were determined. RESULTS: Joint symptoms occurred in all patients. They resolved within a week in 12 patients and persisted beyond one year in 19. On review, none had a picture of rheumatoid arthritis, but three patients had developed carpal tunnel syndrome. Decreased C4 was found in four. The HLA frequencies were similar to those in controls; however, joint symptoms persisted for more than one week in all HLA-DR4 positive patients (p = 0.009). There was no relation between the severity of joint symptoms and either HLA type, or hypocomplementaemia. CONCLUSIONS: Joint symptoms are common in parvovirus infection and the presence of HLA-DR4 may be associated with persistence of joint symptoms beyond one week. This study revealed no evidence of progression to rheumatoid arthritis.

Adult↗

PubMed1980

A hypocomplementemic vasculitic urticarial syndrome. Report of four new cases and definition of the disease.

We describe four new patients with a unique syndrome of persistent urticaria, with leukoclastic angiitis, severe angioedema, occasional life-threatening laryngeal edema, arthritis, arthralgia, neurologic abnormalities and pronounced persistent hypocomplementemia. The complement abnormalities involved markedly reduced levels of the Clq subunit of the first component of complement (Cl) in the presence of near normal levels of Clr and Cls subunits of Cl; modest to marked depletion of the fourth component of complement (C4), the second component of complement (C2) and the third component of complement (C3); and normal levels of the fifth through ninth components of complement (C5 through C9) and properdin factors B and D. A striking serologic abnormality found in all patients was the presence of low molecular weight (7S) proteins which precipitated with Clq in agarose gels; these previously were shown to be comprised at least in part of immunoglobulin G. The present experience is offered to help to define the clinical, histopathologic and serologic characteristics of this entity, designated hypocomplementemic vasculitic urticarial syndrome, and to emphasize its distinctiveness and prevalence.

Adult↗

PubMed1982

Immune complexes in primary biliary cirrhosis. Higher prevalence of circulating immune complexes in patients with associated autoimmune features.

A longitudinal study, examining the levels of immune complexes serially for three years, in serum from 88 patients with primary biliary cirrhosis was performed by the Raji cell radioimmunoassay. Studies of the association of autoimmune features in primary biliary cirrhosis and the effect of D-penicillamine therapy in relation to the levels of complexes were carried out. Twenty-two patients (25 percent) were found to have autoimmune features, such as Sjögren's syndrome, rheumatoid-like arthritis, scleroderma, Raynaud's disease, and Hashimoto's thyroiditis. In this subset of patients with primary biliary cirrhosis, a significantly higher prevalence (86 percent) of circulating immune complexes was detected compared with those patients showing no autoimmune features (60 percent). In addition, patients with associated autoimmune features had higher mean levels of immune complexes (259.7 micrograms AHG eq/ml) compared with those without autoimmune features (202.1 micrograms AHG eq/ml). The mean levels of complement C4, reflecting activation of classic complement pathway, were significantly lower in patients with elevated immune complexes and associated autoimmune features. The mean level of immune complexes in 13 patients receiving D-penicillamine, in contrast to the placebo group, decreased at one year but subsequently was greater than the initial level. Patients who had normal levels of immune complexes and received penicillamine therapy continued to have complex levels within the normal range for up to three years of follow-up study, but patients receiving placebo showed significantly elevated levels at subsequent intervals. Thus, levels of immune complexes in primary biliary cirrhosis may reflect the association with autoimmune features.

Antigen-Antibody Complex↗

PubMed2003

Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB.

Alpha-N-acetylglucosaminidase deficiency (mucopolysaccharidosis IIIB, MPS IIIB) and alpha-l-iduronidase deficiency (MPS I) are heritable lysosomal storage diseases; neurodegeneration is prominent in MPS IIIB and in severe cases of MPS I. We have obtained morphologic and molecular evidence for the involvement of microglia in brain pathology of mouse models of the two diseases. In the cortex, a subset of microglia (sometimes perineuronal) consists of cells that are probably phagocytic; they have large storage vacuoles, react with MOMA-2 (monoclonal antibody against macrophages) and Griffonia simplicifolia isolectin IB(4), and stain intensely for the lysosomal proteins Lamp-1, Lamp-2, and cathepsin D as well as for G(M3) ganglioside. MOMA-2-positive cells appear at 1 and 6 months in MPS IIIB and MPS I mice, respectively, but though their number increases with age, they remain sparse. However, a profusion of cells carrying the macrophage CD68/macrosialin antigen appear in the cortex of both mouse models at 1 month. mRNA encoding CD68/macrosialin also increases at that time, as shown by microarray and Northern blot analyses. Ten other transcripts elevated in both mouse models are associated with macrophage functions, including complement C4, the three subunits of complement C1q, lysozyme M, cathepsins S and Z, cytochrome b558 small subunit, macrophage-specific protein 1, and DAP12. An increase in IFN-gamma and IFN-gamma receptor was observed by immunohistochemistry. These functional increases may represent activation of resident microglia, an influx and activation of blood monocytes, or both. They show an inflammatory component of brain disease in the two MPS, as is known for many neurodegenerative disorders.

Animals↗

PubMedDate not supplied

[Plasma concentrations of complement components C3, C4, and C3PA in juvenile nephropathies].

Complement profiles in children suffering for nephropathy have been investigated. The approach has proved useful in differentiating distinct nosologic entities. Plasma C3 and, to a lesser extent, C4 levels were found to be markedly reduced in glomerulonephritis and significantly increased in nephrotic syndrome. Although in both conditions plasma C3PA concentration ranges normally, additional data are request before assuming that alternate pathway is not involved. The extensive serial study of complement profiles should be widely adopted by clinicians managing nephropatic patients.

