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PubMed1986

Diabetes and autonomic neuropathy: an immunological association?

Lymphocytic infiltration of autonomic ganglia found at autopsy and a strong clinical association with iritis suggests that diabetic autonomic neuropathy might have an immunological basis. We measured levels of circulating immune complexes, complement (C3, C4), complement breakdown products (C3d), and insulin antibodies in diabetics with autonomic neuropathy and a history of iritis (n = 17), compared to diabetics of similar age and duration with autonomic neuropathy but no history of iritis (n = 20), and with uncomplicated insulin-dependent diabetics (n = 23), together with normal controls (n = 26). We found higher levels of circulating immune complexes in patients with autonomic neuropathy (irrespective of iritis) compared to normal controls, and differences in C3d levels suggesting complement activation. C4 levels were unexpectedly normal in the diabetics with autonomic neuropathy, in contrast to the uncomplicated insulin-dependent diabetic controls. Insulin antibody levels showed no difference between the three groups of diabetics. These findings suggest that immunological mechanisms may be implicated in the aetiology of diabetic autonomic neuropathy and that further studies are indicated.

Adult↗
PubMed1998

Rapid activation of the complement system by cuprophane depends on complement component C4.

Hemodialysis with cuprophane dialyzer membranes promotes rapid activation of the complement system, which is thought to be mediated by the alternative pathway. Complete hereditary deficiency of complement C4, a classical pathway component, in two hemodialysis patients provided the opportunity to investigate a possible role of the classical pathway. In two hemodialysis patients with both C4 isotypes, C4A and C4B, and in one patient with C4B deficiency complement activation occurred immediately after the onset of hemodialysis, with peak levels of C3a and terminal complement complex (TCC) after ten to fifteen minutes. In patients with complete C4 deficiency, C3a and TCC remained unchanged for fifteen minutes and increased thereafter, reaching the highest level after thirty minutes. The leukocyte nadir was also delayed from fifteen to thirty minutes. In vitro incubation of normal, C4A- or C4B-deficient serum with cuprophane caused complement activation after fifteen minutes. In contrast, no activation was observed in sera of four C4-deficient patients. The addition of normal serum or purified human C4 restored the capacity for rapid complement activation. In one patient with severe immunoglobulin deficiency, C3a and TCC levels increased only moderately after 25 minutes of cuprophane dialysis. This patient's serum also exhibited delayed complement activation in vitro, which was normalized after pretreatment of cuprophane with immunoglobulins. Preincubation of normal serum with MgEGTA, a blocker of the classical pathway, inhibited rapid complement activation through cuprophane. As basal levels of C4a are markedly increased in hemodialysis patients (3450 +/- 850 ng/ml) compared to healthy controls (224 +/- 81 ng/ml), no further elevation of C4a was detectable during cuprophane hemodialysis. Incubation of normal serum with cuprophane, however, caused a slight increase in C4a after five minutes. These results indicate that the initial deposition of complement C3b on the cuprophane membrane, necessary for activation of the amplification loop of the alternative pathway, is mediated by the classical pathway C3-convertase C4b2a. We propose an extended concept of complement activation through cuprophane, which is based on four steps: (a) binding of anti-polysaccharide antibodies, (b) classical pathway activation, (c) alternative pathway activation and (d) terminal pathway activation.

Adolescent↗
PubMed1988

Differential effect of inflammatory stimuli on murine plasma C4 and factor B concentrations.

