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PubMed1988

IgA serum levels and HLA complement markers in gastric cancer patients.

Immunoglobulin serum levels and class III HLA polymorphisms (Bf, C4A, and C4B) have been analyzed in 55 gastric cancer patients (13 having at least a first-degree relative affected by the same tumor) from the Republic of San Marino. This was done to search for possible immunoglobulin deficiencies (in particular IgA), which have been proposed to have a prognostic value in gastric cancer, and to identify possible associations between such a tumor and HLA class III determinants. All subjects had normal Ig levels with the exception of one patient (having the worst prognosis) characterized by a combined IgA, IgG, and IgM deficiency. Normal Ig levels were found in all the examined relatives of the proband. The Bf, C4A, and C4B allele frequencies we found did not differ significantly from those reported for healthy subjects in Italian samples.

Alleles↗

PubMed2006

Identification of the size and antigenic determinants of the human C4 gene by a polymerase chain-reaction-based amplification method.

The human C4 complement components of the C4 locus are encoded by two genes, C4A and C4B, located on chromosome 6p21.3 of the major histocompatibility complex of the human leukocyte antigen class III region. The size difference between the two genes is due to the presence of HERV-K (C4), an endogenous retroviral sequence (6.7 kb long), in intron 9 of the long C4 gene. Whether the C4 is the long (L) or short (S) gene was determined by the Southern blot method, and the antigenic determinants in residues 1,054-1,106 of Rodgers and Chido were generally identified by immunoblot analysis. Herein, we explore a polymerase chain reaction (PCR) amplification method for directly determining the size of C4 loci adjacent to the respective RP1 and RP2 genes and antigenic determinants by DNA sequencing. From the results of this study, we concluded that all of the C4 genes adjacent to the RP1 gene presented the long gene. In addition, 47% of the C4 genes adjacent to the RP2 gene were the short gene and 53% were the long gene. This result was consistent with that of the Southern blot analysis. The PCR method is practical for identifying the C4 genotype and can be used to detect other polymorphisms among variants of C4 genes.

Asian People↗

PubMed1989

21-hydroxylase deficiency families with HLA identical affected and unaffected sibs.

During our investigations of polymorphisms at, and in the immediate chromosomal vicinity of, the 21-hydroxylase locus in families with 21-hydroxylase deficiency, three families were found to show marked discordance in clinical features of HLA identical subjects. In one family, there is discordance between a boy with the simple virilising form of 21-hydroxylase deficiency and his two younger sisters, who are both HLA identical to their brother, but who have additional salt wasting features. In the other two families, one subject is severely affected and has very high 17-hydroxyprogesterone levels, but has an HLA identical sib who is asymptomatic and shows only slightly raised 17-hydroxyprogesterone levels. In all cases, HLA identity, as indicated by protein polymorphism studies (HLA-A, B, DR, C4A, C4B, and Bf typing), has been verified at the gene organisation level using 21-hydroxylase and complement C4 DNA probes. An HLA-Bw47 bearing haplotype in one of the latter families has not been transmitted to the affected child and appears to carry a normal 21-OHB allele and two genes which specify C4A allotypes.

Adrenal Hyperplasia, Congenital↗

PubMed1999

Anti-cardiolipin antibodies and circulating immune complexes in type 1 diabetes mellitus: increased prevalence and relation to vascular complications.

