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PubMed1994

Polymorphism in the human complement C4 genes and genetic susceptibility to autoimmune hepatitis.

Susceptibility to autoimmune hepatitis is associated with the HLA-DR3 and DR4 haplotypes, but which genes are directly involved in the pathogenesis, has not been established. Low levels of complement component C4 and elevated frequencies of C4 null allotypes have been described in patients, suggesting that the C4 genes, which are closely linked with the HLA loci, may play a role. We therefore examined restriction fragment length polymorphisms in the C4 and 21-hydroxylase genes, and determined HLA-A and B phenotypes, and HLA-DR, DQ and DP genotypes in a large series of Caucasoid patients with autoimmune hepatitis and matched controls. A DNA deletion of the C4A gene and the 21-hydroxylase A pseudogene was found to be present in 50% of patients compared to 23% of controls (Pc < 0.005, relative risk = 3.3). This increase, however, appears to be due to linkage disequilibrium with HLA-DR52a which was most strongly associated with the disease. Complete C4A deficiency, determined by homozygosity for the deletion increased the risk to 18.1 (16% versus 1%, Pc < 0.005), suggesting an additional role for C4 in disease susceptibility. C4 deletions were associated with an increased mortality and tendency to relapse whilst on treatment but did not correlate with age of onset of disease. Our data suggest that MHC-encoded susceptibility to autoimmune hepatitis is polygenic, involving the HLA-DR genes plus other loci, and C4 deficiency may be a marker of disease susceptibility and/or severity.

Adolescent↗
PubMed1993

[Immunologic follow-up of HIV-positive patients. C3, C4 complement components during HIV infection].

Investigations of the authors' patients with HIV infection revealed marked changes in the C3 and C4 components of complement. Of 61 investigated patients with HIV infection only 23 patients (37.7%) had values of the C3 component at the level recorded in controls. Values of the C4 component comparable with the control group were recorded in 24 patients (39.3%). From figures 1 and 2 it apparent that in the investigated group there is a striking hypercomplementaemia of both components, as compared with hypocomplementaemia.

AIDS-Related Complex↗
PubMed2001

Complement C4 deficiency and HLA homozygosity in patients with frequent intraoral herpes simplex virus type 1 infections.

Three consecutive patients with no apparent immunodeficiency who had frequent intraoral herpes simplex type 1 recurrences, a rare complication of herpes simplex virus infection, were found to have a total deficiency of either the A or B isotype of the complement component C4 and to be homozygous for the studied HLA antigens. A combination of HLA homozygosity, which may lead to impaired T cell recognition of viral peptides, and deficiency in the classical complement pathway, which can compromise virus neutralization, may predispose to severe and frequent herpes simplex virus infections.

Adult↗
PubMed1985

Multiple duplications of complement C4 gene correlate with H-2-controlled testosterone-independent expression of its sex-limited isoform, C4-Slp.

Mouse liver cDNA clones related to the C4 and C4-Slp isoforms of the fourth component of complement differ by few nucleotide changes within a region of substantial divergence from human C4. It is suggested that the mouse C4 gene duplication is an evolutionarily recent event with respect to the time of mammalian radiation. This conclusion is reinforced by the presence of a single C4 gene in the Syrian hamster. Most H-2 haplotypes, including those characterized by an undetectable C4-Slp protein, possess two C4 gene copies which, in contrast to the neighboring factor B, show a marked restriction site polymorphism. The genetic variation of this region is emphasized by the presence in the mouse of a rare "polymorphism" for C4 gene number. Multiple C4-related gene copies characterize those exceptional wild-derived H-2 haplotypes, H-2w7, H-2w16, and H-2w19, that determine the expression of the C4-Slp protein in female animals.

Animals↗
PubMed1990

Restriction fragment length polymorphism of complement C4 in Japanese patients with rheumatoid arthritis and normal Japanese.