The in vivo effects of a variety of inflammatory stimuli on complement C4 and factor B plasma levels have been examined. MRL/++ (H-2k) mice were given intraperitoneal injections of lipopolysaccharide, turpentine, Corynebacterium parvum pyridine extract residue or high doses of indomethacin. All of these treatments induced an increase in plasma factor B concentrations, which in the case of C. parvum was dose dependent and persisted for at least 7 days. Lipopolysaccharide, turpentine and indomethacin produced decreases in plasma complement C4. C. parvum, however, produced an increase in plasma complement C4 to approximately 240% of controls which was independent of gender. It was also independent of major histocompatibility complex haplotype, since the same effect was seen in C57B1/6J-bg/bg and C57B1/6J-bg/+ mice. The gross increment in complement C4 was, however, related to the major histocompatibility complex. H-2K mice ("low complement C4") had smaller increments than H-2b ("high complement C4"). Mycobacterium bovis (BCG) also produced a transient increase in C4 in the H-2b mice as well as a prolonged increase in factor B levels. These data (i) suggest that different inflammatory stimuli induce different mediators which may have differential effects on factor B and complement C4 synthesis, and (ii) emphasize the independent regulation of complement C4 and factor B. Qualitative variations in the mediators elaborated during chronic inflammatory diseases may help determine complement C4 fluctuations in systemic lupus erythematosus and the wide range of complement C4 concentrations seen in MRL/1 pr mice with active immune complex disease.

Animals↗
PubMed1988

Low serum haemolytic function of the fourth complement component (C4) in insulin dependent diabetes.

Low serum concentrations of the fourth component of complement (C4) are found in insulin dependent diabetes, and may be important in the aetiology of the disease. To ascertain whether function of C4 is also impaired both its haemolytic activity and its concentration were measured in 34 insulin dependent diabetics, 15 non-insulin dependent diabetics, 20 healthy subjects, and 12 pairs of monozygotic twins discordant for insulin dependent diabetes. C4 function was measured by a radial immune haemolytic assay, and C4 concentration by laser nephelometry. Both measurements were significantly lower in insulin dependent diabetics (C4 function: median 47%, range 4-100%; C4 concentration: 0.22 g/l, 0.10-0.38 g/l) than in non-insulin dependent diabetics (67%, 33-138%, p less than 0.01; 0.27 g/l, 0.16-0.50 g/l, p less than 0.02) and controls (74%, 33-138%, p less than 0.01; 0.27 g/l, 0.18-0.40 g/l, p less than 0.03). C4 function and concentration were lower in both diabetic (48%, 12-100%; 0.17 g/l, 0.08-0.31 g/l) and non-diabetic twins (47%, 12-100%; 0.17 g/l, 0.07-0.36 g/l) than controls (p less than 0.01; p less than 0.01). Thirteen (38%) of the insulin dependent diabetics had a reduction in either C4 function or concentration, but in only five were both features reduced. Values of function and concentration were strongly correlated in both diabetic and non-diabetic twins (r = 0.95, p less than 0.001; r = 0.92, p less than 0.001). These results show defects in C4 function and concentration in insulin dependent diabetes, which--being present in the non-diabetic co-twin of diabetics--may represent a genetic predisposition to the disease.

Adult↗
PubMed2004

Antigen localization within the splenic marginal zone restores humoral immune response and IgG class switch in complement C4-deficient mice.

Defects of early complement components (C1, C4 and C2) are associated with the development of systemic lupus erythematosus (SLE). The availability of complement knockout mice has increased our knowledge on the role of complement in the regulation of adaptive immunity. An impaired removal of apoptotic bodies, a disturbed clearance of IgG immune complexes (ICs) and an insufficient B-cell regulation via complement receptors CD21/CD35 have been discussed as explanations for the induction of autoimmunity; however, a unifying hypothesis for the loss of B-cell tolerance in the absence of C1 or C4 is still lacking. Using IgM-containing ICs, we observed a significant accumulation of antigen within the splenic marginal zone (MZ) of C4-deficient mice but not in C3-deficient or complement receptors CD21/CD35-deficient mice. The targeting of antigen toward the MZ restored adaptive immunity (antibody response and class switch) in C4-deficient animals. A new explanation for the association of SLE and complement C4 deficiency would be that in the absence of C4, natural antibodies (IgM type) localize more self-antigen toward the MZ so that the auto-antibody response is increased and autoimmune disease ensues. As such, an inadequate localization of self-antigens might be responsible for the annulment of peripheral B-cell tolerance in the absence of C4.

