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PubMed1987

Genetic markers in patients with intracranial aneurysms.

HLA antigens, blood group systems (ABO, Rh, MNSs, P, Kell, Lewis and Duffy) and serum group systems (Hp, Tf, Gc, Pi, Bf, C3 and C4) were studied in a series of patients with intracranial aneurysms. A significantly increased frequency of HLA antigen A28, a significantly decreased frequency of HLA antigen B40, and a significantly decreased frequency of complement factor C4 B2 was found among the patients when compared with controls from the same geographic area.

Complement C4↗
PubMedDate not supplied

An investigation into the relationships between serum levels of C3, C4 and CH50.

Aliquots of 213 specimens were assayed for C3, C4 and CH50. A graphical presentation of the data was obtained by a block diagram. This showed a generally flat plane with good agreement to quoted normal ranges. Only 2 of 68 specimens with C3 and C4 normal have a low CH50. If either the C3 or C4 is low then the CH50 may be normal or even high, but if both fractions are low then so is the Ch50. A low CH50 can occur with both C3 and C4 in the normal range or even higher. This implicates other complement factors as being deficient with a sufficiently high occurrence rate to require that the CH50 be kept as a routine laboratory procedure.

Animals↗
PubMed1991

Serum and CSF immunological findings in ALS.

Serum and CSF immunological findings were analysed in 37 patients with amyotrophic lateral sclerosis (ALS). ALS patients had significantly higher mean values of serum IgG and complement component C4 and significantly lower mean value of total haemolytic titre of complement (THC) compared with normal controls. Incidence of immune complexes (ICs) was significantly higher in sera of ALS patients than in normal controls. There was no significant difference regarding mean serum levels of IgM, IgA, and complement components C3 and Factor B between patients and controls. The blood-brain barrier (BBB) damage was found in 46% of patients. Intrathecal IgG synthesis was detected in six patients (16%). These results support the hypothesis of immune system involvement in ALS.

Adult↗
PubMed1988

[Efficacy of a low-residue diet in the prevention of immuno-nutritional changes caused by the preparation of the colon for surgery].

Twenty-four patients about to undergo colorectal resection for cancer were randomly divided into two groups of 12: A and B. All had an uninterrupted colonic preparation for colonoscopy and surgery involving dietary restrictions for 4-8 days (450 calories; 25 g. proteins daily). In the group B an additional intake of 1200 Kcal. and 32 g. protein daily was given by a low-residue diet. Body weight, lymphocytes, albumin, prealbumin, C3, C4 and Complement activity (CH100) were evaluated on admission and after bowel preparation. In group A statistically significant decrease were found in all the parameters. In group B significant reduction occurred only in C4. The data confirm a relationship between immuno-nutritional state and preparation for colonic surgery, and suggest that a preoperative nutritional support may avoid or limit bio-humoral changes, indicative of an immuno-nutritional impairment.

Aged↗
PubMed1987

HLA and C4 in subacute sclerosing panencephalitis.

The frequencies of HLA-A, B, C, DR and DQ antigens were studied in 63 Japanese patients with subacute sclerosing panencephalitis (SSPE). The results could not confirm the statistical association between SSPE and HLA antigens. In addition, the allele frequencies of complement components C4, C2 and BF were determined in the 20 haplotypes with 10 unrelated SSPE patients. A significant association of C4A QO with SSPE in Caucasians was not found in Japanese.

Complement C2↗
PubMed1983

Relative importance of C4 binding protein in the modulation of the classical pathway C3 convertase in patients with systemic lupus erythematosus.

Serum concentrations of C1q, C4, C4 binding protein (C4bp), C3 and C2 haemolytic activity have been measured in 110 samples from 20 patients with systemic lupus erythematosus (SLE). Significant reductions in comparison to normal levels were found in the mean serum concentrations of C4, C3 and C4bp as well as C2 haemolytic activities. For patients serum concentrations of C4 correlated with C2 haemolytic activities (r = 0.91) and C4bp (r = 0.79); the C2 haemolytic levels correlated with the concentration of C4b (r = 0.72). It is concluded that serum concentrations of the complement components C4 and C2, which are the constituents of the classical pathway C3 convertase, are regulated by C4bp in vivo. Further metabolic studies are required to determine the causes of decreased serum concentrations of C4bp in patients with SLE.

Carrier Proteins↗
PubMed1998

Male-specific transcription initiation of the C4-Slp gene in mouse liver follows activation of STAT5.