Anti-cardiolipin antibodies, oxidatively modified low-density lipoproteins (oxLDL) and circulating immune complexes are humoral factors that have been linked to vascular damage. To analyse their possible role in the vascular complications in type 1 diabetes mellitus, we investigated patients with and without vascular complications (retinopathy, nephropathy, polyneuropathy, foot ulcers). The patients were matched for age, sex and duration of diabetes. The patients were also compared with 102 healthy individuals. Anti-cardiolipin antibodies of IgG and IgA type were more common in patients compared with healthy individuals. There was no difference between patients with and without vascular complications. There was no increased prevalence of IgM anti-cardiolipin antibodies, but the levels of these antibodies were higher in patients with vascular complications compared with patients without complications and controls. Eighty-three percent of patients had circulating immune complexes in comparison with 5% of healthy individuals. Such complexes were more common in patients with complications. Both the prevalence and the levels of immune complexes were higher in patients with null alleles of complement factor C4. Patients with vascular complications had higher prevalence of C4A than of C4B null alleles. Anti-cardiolipin antibodies were present in higher relative concentrations in immune complex form than in serum in all six patients analysed. There was no increased prevalence of antibodies against oxidatively modified LDL in the patients. The higher prevalence and levels of anti-cardiolipin antibodies and circulating immune complexes in patients with vascular complications suggests that these humoral factors might be involved in the vascular complications of type 1 diabetes mellitus.

Adult↗

PubMed1992

Lack of deletion of complement C4 and steroid 21-hydroxylase genes in Japanese patients with primary Sjögren's syndrome.

A null allele at C4A (C4AQO) is associated with primary Sjögren's syndrome (SS) in Japanese. Since a deletion of the C4A and CyP21A genes is reported to account for C4AQO in patients with systemic lupus erythematosus (SLE) in Caucasians, we studied the restriction fragment length polymorphism (RFLP) of genomic DNA to determine whether similar deletions of the C4A and CyP21A genes occur in Japanese patients with SS. Patients with C4AQO did not show the extensive deletion of C4A and CyP21A, which would be recognized by the appearance of 8.5 kb/HindIII and 6.4 kb/TaqI fragments hybridizing with a C4 probe. It is yet to be shown whether the lack of expression of C4A genes in Japanese patients with primary SS is due to point mutations, or to small deletions or insertions that were not detected by the RFLP approach.

Alleles↗

PubMed1990

Recurrent haemolytic uraemic syndrome and acquired hypomorphic variant of the third component of complement.

In a girl with recurrent haemolytic uraemic syndrome (HUS), persistently low serum levels of C3 were found. Analysis of complement phenotype revealed a hypomorphic variant of C3 Fast in the patient (C3fS) and a normal heterozygous pattern in both parents and the brother (C3FS). Other complement aberrations in the patient were: the presence of a null gene for C4A and C4B and low serum levels of factor H. The father also had partial factor H deficiency. It is hypothesized that the hypomorphic C3 variant may predispose to recurrent HUS. In the acquired forms the role of uraemia in alteration of C3F should be considered.

Complement C3↗

PubMed1987

Molecular genetics of the fourth component of human complement.

The fourth component of complement in humans is coded for by two closely linked loci, i.e., C4A and C4B, that have been positioned within the class III region of the human major histocompatibility complex along with the genes for C2, Bf, and steroid 21-OH. Both C4 loci are highly polymorphic and certain alleles, particularly the nulls, are associated with susceptibility to autoimmune disease. About one-half of the null alleles are due to a large deletion that includes both a C4 and flanking 21-OH gene. Despite the near identity of the products of the two loci, the proteins differ dramatically in their efficiency of covalent binding to antigen. The amino acid substitutions responsible for the functional differences have been identified and they are clustered relatively near the covalent binding site within the C4d region of the alpha chain. These observations support the hypothesis that the susceptibility to autoimmune disease is related to the structural variation of the C4 protein.

Alleles↗

PubMed1983

Phenotypes of the fourth complement component (C4) in black Americans from the southeastern United States.

C4 is composed of two tightly linked genes (C4A and C4B) lying within the major histocompatibility complex of chromosome 6 that can be demonstrated by agarose gel electrophoresis. Seven alleles and five alleles at the C4A and C4B loci, respectively, were detected in 169 black individuals from the southeastern United States. Furthermore, the phenotypic frequencies of C4A6, C4A5, C4A4, C4B4, C4B3 and C4BQ0 were significantly different between black and white Americans.

Alleles↗

PubMed2005

Complement C3a enhances CXCL12 (SDF-1)-mediated chemotaxis of bone marrow hematopoietic cells independently of C3a receptor.

