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PubMed1987

Recombination of two homologous MHC class III genes of the mouse (C4 and Slp) that accounts for the loss of testosterone dependence of sex-limited protein expression.

In most mouse strains, expression of a gene encoding sex-limited protein (Slp), an isotype of the fourth component of complement (C4), is induced by testosterone, or the gene is not expressed at all; however, in some wild-derived strains carrying H-2w7, H-2w16, or H-2w19 haplotype, Slp is expressed constitutively in the same way as C4. To examine the structural basis for the testosterone-independent expression of Slp, 41 overlapping clones together encoding the S region were isolated from C3H.W7 mouse (H-2w7) cosmid library. Five C4-related genes each spanning approximately 16 kb were identified among the cluster of cosmid clones and were isolated for structural study. One of the genes (C4w7) hybridized with the C4-specific oligonucleotide probe but not with the Slp-specific oligonucleotide probe, whereas the other genes (Slpw7a, Slpw7b, Slpw7c, and Slpw7d) hybridized only with the Slp-specific probe. Restriction mapping of these genes and sequencing of the selected regions of 5'-flanking regions of the genes were performed, and the results were compared with the data obtained with the C4 and Slp genes of FM (H-2d) and B10.BR (H-2k). These studies showed that three of the C4-related genes of C3H.W7 (Slpw7b, Slpw7c, and Slpw7d) are C4-Slp recombinant genes comprising a 5'-region derived from C4 gene and a 3'-region derived from Slp gene. It is suggested that 5'-flanking region derived from C4 in these C4-Slp recombinant genes accounts for testosterone-independent expression of Slp in C3H.W7 mouse.

Animals↗
PubMed2005

Classical pathway complement activity in schizophrenia.

There is considerable evidence to suggest a role for complement in the pathogenesis of schizophrenia, but the data related to the classical pathway complement activity in patients with schizophrenia are conflicting. In the present study, the total hemolytic activity of the complement and the activities of individual complement components, C1, C2, C3 and C4, were determined in the blood serum of schizophrenic patients with positive family history of the disease and healthy subjects. In comparison to the healthy subjects, the mean values of the hemolytic activities of the C1, C3 and C4 complement components in the serum of the schizophrenic patients were significantly higher, and the mean value of the hemolytic activity of the C2 complement component was significantly lower. However, no significant difference was found between the mean values of the total hemolytic activity of complement in schizophrenic patients and healthy subjects. The C3 hemolytic activity was 2.17 times higher in medicated patients than in drug-free patients. Within each group examined no significant difference was found between smokers and non-smokers or between males and females. The results of this study suggest that the pathogenesis of schizophrenia is associated with alterations in activities of complement classical pathway components.

Adult↗
PubMed1979

Studies on murine Ss protein: demonstration that S region encodes structural gene for fourth component of complement.

Although genes controlling the expression of certain complement components have been shown to be linked to the major histocompatibility complex of several species, the structural genes that encode these molecules have been more difficult to map. In this study, the three constitutive polypeptide chains of the fourth component of murine complement (C4) (alpha, beta, and gamma) were isolated from 14 different inbred strains and compared by peptide mapping on analytical sodium dodecyl sulfate gels. The peptide patterns of the alpha and gamma subunits appeared to be nearly identical, but two distinctly different patterns were observed for the C4 beta chain. This structural variant was mapped to the S or G region and, as such, provides direct evidence that a structural gene for a complement component is encoded within a major histocompatibility complex.

Animals↗
PubMed1987

Correlation between peripheral blood and follicular fluid autoantibodies and impact on in vitro fertilization.

Total immunoglobulins, C3 and C4 complement, and autoantibodies to phospholipid antigens, histones, histone subfractions, and nucleotides were measured in serum and follicular fluids of 26 patients undergoing in vitro fertilization. Immunoglobulins and complement fractions appeared in statistically lower concentrations in follicular fluid than in serum. This gradient was clearly larger for immunoglobulin M (IgM) than for IgG, IgA, C3, or C4. Ten patients who were autoantibody positive to one or more of the evaluated antigens demonstrated statistically higher total IgG and IgM levels and lower C3 and C4 than 16 autoantibody negative patients. With regard to follicular fluid, positive patients had significantly elevated IgM levels in comparison with negative control patients, and significantly decreased C3 and C4 concentrations. Patients who were autoantibody positive in serum also exhibited uniformly abnormal follicular fluid autoantibodies. Positive patients had significantly higher IgG antiphospholipid antibodies in follicular fluid than controls, and demonstrated a similar trend for IgM and IgA antiphospholipid antibodies. Positive patients demonstrated no significant differences from negative patients in number of in vitro fertilization attempts, number of oocytes retrieved, fertilization rate, cleavage rate, and number of abnormal (granular) oocytes. However, positive patients experienced a lower pregnancy rate (5.4%) than negative patients (26.1%), although the difference did not reach statistical significance (P = .07). This observation strongly suggests that the presence of abnormal autoantibodies in the female may reduce the chance of pregnancy for in vitro fertilization patients. A similar effect of abnormal autoantibodies can then also be expected in attempts at spontaneous conception.