The mouse genes encoding the constitutively expressed complement component C4 and its closely related isoform C4-Slp (sex-limited protein), which is expressed only in male animals of several strains, provide a unique model to study sequence elements and trans-acting factors responsible for androgen responsiveness. Our previous studies have shown that hormonal induction of C4-Slp is mediated by a sex-specific pattern of growth hormone secretion. Promoter analyses in vitro have led to contradictory conclusions concerning the significance of C4-Slp-specific sequences in the 5' flanking region. Mutant mice carrying the H-2(aw18) haplotype, which is characterized by a large deletion in the S region covering the C4 and 21-OHase A genes, permit the direct in vivo analysis of C4-Slp transcription, unhindered by the presence of C4. Run-on analysis of transcription in liver nuclei of males and females of this strain demonstrated a 100-fold higher transcriptional activity in males, essentially determined at the transcription initiation level. The androgen dependence of transcription initiation was confirmed by run-on analysis of testosterone-treated females, where transcriptional activity started after 6 days of androgen treatment and reached male levels after 20 days. Conversely, the growth hormone-regulated activity of transcription factor STAT5 was already detected in liver nuclei after 48 hr of androgen treatment. Furthermore, we demonstrate that activated STAT5 recognizes in vitro two upstream gamma interferon-activated sequence (GAS) elements of the C4-Slp gene, centered at positions -1969 and -1831. We postulate that binding of STAT5 to these C4-Slp-specific GAS elements plays a crucial role in the chromatin remodelings that lead to transcriptional competence of the C4-Slp gene in the liver.

Animals↗
PubMed1988

The fluid-phase binding of human C4 and its genetic variants, C4A3 and C4B1, to immunoglobulins.

Covalent binding of the fourth complement protein, C4, to immune complexes is an important first step in the complement mediated processing of the complexes. Many of the initial encounters between the proteins of the complement system and antigen and antibody occur in solution, and prior to this report, studies of the interactions between them have focused on complement binding to preformed immune precipitates that most likely are not found in vivo. We have characterized the covalent binding of C4b to immunoglobulin molecules in a fluid-phase system consisting only of antibody in solution and purified C4 and C1s. We demonstrate that human C4b binds to IgG in the fluid phase, that its covalent binding is predominantly to the heavy chain of IgG, and that the covalent linkage is by either amide or acyl ester bonds. In addition, we compare the covalent binding efficiencies of two genetic variants of C4, C4A3 and C4B1, to IgG. C4A3 binds 3-4 times more IgG than C4B1 over a range of C4 concentrations, and C4A3 has a higher binding efficiency than C4B1 for IgM, IgA, IgG2a and F(ab')2 as well as for a protein antigen, BSA. Furthermore, we found that whereas C4A3 is bound to immunoglobulins in the fluid-phase predominantly by amide linkage, C4B1 is bound by either amide or acyl ester bonds. The results presented here suggest that the covalent binding efficiency of C4A3 and C4B1 to IgG is similar to that reported for their covalent binding to small molecules.

Chemical Phenomena↗
PubMed2001

Immunological and clinical follow up of hepatitis C virus associated cryoglobulinaemic vasculitis.

OBJECTIVE: To study immunological markers and compare these markers with standard measures for the clinical and immunological follow up of vasculitis activity in hepatitis C virus (HCV) associated cryoglobulinaemic vasculitis (CV). METHODS: Serial serum samples from eight patients with newly diagnosed HCV associated CV were followed during interferon alpha treatment induced remission of the CV. Vasculitis activity and disease extent were evaluated with the Birmingham vasculitis activity score (BVAS) and disease extent index (DEI). Cryoglobulinaemia, complement levels (C3c, C4, and CH50), rheumatoid factor (RF), autoantibodies such as antinuclear antibodies, soluble interleukin 2 receptor (sIL2r), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble CD30 (sCD30) were determined. RESULTS: All patients achieved either complete or partial remission of their CV during interferon alpha treatment. There was a significant reduction in vasculitis activity and disease extent (BVAS, DEI), cryoglobulinaemia, RF, sIL2r, sICAM-1, and sCD30. Complement C3c levels increased significantly during this period. Erythrocyte sedimentation rate and levels of complement C4 and CH50 did not change significantly. Both clinical measures (BVAS and DEI) correlated significantly only with C3c and sCD30. CONCLUSIONS: Although this study was of only a small group of patients, it shows that BVAS and DEI as clinical measures and C3c and sCD30 as immunological markers may be useful in the follow up of disease activity of HCV associated CV. The data indicate that activity of the humoral (cryoglobulinaemia, RF, autoantibodies) and cellular (sIL2r, sICAM-1, sCD30) immune response and endothelial damage (sICAM-1) are found in HCV associated CV.

Antibodies, Antinuclear↗
PubMed1984

Sequence heterogeneity of murine complementary DNA clones related to the C4 and C4-Slp isoforms of the fourth complement component.