Animals↗
PubMed1987

A high frequency of inherited deficiency of complement component C4 in Darwin Aborigines.

A high frequency of serum complement component C4A deficiency may explain the higher prevalence and greater severity of systemic lupus erythematosus reported in Australian Aborigines. Inherited deficiencies of serum complement components C4A, C4B, and C2 were examined in two Australian Aboriginal populations from Darwin and Alice Springs and compared with the prevalence of complement deficiencies in white Australian blood donors. The frequency of C4A deficiency alleles was 29% in Darwin Aborigines compared with 12% in Alice Springs and 17% in Canberra blood donors. Partial C4B deficiency was also higher in Darwin Aborigines than in the other populations. Inherited deficiency of serum complement component C2 was not observed.

Alleles↗
PubMed2006

Immunoglobulins and complement factor C4 in adult rhinosinusitis.

We assessed whether complement and its factor C4 or abnormal immunoglobulin levels are associated with chronic or recurrent rhinosinusitis. We used multiple patient and control groups to obtain clinically meaningful data. Adult chronic or recurrent rhinosinusitis and acute purulent rhinosinusitis patients were compared with unselected adults and controls without previous rhinosinusitis. Associated clinical factors were reviewed. Levels of immunoglobulins, plasma C3, C4 and classical pathway haemolytic activity were analysed. C4 immunophenotyping was used to detect C4A and C4B deficiencies as null alleles. Complement was up-regulated in rhinosinusitis. C4A nulls and low IgA, IgG, IgG1, IgG2, IgG3 and IgG4 levels were all more common in chronic or recurrent rhinosinusitis patients than in unselected and healthy controls. We searched for relevant differences between the patient groups. According to stepwise logistic regression analysis, nasal polyposis [odds ratio (OR) 10.64, 95% confidence interval (CI) 2.5-45.7, P = 0.001], bronchial asthma (OR 8.87, 95% CI 2.3-34.9, P = 0.002), C4A null alleles (OR 5.84, 95% CI 1.4-24.9, P = 0.017) and low levels of IgG4 together with either IgG1 or IgG2 (OR 15.25, 95% CI 1.4-166.8, P = 0.026) were more common in chronic or recurrent rhinosinusitis than in acute rhinosinusitis patients. Isolated low IgG subclasses had limited value in patient assessment. C4A null alleles are associated with chronic or recurrent rhinosinusitis, potentially through their effect on immune defence and inflammation control. Multiple clinical and immunological parameters may need to be evaluated when searching for prognostic variables.

Adult↗
PubMed2004

The intricate role of complement component C4 in human systemic lupus erythematosus.