Autoantibodies↗
PubMed1982

Systemic lupus erythematosus in hereditary deficiency of the fourth component of complement.

Three patients from two families with complete hereditary deficiency of the fourth component of complement (C4) and systemic lupus erythematosus are described. The syndrome presented by these patients is characterized by early onset in life; exquisite sensitivity to sunlight and to cold exposure, the latter resulting Raynaud's phenomenon; and skin lesions involving not only exposed areas of the body but also palms and soles and presenting as butterfly rashes, maculopapular eruptions, and lesions similar to those of chronic discoid lupus erythematosus, with marked scaling, atrophy, and scarring. Lupus erythematosus (LE) cell tests were negative and antinuclear antibody (ANA) titers low or negative. The male patient of our series died at the age of 31/2 years from septicemia, whereas the two girls, aged 18 and 11 years, respectively, were alive at the time of writing. The C4-deficient gene is associated with HLA-Aw32, Bw38, and Bf S in one family and with HLA-A30, B18, DR7, and Bf S1 in the other family; the latter is the second family in which this HLA haplotype has been found to be associated with hereditary C4 deficiency.

Adolescent↗
PubMed1980

Inherited structural polymorphism of the fourth component of human complement.

Human fourth component of complement (C4) was found to be highly polymorphic by agarose gel electrophoresis of neuraminidase-treated plasma. The system allows clear-cut separation of the products of the two C4 genetic loci, C4A (acidic or Rodgers) and C4B (basic or Chido). There are at least six structural variants and a deletion allele at the C4A locus and two structural variants and a deletion allele at the C4B locus. Close linkage with no crossovers was found between the two C4 loci, allowing the definition of C4AB haplotypes, and between C4 haplotypes and the C2 and BF loci of the human histocompatibility complex. Nine C4 haplotypes, each with a frequency of 0.005 or more in Caucasians, were found. These studies provide direct evidence for two distinct but closely linked genetic loci for human C4 in the major histocompatibility complex on the short arm of chromosome 6.

Alleles↗
PubMed1983

Cultured hepatocytes from mouse strains expressing high and low levels of the fourth component of complement differ in rate of synthesis of the protein.

Primary hepatocyte cultures prepared from the livers of inbred strains of mice show different rates of synthesis for the fourth component of complement (C4). The relative amounts of C4 synthesized by hepatocyte cultures correspond to the relative plasma levels of C4 among strains, a trait determined by the S region of the H-2 major histocompatibility complex. There is no evidence for increased intracellular catabolism of C4 in hepatocyte cultures from a strain with a low level of plasma C4. Processing and secretion of C4 proceed very slowly in vitro relative to other hepatocyte proteins.

Animals↗
PubMed1984

DNA polymorphism of the C4 genes. A new marker for analysis of the major histocompatibility complex.

Polymorphisms of the proteins encoded by genes that lie within the major histocompatibility complex (MHC) have served as useful markers for organ transplantation and in genetic analysis of a large number of MHC-linked diseases. To extend the range of MHC polymorphic markers, we used a complementary-DNA probe specific for the fourth component of human complement (C4) to identify a new variant within the MHC. Polymorphic variants at the DNA level were detected among subjects with identical phenotypes of the corresponding protein. C4 genomic polymorphisms are inherited with the segment of the short arm of chromosome 6 that carries the HLA-DR and complement loci. The autosomal codominant mode of inheritance of this genetic marker and its utility for evaluation of 21-hydroxylase-deficiency congenital adrenal hyperplasia, one of the many MHC-linked diseases, were established.

Adrenal Hyperplasia, Congenital↗
PubMed1979

The isolation and characterization of bovine C4a, an activation fragment of the fourth component of complement.

The fourth component of bovine complement, C4, was cleaved specifically by subcomponent C1s to produce two fragments, C4a and C4b. The smaller, C4a, was isolated in pure form and is a peptide of 9500 mol.wt. containing approx. 84 amino acids and no detectable carbohydrate. C4a has an amino acid composition that is comparable with the anaphylatoxins C3a and C5a, containing six cysteine residues/mol and a high proportion of basic residues. The amino acid sequence of the first thirteen residues shows four identities with the porcine C3a sequence. There is almost complete identity between the C4a sequence and that of the alpha-chain of human C4, indicating that this region is highly conserved. This evidence also clearly establishes that C4a is cleaved from the N-terminal of the alpha-chain of C4.