Two classes of mRNA encoding the murine C4 protein were identified by sequence analysis of clones isolated from a liver complementary DNA library. The divergence found within a 357 base pair sequence available for comparison is limited to five nucleotide replacements located in the region corresponding to the carboxy-terminal end of the C4d peptide fragment. One of the nucleotide substitutions influences the presence of a site for the Hind III restriction endonuclease. That this restriction site indeed discriminates the two non-allelic genes encoding the mouse C4 and C4-Slp isoforms has been demonstrated by Southern blot analysis and nucleotide sequencing at the genomic level. Circumstantial evidence supports the identification of the gene lacking the Hind III site in the region corresponding to the carboxy-terminal end of the C4d fragment as the one encoding the C4-Slp isotype.

Animals↗
PubMed2006

Antibody-independent B cell-intrinsic and -extrinsic roles for CD21/35.

Mice lacking C3, C4 or complement receptor 1/2 (Cr) have defective germinal centers (GC). The requirement for C4 implicates complement fixation by immune complexes (IC) via the classical pathway. Yet, transgenic (Tg) mice that lack circulating antibody but still express membrane IgM (mIgM) have normal GC responses. We showed previously that cross-linking mIgM leads to the deposition of C3 on the B cell surface and that disruption of this pathway diminishes GC responses. Here, we investigate the role of Cr in this process by generating mIgM-Tg mice that lack Cr and serum Ig. These mIgM/Cr-/- mice have smaller, transient GC, with incomplete B cell receptor down-regulation and peanut agglutinin up-regulation, compared to mIgM/Crwt counterparts. BM chimera experiments showed that Cr on B cells is required for normal GC responses. These results establish that Cr ligands generated at the B cell surface are sufficient for normal GC responses and function by signaling Cr on B cells. Unexpectedly, chimera experiments also showed a critical role for Cr on follicular dendritic cells (FDC), even in the absence of IC, indicating novel functions for FDC-expressed Cr beyond the capture of C3-coated IC.

Animals↗
PubMed2006

House dust mites and allergic manifestations among some children in Dammam, Saudi Arabia.

The house dust mites is (=HDM) still one of the many causes of allergy, particularly atopic dermatitis. In the houses of children who were suffering allergic manifestations as atopic dermatitis, respiratory allergy, bronchitis, skin rash and fever. Double manifestations with fever were reported in four children. In the present study, two types of mites were recovered, Dermatophagoides farinae and Ornithonyssus bacoti. The immunoglobulins (G., M., A. & E) as well as complements (C3 & C4) were measured in the patients and cross-matched controls. The complements did not show any significant difference among patients and controls. Elevation was detected in IgG and IgM, but not in IgA. However, high significant elevation was in IgE. The results were discussed on the light of regional work.

Adolescent↗
PubMed1975

EAC4 and EAC14 production without purified Ci.

EAC4 and EAC14 of high activity were prepared by treating sensitized red cells with human or guinea pig serum in the presence of TTHA, a chelating agent whid at low pH to maximize C1 and C4 activity and to minimize C3 contamination. Cells prepared with guinea pig complement were contaminated with C2, which could be decayed away at 37 degrees C. Cells sensitized with IgG antibody were more reactive than those sensitized with whole serum or with IgM, and preparations made with TTHA-complement were more reactive than those prepared with purified C1 plus EDTA-complement. EAC14 stored at 0 degrees C for 3 weeks lost very little activity.

Animals↗
PubMed1988

HLA, C4, Bf, Gm and autoantibodies in rheumatoid arthritis.

Sera from 48 subjects with rheumatoid arthritis (RA), more than 80% of which were seropositive, were examined for the presence of antibodies to intact nuclei (ANA) by immunofluorescence, extractable nuclear antigens (ENA), double-stranded DNA by immunoassay and immunoglobulins, i.e. rheumatoid factors (RF) by haemagglutination. The genetic markers of HLA, the fourth complement component (C4) and properdin factor (Bf), which are all coded for within the major histocompatibility complex and Gm immunoglobulin allotypic markers were all analysed in relation to various parameters of these autoantibodies. The only significant association to emerge was between low ENA antibody affinities and the Bf Fs phenotype (p less than 0.02). Although weak associations between individual autoantibody parameters and the other immunogenetic markers were detected, there were no significant HLA, C4 or Gm association with either ANA subsets or RF, a finding which agrees with, and also extends previous HLA studies of predominantly seropositive RA cohorts.

Adolescent↗
PubMed1995

A novel ELISA for the assessment of classical pathway of complement activation in vivo by measurement of C4-C3 complexes.