It was observed about 50 years ago that low serum complement activity or low protein concentrations of complement C4 concurred with disease activities of systemic lupus erythematosus (SLE). Complete deficiencies of complement components C4A and C4B, albeit rare in human populations, are among the strongest genetic risk factors for SLE or lupus-like disease, across HLA haplotypes and racial backgrounds. However, whether heterozygous or partial deficiency of C4A (C4AQ0) or C4B (C4BQ0) is a predisposing factor for SLE has been a highly controversial topic. In this review we critically analyzed past epidemiologic studies on deficiency of C4A or C4B in human SLE. Cumulative results from more than 35 different studies revealed that heterozygous and homozygous deficiencies of C4A were present in 40-60% of SLE patients from almost all ethnic groups or races investigated, which included northern and central Europeans, Anglo-Saxons, Caucasians in the US, African Americans, Asian Chinese, Koreans and Japanese. In addition, French SLE and control populations had relatively low frequencies of C4AQ0, but the difference between the patient and control groups was statistically significant. The relative risk of C4AQ0 in SLE varied between 2.3 and 5.3 among different ethnic groups. In Caucasian and African SLE patients, the two major causes for C4AQ0 are (1) the presence of a mono-S RCCX (RP-C4-CYP21-TNX) module with a single, short C4B gene in the major histocompatibility complex; and (2) a 2-bp insertion into the sequence for codon 1213 at exon 29 of the mutant C4A gene. Both mono-S structures and 2-bp insertion in exon 29 are absent or extremely rare in the C4AQ0 of Oriental SLE patients. The highly significant association of C4AQ0 with SLE across multiple HLA haplotypes and ethnic groups, and the presence of different mechanisms leading to a C4A protein deficiency among SLE patients suggested that deficiency or low expression level of C4A protein is a primary risk factor for SLE disease susceptibility per se. On the other hand, Spanish, Mexican, Australian Aborigine SLE patients had increased frequencies of C4B deficiency instead of C4A deficiency. Such observations underscore the importance of both C4A and C4B proteins in the fine control of autoimmunity. Different racial and genetic backgrounds could change the thresholds for the requirement of C4A or C4B protein levels in immune tolerance and immune regulation. Most past epidemiological studies of C4 in human SLE did not consider the polygenic and gene size variations of C4A and C4B. In addition, many studies were overly dependent on phenotypic observations or methods that did not distinguish differential C4A and C4B protein expression caused by unequal gene number or different gene size from the absence of a functional C4A or C4B gene. For further longitudinal studies on clinical manifestations of SLE, it would be informative to stratify the patients with accurately defined C4A and C4B genotypes. Likewise, elucidation of epistatic genetic factors interacting with C4AQ0 would provide important insights into the intricate roles of C4 in SLE disease susceptibility and pathogenesis.

Alleles↗
PubMed1999

The complement component C4 in sudden infant death.

UNLABELLED: The aim of the present study was to compare partial deletions of the complement C4 gene in victims of totally unexplained sudden infant death (SID) (n = 89) and borderline SID (n = 15) with and without slight infections prior to death, in cases of infectious death (n = 19), and in living infants with and without infections (n = 84). The SID and borderline SID groups were pooled. In this total SID group slight infections prior to death was associated with deletion of either the C4A or the C4B gene (P = 0.033), and the SID victims with such infections had a higher deletion frequency than the controls (P = 0.039). There were no differences between the living infants with and without upper airway infections. CONCLUSION: The present study confirms that partial deletions of the C4 gene in combination with slight upper airway infections may be a risk factor in sudden infant death.

Child, Preschool↗
PubMed2003

Elevated serum values of procollagen III peptide (PIIIP) in patients with ulcerative colitis who will develop pseudopolyps.

AIM: To assess the impact of procollagen III peptide as a marker of collagenesis in the development of pseudopolyps in patients with ulcerative colitis. METHODS: Development of pseudopolyps was monitored in 25 patients with ulcerative colitis classified according to Powell-Tuck index as mild (n=12) or moderate (n=13) form of disease. Patients with a mild form of disease were treated with oral mesalazine medication (2-4 g/day) and local mesalazine preparation (suppository). Patients with a moderate form of disease received oral mesalazine medication (2-4 g/day), local mesalazine preparation (suppository) and local methylprednisolone at an initial dose of 60 mg/day, followed by dose tapering. How many significant variables (previously determined by analysis of variance) were elevated in the groups with and without pseudopolyp developement was observed. ROC analysis for calculation of new index was made. RESULTS: Serum values of procollagen III peptide (PIIIP), C-reactive protein (CRP) and C4 complement component (C4) were statistically significantly lower in the group of patients free from pseudopolyp development than those who developed one or more pseudopolyps (0.45+/-0.12 vs 1.42+/-0.70, P<0.0027; 7.6+/-4.7 vs 17.8+/-9.17, P<0.035; and 0.46+/-0.11 vs 0.34+/-0.16, P<0.068, respectively) at endoscopic conrtrols with patohistologically samples during 13 months. There were no statistically significant differences in the values of C3, ceruloplasmin and IgM between the two groups (P>0.05). Discrimination function analysis yielded highest standardized cannon coefficients for PIIIP (0.876), CRP (0.104), C3 (-0.534) and C4 (0.184) (P<0.036). The elevation in two of three laboratory variables (PIIIP, CRP and C4) reached sensitivity of 93 % and specificity of 90 % in the development of pseudopolyps. CONCLUSION: It is proposed that an increase in two of the three laboratory parameters (PIIIP, CRP and C4) could improve the accuracy of prediction of the development of pseudopolyps. When using PIIIP, CRP and C4 on decision making, the positive predictive value and accuracy were 90 % and 92 %, respectively.