Amino Acid Sequence↗
PubMed1999

C4 null alleles and myocardial infarction.

The classical risk factors, hypercholesterolemia, smoking, hypertension and diabetes, explain only a part of the epidemiological features of atherosclerotic coronary heart disease. Investigations in the past few years have shown involvement of immunological mechanisms in atherosclerosis. Circulating immune complexes accelerate atherosclerosis both in experimental animal models and in humans. The fourth component of complement (C4) plays an important role in the solubilisation and elimination of immune complexes. C4 consists of two allotypes, C4A and C4B. An earlier report showed an association between C4B null alleles (C4B*Q0) and myocardial infarction and to infarction related mortality. In the present investigation, C4A*Q0 and C4B*Q0 were studied in two population samples. The first (Group I) was a cross sectional study of 100 consecutive males with myocardial infarction before the age of 45 years and 164 population based healthy controls, age and sex matched. The second (Group II) was a nested case control study in which a cohort of 50 year-old males were followed for 20 years for development of myocardial infarction between 50-60 and 60-70 years, and the results compared with those who did not develop MI. We observed no association of homozygous and/or heterozygous C4A*Q0 or C4B*Q0 with myocardial infarction occurring in the age groups < 45, 50-60 and 60-70 years or with the infarction related mortality (P > 0.05). The prevalence/frequency of C4A*Q0 and C4B*Q0 was not related to the age at which MI occurred. The prevalence of C4A*Q0 was not affected by age. We thus conclude that partial deficiency of C4 does not appear to be a major risk factor for myocardial infarction.

Adult↗
PubMed1992

A unique recombination event resulting in a C4A*Q0,C4B*Q0 double null haplotype.

The fourth component of complement (C4) is encoded by two closely linked genes (C4A and C4B) within the MHC. Null alleles at either locus (C4AQ0 or C4BQ0) are relatively common, occurring at the C4A locus in approximately 10% of normal individuals and at the C4B locus in approximately 16% of normal individuals. However, the presence of the double null haplotype (C4A*Q0,B*Q0) on the same chromosome is extremely rare. We recently studied a 7-yr-old patient with recurrent sinopulmonary infections in whom we documented the mechanism by which the C4A*Q0,B*Q0 double null haplotype arose. Evaluation revealed significantly reduced levels of both C4 antigen and C4 hemolytic activity. Analysis of extended haplotypes in the family was performed using MHC typing and genomic DNA analysis. The patient was found to have a C4A*3,B*Q0 haplotype and a C4A*Q0,B*Q0 haplotype. The C4A*3,B*Q0 haplotype was contributed by the father. The mother possessed a C4A*Q0,B*1 haplotype and a C4A*3,B*1 haplotype. The first maternal haplotype was involved in a recombination event within the C4B locus on her other chromosome and resulted in a new C4B*Q0 null allele and the patient's C4A*Q0,B*Q0 haplotype. Segregation analysis mapped the recombination to a region 3' to the unique 6.4-kb TaqI restriction fragment of the maternal C4B locus. This is the first demonstration of a recombination event producing a C4 double null haplotype.

Blotting, Southern↗
PubMed1979

Immune response of a patient with deficiency of the fourth component of complement and systemic lupus erythematosus.

The clinical details of a five-year-old boy with systemic lupus erythematosus and an inherited deficiency of the fourth component of complement (C4) have been reported elsewhere. In this study of his immune responses, immunization with bacteriophage phi X 174 demonstrated diminished antibody formation, abnormal immunologic memory and failure to switch from IgM to IgG during secondary response. We also noted persistent lymphopenia and reductions in peripheral-blood T lymphocytes, lymphocyte responses to mitogens and allogeneic cells and granulocyte chemotaxis. Kinetic studies revealed that delayed activation of the alternative pathway was corrected by purified C4 only if the classical pathway was not blocked. This finding is consistent with the concept that minute amounts of C3b provided through the classical pathway are necessary to prime the properdin system. Inability to activate the classical complement pathway, abnormal kinetics of alternative-pathway activation and depressed antibody responses to a T-cell-dependent antigen may predispose C4-deficient patients to viral infection or immune-complex formation.

Antibodies, Bacterial↗
PubMed1987

A review of major histocompatibility complex-disease associations in man and dog.