Restriction fragment length polymorphism (RFLP) of the two genes for complement C4A and C4B was studied in 56 Japanese patients with rheumatoid arthritis (RA) and 161 normal individuals. HindIII digestion revealed six common patterns, from which the segregation of three common RFLP-types were deduced; 32-15 kb, 32-25 kb, and 32-20-13-6.5 kb. The last type showed positive associations with C4B5 and HLA-DR4. In the RA patients, an increase of this type was found as well as a decrease of the 32-15 kb/32-25-15 kb heterozygotes.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Antigenic determinants of C3 and C4 complement components on washed erythrocytes from normal persons.

Well-washed erythrocytes from normal persons were agglutinated by antisera to C3, C3d, and C4, and this agglutination was specifically inhibited by the corresponding C3 or C4 protein. C3 and C4 antigenic determinants were present on the red blood cells of freshly shed blood promptly anticoagulated with EDTA, heparin, ACD, or CPD, and no significant changes in degree of agglutination were observed on storage of EDTA or CPD blood for two weeks at 4 C. Marked differences in degree of agglutination by anti-C3, anti-C3d, and anti-C4 were observed when erythrocytes of 16 normal persons were assayed, and significant correlations were obtained when the quantitative results with any two antisera were compared. Anti-C3c did not agglutinate erythrocytes from normal persons, suggesting that the C3 antigens detected on normal cells are carried by the C3d fragment. To avoid significant agglutination of the erythrocytes from some normal persons, very dilute preparations of anti-C3, -C3d, and -C4 had to be used for instrumented diagnostic direct antiglobulin tests. Stronger reagents could be used for indirect antiglobulin tests when the result of a suitable control could be subtracted.

Animals↗
PubMed2000

[Isotyping of human C4 complement using differences in the functional activity of C4A and C4B isotypes].

The difference in the functional activity of the isotypes A and B of component C4 of human complement was used to determine their ratio and to detect the inherited deficiency of the isotypes. ELISA methods were developed for the quantitative assay of component C4 (conventional sandwich method) and its functional activity. When determining the functional activity, the classic pathway of the complement and therefore of component C4 was activated by activators sorbed on ELISA microplates (immunoglobulin IgG3 or liposaccharide of the Shigella sonnei cell walls, which activates the complement by binding component C1). The nascent fragment C4b is covalently bound to the target activator; C4Ab binds better to the target protein (immunoglobulin), and C4Bb to the target carbohydrate (liposaccharide). Therefore, when immunoglobulin is a target activator, isotype C4A is bound and determined; and when the complement is activated by liposaccharide, isotype C4B is determined. The ratio of the activities determined by the two methods indicates a deficiency in the individual isotypes of component C4 or its absence. The rabbit polyclonal monospecific antibodies against the human component C4 and the conjugates of these antibodies with horseradish peroxidase were used in the methods described.

Animals↗
PubMed1990

Null alleles of human complement C4. Evidence for pseudogenes at the C4A locus and for gene conversion at the C4B locus.

The two genes for the C4A and C4B isotypes of the fourth component of human complement are located in the MHC class III region. Previous studies have demonstrated the unusual expression of C4 genes in the form of aberrant or duplicated haplotypes. Null alleles of C4A or C4B (AQ0 or BQ0) have been defined by the absence of gene products and occur at frequencies of 0.1-0.3. However, only some C4 null alleles are due to gene deletions, the remainder were thought to be nonexpressed genes. We have analyzed the C4 gene structure of 26 individuals lacking either C4A or C4B protein. The DNA of individuals with apparently nonexpressed C4 genes was tested for the presence of C4A- and C4B-specific sequences using restriction fragment analysis and isotype-specific oligonucleotide hybridization of DNA amplified by polymerase chain reaction. All nondeleted AQ0 allels had C4A-specific sequences and may thus be described as pseudogenes, whereas the nondeleted BQ0 alleles had C4A-instead of C4B-specific sequences. Gene conversion is the probable mechanism by which a C4A gene is found at the second C4 locus normally occupied by C4B genes.

Alleles↗