Complement C3a promotes CXCL12-induced migration and engraftment of human and murine hemopoietic progenitor cells, suggesting a cross-influence between anaphylatoxin and chemokine axes. Here we have explored the underlying mechanism(s) of complement anaphylatoxin and chemokine cooperation. In addition to C3a, C3a-desArg and C4a but not C5a, are potent enhancers of CXCL12-induced chemotaxis of human and murine bone marrow (BM) stem/progenitor cells and B lineage cells. C3a enhancement of chemotaxis is chemokine specific because it is also observed for chemotaxis to CCL19 but not to CXCL13. The potentiating effect of C3a on CXCL12 is independent of the classical C3a receptor (C3aR). First, human BM CD34(+) and B lineage cells do not express C3aR by flow cytometry. Second, the competitive C3aR inhibitor SB290157 does not affect C3a-mediated enhancement of CXCL12-induced chemotaxis. Third, enhancement of chemotaxis of hemopoietic cells is also mediated by C3a-desArg, which does not bind to C3aR. Finally, C3a enhances CXCL12-induced chemotaxis of BM cells from C3aR knockout mice similar to BM cells from wild-type mice. Subsequent studies revealed that C3a increased the binding affinity of CXCL12 to human CXCR4(+)/C3aR(-), REH pro-B cells, which is compatible with a direct interaction between C3a and CXCL12. BM stromal cells were able to generate C3a, C3a-desArg, C4a, as well as CXCL12, suggesting that this pathway could function in vivo. Taken together, we demonstrate a C3a-CXCL12 interaction independent of the C3aR, which may provide a mechanism to modulate the function of CXCL12 in the BM microenvironment.

Anaphylatoxins↗

PubMed1990

Complement genetics and host defence.

There is a surprisingly high frequency of allelic variation in complement proteins. The best candidate for a true selective polymorphism is that of C3. For C4 and factor B within the MHC it is more difficult to identify the effects of individual alleles. No evidence suggests other alleles of C4 (and C2) than the null alleles (or the two isoproteins C4A and C4B) to have any functional differences with resistance. Thus, the major functions of complement, as shown by the effects of deficiency, are to resist infection against bacteria and particularly against Neisseria, and to prevent immune complex disease. There are also undoubtedly balancing contributions to the pathogenesis of some infections and to all immune complex disease. Data from studies of C4 polymorphism and from the presence of control proteins on micro-organisms suggest there may be in addition more subtle contributions to immunity against a variety of other infections.

Alleles↗

PubMedDate not supplied

Complement activation products and factors influencing phagocyte migration in synovial fluids from children with chronic arthritis.

Synovial fluids from children with chronic arthritis were examined simultaneously for the presence of complement activation products and factors affecting phagocyte migration. The concentrations of C3a and C5a, but not C4a, were found to be elevated relative to normal plasma. However, the C3a and C5a concentrations in synovial fluid did not correlate with C1q binding values or with degree of migration inhibition or chemoattraction caused by that fluid. Although this data implies complement activation occurs in inflamed joints in juvenile arthritis, the specific role of immune complexes remains unproven.

Arthritis, Juvenile↗

PubMed1987

The complement component C1s catalysed hydrolysis of peptide 4-nitroanilide substrates.

The kinetic parameter kcat/Km has been determined for the hydrolysis of peptide 4-nitroanilides, catalysed by complement component C1s. Substrates based on the C-terminal sequence of human C4a (Leu-Gln-Arg) were synthesised. Replacement of the glutamine residue by glycine or serine increased kcat/Km. Substitution of valine for the leucine residue increased kcat/Km, while substitution of glycine or lysine for the leucine residue decreased kcat/Km slightly. D-Val-Ser-Arg 4-nitroanilide is the most reactive 4-nitroanilide substrate towards C1s, so far. These results are discussed in relation to the amino acid sequences near the bonds cleaved by C1s in C4, C2 and C1 inhibitor.