The organization and biology of the Major Histocompatibility Complexes (MHC) of man (HLA) and dog (DLA) are reviewed, and a summary is presented of laboratory techniques used to define allotypes. The nomenclature of this field and the mechanisms of disease association with the MHC are discussed. Currently recognized HLA-disease associations are enumerated, with emphasis on the value of the complement C4 marker. DLA-disease association studies into autoimmune disease, allergy and neoplasia are reviewed.

Animals↗
PubMed1994

Unique C1 inhibitor dysfunction in a kindred without angioedema. I. A mutant C1 INH that inhibits C1-s but not C1-r.

We have described hereditary incomplete deficiency of the fourth component of complement (C4) in 10 members of a large kindred. C4 deficiency in this kindred is not linked to C4 loci in the HLA region. C4 synthesis is decreased, and C4 catabolism is normal in kindred members with low serum C4 levels. We have discovered a uniquely dysfunctional C1 inhibitor in all C4-deficient members of this kindred. C1 inhibitor dysfunction is revealed by incubating sera of affected members with EDTA, which destroys all C4 activity in these sera, but not in normal sera or sera from individuals with partial C4 deficiencies. The M(r) of C1 inhibitor purified from affected members is normal, but approximately 50% of this C1 inhibitor resists cleavage by trypsin (0.14 microM) at arg444, suggesting a substitution at this position. Moderate increases in trypsin, however, result in cleavage of the resistant molecules, which would not be expected if arg444 were the site of the mutation. All molecules in C1 inhibitor purified from affected members' plasma bind to activated C1s (C1-s), but approximately 50% of molecules in these preparations do not bind to activated C1r (C1r). These findings show that affected kindred members have a unique mutation in C1 inhibitor. The mutant C1 inhibitor does not prevent the activation of C1s by C1-r when serum Ca2+ is chelated by EDTA, but its inhibition of C1-s is normal in vivo, as shown by normal C2 levels, normal C4 catabolism, and absence of angioedema in C4-deficient members. The nature of the mutation, its selective failure to inhibit C1-r, and its relationship to decreased C4 synthesis remain to be defined.

Angioedema↗
PubMed1986

Immunodiagnosis of autoimmune skin disease in the dog, cat and horse.

Skin biopsies from 47 dogs, 6 cats and 5 horses with suspected autoimmune skin disease were submitted for immunofluorescence from 1978 to 1985. These cases were predominantly Western Australian in origin, although a number were also referred from Queensland and Victoria. In 5 dogs, 2 cats and 2 horses immunoglobulin binding to intercellular cement substance and/or basement membrane was demonstrated by direct immunofluorescence. Antinuclear antibody was also demonstrated in several of these cases. Immunofluorescence was used in combination with histopathological examination to confirm the clinical diagnosis of autoimmune disease in 19/47 dogs, 4/6 cats and 2/5 horses. There was no age, breed or sex predisposition amongst the 19 positive dogs, however there was a higher incidence of antinuclear antibody (54%) than the normal canine population (10%) and other autoantibodies (rheumatoid factor) were sometimes present. Abnormalities in serum protein electrophoresis and serum complement C4 levels were also recorded in this group.

Animals↗
PubMed1984

[Systemic lupus erythematosus in hereditary complement 4 deficiency].

A genetically determined complete absence of the fourth component of complement, C4, associated with systemic lupus erythematosus has been detected in one member of another family. Observations made in this patient, the ninth described so far in whom systemic lupus erythematosus and C4 deficiency occur have confirmed that this condition presents with a characteristic clinical picture: there is pronounced sensitivity to sunlight and to cold with Raynaud's phenomenon; skin lesions are found predominantly in locations typical for subacute cutaneous lupus erythematosus and, remarkably, on the palms and soles. As was the case in two families described earlier, the C4-deficient gene was associated with the HLA-haplotype AW30, B18, DR7; BfS1.

Adult↗
PubMed1992

Complement 4 gene deletion in patients with IgA nephropathy and Henoch-Schönlein nephritis.

The fourth component of complement (C4), especially B isotype, has been said to be deficient in the IgA nephropathy and Henoch-Schönlein nephritis. However, the association between these diseases and C4 deficiency was questioned recently, and the usual C4 allotyping method is unable to discriminate the C4 deficiency from the C4 duplication. So by combining the DNA restriction fragment length polymorphism with the usual C4 allotyping, we tried to determine whether the deficiency of C4 can be demonstrated in the DNA level. We found that the frequency of C4 gene deletion was increased, although the frequency of null phenotype was not different from the control. From these results we can say that C4 gene deletion is a genetic risk factor in these diseases, at least in the Japanese population.

Child↗