Acute Disease↗

PubMed1997

Allelic polymorphism of two multifunctional regions in the central human MHC: tenascin X, XB-S and YB, and their duplicated fragments XA and YA.

Two highly polymorphic sequences have been discovered in the complement C4 region of the human major histocompatibility complex (MHC). They are part of a duplicated unit of overlapping genes, transcribed in opposite directions and containing the sequences of tenascin X (XB), XB-S, XA, YB and YA. Fragments of 1014 bp and 894 bp were co-amplified by polymerase chain reaction (PCR) and digested with two different restriction enzymes. This preliminary study provides evidence for more than five different alleles each of XA (YA) and XB (XB-S, YB), and at least 11 XA-XB haplotypes. Their association with extended HLA-B-DR haplotypes, C4 complotypes, and C4 region restriction fragment length polymorphisms (RFLP) is discussed. X gene polymorphisms are a complement region marker system that should be uniquely suited for PCR-based typing methods. They could become a useful addition to HLA class I and class II markers in the mapping of candidate genes for MHC-associated diseases, including the X and Y genes themselves.

Alleles↗

PubMed2001

TINU syndrome associated with reduced complement levels.

The TINU syndrome (tubulointerstitial nephritis and uveitis) was first described by Dobrin et al. in 1975. Since then, more than 50 cases have been documented each with diverse immunopathogenetic and genetic characteristics. The aim of this report is to describe a case of TINU associated with reduced complement levels. We profile a 48-year-old white female with persistently reduced C4 complement levels during the acute phase of the pathology and with an unaltered immunologic profile. Renal biopsy evidenced a significant lymphocytic interstitial infiltration. Immunohistochemical studies of the interstitium infiltrates was positive for the presence of the T (CD3) markers (CD4 > CD8). Steroid therapy yielded a complete regression of the symptomatology with normalization of the complement levels. We suggest that it is possible to hypothesize that the various immunologic alterations associated with TINU, including the transient reduction complement levels, may be secondary to multiple inflammatory mechanisms which express themselves throughout the pathology.

Acute-Phase Reaction↗

PubMed1982

Modulation of lymphocyte proliferative responses to mitogens and antigens by complement components C1, C4 and C2.

Recent data have shown a definite relationship between complement and lymphocytes. Genetic studies have demonstrated close linkage between the genes controlling synthesis of complement components C4 and C2 and the major histocompatibility complex. Working in a complement-free environment, we studied the effect of purified human complement components, individually and in various combinations, upon in vitro proliferative responses of human lymphocytes to mitogens and antigens. It was found that the early complement components C1, C4 and C2, together, modulate lymphocyte responses to these various stimuli. In general, doses up to 1,000 effective molecules of each component per lymphocyte enhanced the cells' responses to both mitogens and antigens. Higher doses, up to 3,000 effective molecules of each per lymphocyte, progressively inhibited the cells' responses to the mitogens whereas responses to the antigens showed continued enhancement. This effect was removed by prior heat-inactivation of the complement. It persisted when the cells were exposed to C1, C4 and C2 for 1 hr, then washed and cultured with mitogen. It required active C1 in the fluid-phase prior to addition of C4 and C2. It correlated with the amount of activated C2 to which the cells were exposed. Enriched populations of T and B cells were affected equally.

Antigens↗

PubMed1983

Post-translational modification of the fourth component of complement. Sulfation of the alpha-chain.

The fourth component of complement (C4) was found to incorporate radiolabel from [35S]O4 during synthesis in murine peritoneal macrophages and the human hepatoma-derived cell line, HepG2. The sulfate label was localized to the COOH-terminal autolytic fragment of the C4 alpha-chain. No label was seen associated with intracellular pro-C4. The structurally similar third and fifth components of complement, and alpha 2-macroglobulin, did not incorporate labeled sulfate. Tryptic peptides from [35S]O4-labeled C4 alpha-chain were analyzed by reversed phase liquid chromatography and found to elute in a single, homogeneous peak, suggesting a unique sulfation site in the C4 alpha-chain. Thin layer chromatography of a base hydrolysate of [35S]O4-labeled C4 alpha-chains, or C4 isolated from human plasma, revealed the presence of tyrosine-O-sulfate. The possible significance of this unusual amino acid modification for the function of C4 is unknown.

Animals↗

PubMed1996

Fourth component of Xenopus laevis complement: cDNA cloning and linkage analysis of the frog MHC.

Complement C4 shows extensive structural and functional similarity to complement C3, hence these components are believed to have originated by gene duplication from a common ancestor. Although to date C3 cDNA clones have been isolated from all major classes of extant vertebrates including Xenopus, C4 cDNA clones have been isolated from mammalian species only. We describe here the molecular cloning and structural analysis of Xenopus C4 cDNA. The cDNA sequence encoding the thioester region of Xenopus C4 was amplified by reverse transcriptase-polymerase chain reaction using Xenopus liver mRNA as a template, and then used to screen a liver cDNA library. The amino acid sequence of Xenopus C4 deduced from a clone containing the entire protein-coding sequence showed 39%, 30%, 25%, and 20% overall identity with those of human C4, C3, C5, and alpha2-macroglobulin, respectively. The predicted amino acid sequence consisted of a 22-residue putative signal peptide, a 634-residue beta chain, a 732-residue alpha chain, and a 287-residue gamma chain. Of 30 cysteine residues, 27 were found in exactly the same positions as in human C4. Genomic Southern blotting analysis indicated that C4 is a single copy gene in Xenopus and is part of the frog MHC cluster. These results clearly demonstrate that C3/C4 gene duplication and linkage between the C4 gene and the major histocompatibility complex predate mammalian/amphibian divergence.

Amino Acid Sequence↗