Amino Acid Sequence↗

PubMed2004

Immunological analysis in paediatric HIV patients at different stages of the disease.

There are only few clinical studies on complement in well-defined (or characterized) paediatric HIV patients. Aim of this study was to evaluate the complement system and immunoglobulins in HIV-infected children and to correlate data to stage of disease. Blood samples of 127 HIV-infected children (11-134 months; 62 male : 65 female) were collected in order to evaluate humoral immunity. The patients were classified according to CDC clinical (N-asymptomatic; A-mild symptoms such as common recurrent infections; B-moderate symptoms such as Candidiasis and herpes infections, meningitis, sepsis and anaemia; C-severe symptoms such as opportunistic infections and neoplasia) and with respect to immunological criteria (T CD4(+) cell count). Analysis of complement system included the classical (CH50), alternative (APH50) pathway activities and plasma concentrations of mannan-binding lectin (MBL), of the C4 allotypic variants C4A and C4B. (ELISA), and of the C3 split product C3d (rocket immunoeletrophoresis). Immunodiagnosis also included CD4(+) and CD8(+) lymphocyte count and immunoglobulin concentrations. Complement activation and consumption was observed in all patients correlating with disease activity. Activated classical and alternative pathways and elevated C3d were significantly correlated with immunologic category 3. C3d levels were also significantly correlated with immunologic category 1. Undetectable CH50 and APH50 were found in two (group C) and 10 patients (n = 2, A = 2, B = 2, C = 4), respectively. Low MBL values were found in 13/127 but without correlation to disease severity. Undetectable C4B levels were observed in three patients, favouring the diagnosis of a complete deficiency. Although not related to clinical symptomatology, a strong ongoing complement activation can be observed in all stages of HIV infection. In contrast to earlier reports MBL could not be considered as a risk factor for HIV.

Antibodies↗

PubMed1995

[Changes in the polymorphism and concentrations of components of the class II complement after orthotopic transplantation of the liver].

OBJECTIVES AND METHODS: The genes of complement factor B, C2 and C4 are located within the major histocompatibility complex class III region on chromosome 6 in man. These components demonstrate a genetic polymorphism which, when determinated, can be used to define complotypes (association of C2, factor B, C4A and C4B allotypes). On the other hand the liver is the main source of the circulating complement component synthesis. The aim of this study was to analyse the kinetics of several complement component (C3, factor B and C4) concentrations in the plasma and to assess changes in the polymorphic pattern of the complotypes after orthotopic liver transplantation. Nephelometry was used for plasma level measurements and factor B, C2 and C4 typings were performed with high voltage electrophoresis or isofocalisation and immunofixation at intervals before, during and after orthotopic liver transplantation in eleven patients. RESULTS: Complotypes changes were observed 24 hours after liver transplantation in all patients. A slight decrease in C3, C4, and factor B plasma levels was observed in the first hours after transplantation. A rapid increase in the levels of these components was observed subsequently, with normalization in less than 15 days. CONCLUSION: These results demonstrate a rapid synthesis of complement components and the changes in complement polymorphic patterns after liver transplantation.

Adult↗

PubMed1991

[In vitro and clinical study of complement activation during cardiopulmonary bypass with reference to types of oxygenator, primed autologous blood and patient's factor].

Complement activation during cardiopulmonary bypass (CPB) was studied in vitro and in vivo with regard to types of oxygenator, primed autologous blood and patient's factor. In vitro study was performed using human blood in a simple circuit involving an oxygenator, roller pump and connector tubing. In vivo study was carried out in 118 patients and divided into bubble (BO) and membrane oxygenator (MO) groups. The influence of primed homologous to circulating autologous blood volume (H/A) ratio was also examined. In vitro study, C3a and C4a increased steeply in the BO group. On the other hand, in the MO group, C3a and C4a increased up to minute of 60, and afterwards gradually decreased. In clinical study, complement was more activated in the BO group than in the MO group. These results supported that in the BO group, immunoglobulin denatured by blood-gas interface played an important role in complement activation. In membrane oxygenator, blood-material interface was a major cause of complement activation. In order to reduce these complement activation, we introduced fresh concentrated red cells, which was almost free of immunoglobulin, as a primed blood. Application of this method in clinical study, complement activation was reduced and postoperative lung function was improved significantly. These changes were more significant in the BO group. In the high H/A group, differences of anaphylatoxin level between BO and MO group had a tendency to increase. This method is useful to the CPB case of neonate and infant, which was subjected to be primed with a large amount of blood.