Adult↗
PubMed1987

Neutrophil lysosomal enzyme release and complement activation during cardiopulmonary bypass.

Complement activation and neutrophil degranulation were concomitantly studied during uncomplicated cardiopulmonary bypass (CPB). Plasma concentrations of complement factor C4, complement split product C3d, the neutrophil lysosomal enzyme elastase complexed with alpha 1-proteinase inhibitor (PI) and fibronectin were measured in 12 patients, C3d and elastase/PI increased significantly during CPB (volume-corrected results). The C3d rise was almost linear, whereas elastase/PI showed exponential increase. Mean elastase/PI and mean C3d concentrations at different times during CPB covaried closely. The study showed that during CPB neutrophil lysosomal enzyme release is intimately related to complement activation, although activation of the two systems may be caused by a common third activator within the extracorporeal circuit.

Adult↗
PubMed1982

[Immunological parameters in subjects with essential arterial hypertension. II. Serological observations].

M, G, and A immunoglobulins as well as C3 and C4 complement fractions were determined in 20 patients with essential hypertension: all the values were in the normal range. Nearly half of the patients had an abnormally high value of circulating immune complexes as determined with Clq binding assay and/or with CIC test. The rise of circulating immune complexes is not related to the stage of arterial hypertension.

Adult↗
PubMed2001

Some patients with antiphospholipid syndrome express hitherto undescribed antibodies to cardiolipin-binding proteins.

Contrary to infective anticardiolipin (aCL) antibodies, autoimmune aCL antibodies react with phospholipids (PL) mainly via binding to the plasma glycoprotein cofactor beta2-Glycoprotein I (beta2GPI). While there is a well-documented link between the risk of thrombosis and the presence of beta2GPI-dependent anticardiolipin antibodies, the pathological impact of other antiphospholipid antibodies is less clear. By means of cardiolipin affinity-chromatography, we isolated and identified 3 CL-binding proteins, complement component C4, complement factor H and a kallikrein-sensitive glycoprotein, and tested for the presence of autoantibodies against these proteins in patients with antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and other autoimmune diseases. High titers of autoantibodies to C4 as compared to age- and sex-matched healthy controls were present in 3 of 26 patients with APS, and weak titers were found in 2 of 26 patients with SLE and in none of 26 patients with other autoimmune diseases. Autoantibodies to complement factor H were found in 4 APS, 3 SLE and none of the other autoimmune patients. Autoantibodies to kallikrein-sensitive glycoprotein were detected in 6 APS patients, 1 SLE patient, and 1 patient with another autoimmune disease. A close relationship between these antibodies was found, suggesting their origin from a common macromolecular complex. However, no relationship with anti-beta2GPI antibodies was found, with the three patients with higher levels of autoantibodies having a low titer of anti-beta2GPI antibodies. In conclusion, some patients with APS harbor circulating antibodies to other CL-binding proteins which might be useful to further characterize these patients.

Adolescent↗
PubMed1998

Regulation of transcription of the TATA-less human complement component C4 gene.