Measurements of complement split products by enzyme-linked immunosorbent assays (ELISA) are well established for the assessment of in vivo complement activation. We have combined two monoclonal antibodies (mAb) with specificities for C3b/iC3b/C3dg (mAb I3/15) and C4/C4b/C4d (mAb M4d2), respectively, in a sandwich ELISA to quantitate C4-C3 complexes as an indicator of complement activation. Serum incubated with heat aggregated IgG (HAG) was used as a standard and the C4-C3 levels expressed as microgram equivalent HAG/ml (microgram HAG-equ/ml). Normal values of C4-C3 complexes in plasma (EDTA) of healthy probands (n = 11) were 6.3 micrograms HAG-equ/ml +/- 1.5 (mean +/- 1 standard deviation (SD), with a range from 3.6 to 9.1). In patients with systemic lupus erythematosus (SLE, n = 23) C4-C3 values were clearly elevated (48.8 micrograms HAG-equ/ml +/- 52.9, range 7.5-184.7) as compared to samples from patients with idiopathic hypertension (IDH, n = 10) (6.5 micrograms HAG-equ/ml +/- 1.7, range 4.1-9.4). For SLE patients C4-C3 levels significantly correlated with values for C3b/iC3b/C3d (r = 0.69, p < 0.001) and C3 containing immune complexes (r = 0.68, p < 0.001), but not with the C4d fragment (r = 0.26). C4-C3 levels of 96% of the studied SLE patients were increased more than 2 SD above the normal mean as compared to 74% of C4d and activated C3 values, respectively. Serum treated with zymosan as an activator of the alternative pathway of complement did not exhibit higher C4-C3 values. These results demonstrate that the quantitation of in vivo generated C4-C3 complexes by ELISA provide a novel, sensitive parameter for classical pathway of complement activation.

Antibodies, Monoclonal↗
PubMed1981

Antibody-independent binding of the first component of complement (C1) and its subcomponent C1q to the S and R forms of Salmonella minnesota.

Strong bactericidal effects of normal guinea pig and human sera against the Salmonella minnesota S form and an R form (Re) depend on Ca2+, complement component C4, and subcomponent C1q of complement component C1. Therefore, the interaction of C1 and C1q with these forms was investigated. The bacteria directly bound subcomponent C1q, as demonstrated by fixation and transfer tests and by fluorescent methods. Binding of macromolecular C1 was shown by fixation and transfer tests and by C4 consumption. C1 fixation and transfer tests provide evidence that C1 and C1q were bound more tightly to the Re form than to the S form. At physiological ionic strength, all cell-bound molecules were released from the S form, whereas at least 60% remained on the cell surface of the Re form. The Re form showed another binding behavior for C1: preincubation of bacteria with purified C1q totally prevented C1 uptake by the S form, compared to only 10% inhibition of the uptake by the Re form. Therefore, we conclude that macromolecular C1 is bound differently by the S form than by the Re form. The analysis of five other core-deficient mutants of S. minnesota (Ra, Rb, Rc, Rd1, and Rd2) revealed that the difference could be explained by a deficiency of the O-specific polysaccharide. In contrast, all the C1q bound to Ra, Rb, and Rc mutants was detectable by the transfer test. Therefore, we postulate that binding of macromolecular C1 to these mutants must be due to an additional C1 subcomponent besides C1q.

Animals↗
PubMed1987

Multiple sclerosis in north-east Scotland. An association with HLA-DQw1.

This study reports the frequencies of HLA antigens and the polymorphic variants of C4, C2, and Bf for 200 patients with multiple sclerosis (MS) living in the Grampian region of Scotland, an area of high disease prevalence. A group of 128 normal subjects from the same region were typed for comparison. Although the frequencies of HLA-B7 and DR2 in the patient group (43.3% and 49.4%, respectively) were found to be similar to those reported for other Northern European HLA studies on patients with MS, high frequencies of these antigens were also observed in the group of normal Grampian subjects (38.3% and 40.6%) the differences were not statistically significant. However, a significant association was found between the recently defined Class II HLA antigen, DQw1, and MS (P less than 0.006) when compared with controls. There were no significant differences in frequency of the polymorphisms of C4, C2, and Bf when the group of patients with MS was compared with the control group of normal subjects. The patients were subdivided according to disease severity, remittent versus progressive clinical course, age of onset of the disease and initial symptoms. The frequencies of the HLA and complement polymorphisms (C4, C2, and Bf) were analysed in these subdivisions. DQw1 was found with similar frequency in severe and benign disease (78% and 80%, respectively) but DR2 was most frequent in the group of patients with remittent disease (54%). There were no significant differences in frequency of the polymorphisms of C4, C2, and Bf between the above subgroups of patients and overall no significant HLA associations were found with age of onset of disease or initial symptoms. The findings suggest that in an area of high prevalence of MS, the disease is more closely associated with DQw1 than DR2. Furthermore, there was no evidence to support the hypothesis that the HLA region complement gene polymorphisms show significant association with a putative HLA-linked MS susceptibility gene.

Complement C4↗