Adolescent↗

PubMed1990

C4B deficiency: a risk factor for bacteremia with encapsulated organisms.

The fourth component of complement (C4) is crucial to the activation of the classical complement pathway, a key defense against invading microorganisms. The two isotypes of C4, C4A and C4B, have very different in vitro activities. An increased incidence of total C4B deficiency was found in white patients with Streptococcus pneumoniae, Haemophilus influenzae, or Neisseria meningitidis infection (14% of bacteremic children vs. 2% of race-matched controls, P = .02). In black patients, however, there was no difference in incidence of C4B deficiency between bacteremic patients and race-matched controls (7% and 5%, respectively, P greater than .5). These data suggest that, at least in whites, total C4B deficiency is a risk factor for invasive disease with these three encapsulated organisms.

Adolescent↗

PubMed1994

Hemofiltration during cardiopulmonary bypass: quality assessment of hemoconcentrated blood.

UNLABELLED: Hemofiltration is often used during cardiopulmonary bypass (CPB) for water removal. In a prospective random study 11 patients undergoing elective coronary artery surgery with hemofiltration during CPB were observed and compared to 11 patients without filtration. The quantitative and qualitative aspects of blood before and after filtration while still on CPB and until the first postoperative day were assessed. Intra- and postoperative volume requirements, standard hematology and chemistry, as well as hemolysis, complement activation, and coagulation factors were analysed at nine sequential points in time. RESULTS: There were no significant differences in pre- and postoperative patient data between the two groups except that the majority of patients in the study group (55%) were anticoagulated and required a significantly longer CPB time with higher doses of protamine and had higher postoperative drainage (2.9 vs. 1.4 L). Intra- and postoperative hemoglobin concentrations, transfusion and volume requirements were similar in both groups. 927 ml of plasma water were filtered during CPB within 4 min 20 s without hemodynamic changes or electrolyte imbalance. Hemoglobin and protein concentrations increased significantly during hemofiltration (Hb increases 3.6 g/dl). Hemolysis and activated complement fractions were elevated during CPB but showed no further increase during filtration; in contrast C4a, C5a, and prothrombin F1 + 2 increased significantly after cessation of CPB. In conclusion, hemofiltration during CPB is a safe and efficient method for water removal and for concentration of red blood cells and proteins without adverse effects on the patient's hemodynamics, blood quality, and volume requirements. More especially, no negative influence of hemofiltration could be determined with regard to activation of the coagulation and complement system.

Blood Cell Count↗

PubMed1992

Combined total deficiency of C7 and C4B with systemic lupus erythematosus (SLE).

The first inherited combined total deficiency of C7 and C4B complement components associated with SLE is described in a young female. Functional C7 assays showed a homozygous C7 deficiency in the propositus and her sister, and an heterozygous one in their parents. C4 molecular analyses showed that both the propositus and her mother had two HLA haplotypes carrying only C4A-specific DNA sequences and a normal C4 gene number. Thus, only C4A proteins could be expressed, with resultant normal C4 serum levels. The coexistence of a combined complete C7 and C4B deficiency may therefore abrogate essential functions of the complement cascade presumably related to immune complex handling and solubilization despite an excess of circulating C4A. These findings challenge the putative pathophysiological roles of C4A and C4B and stress the need to perform both functional assays and C4 allotyping in patients with autoimmune pathology and low haemolytic activity without low serum levels of a classical pathway complement component.

Adult↗