The 5'-sequences flanking the human complement component C4 genes (C4A and C4B) have been analyzed for their ability to direct expression of a reporter gene in cell lines that constitutively express or do not express C4. No difference in the level of reporter gene expression was detected in cells transfected with C4A- or C4B-specific constructs. A series of reporter constructs containing progressively truncated C4 promoter fragments transfected into the hepatocyte Hep G2 cell line, identified the sequence contained within the region -178 to -39 as that associated with maximal reporter gene expression. This region contains consensus binding motifs for nuclear factor 1 (-110 to -97), Sp1 (-57 to -49), and three basic helix-loop-helix (-137 to -132, -98 to -93, and -78 to -73)-like transcription factors. Electromobility shift assays and DNase I footprinting analysis showed specific DNA-protein interactions of the C4 promoter at the nuclear factor 1, two E box (-98 to -93 and -78 to -73), and Sp1 binding domains. Site-directed mutagenesis of the Sp1 binding site resulted in total abrogation of reporter gene expression and mutation of the E box (-78 to -73) resulted in a 8-fold reduction in expression. We conclude that the Sp1 binding site at position -57 to -49 is critical for accurately initiated, basal transcription of C4.

Base Sequence↗
PubMed1983

cDNA clone spanning the alpha-gamma subunit junction in the precursor of the murine fourth complement component (C4).

cDNA clones carrying parts of murine fourth complement component (C4, serum substance protein) mRNA sequences have been identified by differential hybridization to mRNA from a high C4-producing strain, B10.WR, and a congeneic low C4 strain, B10.BR, followed by hybrid-selected translation and DNA sequence analysis. One clone, pMLC4/w7-2, encodes an open amino acid reading frame that includes four tandem arginine residues immediately preceding a sequence 85% homologous with the NH2-terminal sequence of the human C4 gamma-chain. The amino acid composition of the predicted sequence upstream of the tandem arginines matches quite closely with the composition of a similar sized peptide at the COOH terminus of the human C4 alpha chain. The latter result raises questions regarding the nature and extent of plasma-mediated postsynthetic processing of the C4 alpha-chain COOH terminus. The results also demonstrate that strain differences in plasma C4 levels (low C4 vs. high C4) reflect differences in steady-state levels of liver C4 mRNA in these strains.

Amino Acid Sequence↗
PubMed1995

Complement component C4 gene intron 9 as a phylogenetic marker for primates: long terminal repeats of the endogenous retrovirus ERV-K(C4) are a molecular clock of evolution.

The complement component C4 genes of Old World primates exhibit a long/short dichotomous size variation, except that chimpanzee and gorilla only contain short C4 genes. In human it has been shown that the long C4 gene is attributed to the integration of an endogenous retrovirus, HERV-K(C4), into intron 9. This 6.36 kilobase retroviral element is absent in short C4 genes. Here it is shown that the homologous endogenous retrovirus, ERV-K(C4), is present precisely at the same position in the long C4 gene of orangutan and African green monkey. Determination of the short C4 gene intron 9 sequences from human, three apes, two Old World monkeys, and a New World monkey allowed the establishment of consistent phylogenetic trees for primates, which favors a chimpanzee-gorilla clade. The 5' long terminal repeats (LTR) and 3' LTR of ERV-K(C4) in long C4 genes of human, orangutan, and African green monkey have similar sequence divergence values of 9.1%-10.5%. These values are more than five-fold higher than the sequence divergence of the homologous intron 9 sequences between the long and short C4 genes in higher primates. The latter is probably a result of homogenization or concerted evolution. We suggest that the 5' LTR and 3' LTR of an endogenous retrovirus can serve as a reliable reference point or a molecular clock for studies of gene duplication and gene evolution. This is because the 5'/3' LTR sequences were identical at the time of retroviral integration and evolved independently of each other afterwards. Our data provides strong evidence for the short C4 gene being the ancestral form in primates, trans-species evolution, and the "slow-down" phenomenon of the sequence divergence in great apes.

Amino Acid Sequence↗