Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a multicenter study more than 300 central European systemic lupus erythematosus (SLE) patients were examined for HLA-B, HLA-DR, and complement C4 phenotypes. For 174 SLE patients MHC haplotypes were determined by family segregation analysis, and for 155 patients C4 gene deletions were determined by TaqI restriction fragment length polymorphism. Two haplotypes, B8-C4AQ0-C4B1-DR3 and B7-C4A3-C4B1-DR2, were identified as risk factors for SLE. These findings were confirmed by applying the haplotype frequency difference (HFD) method, which uses nontransmitted haplotypes from the family study as internal controls. Furthermore, only HLA-DR2, but not DR3, B7, or B8, was significantly increased in SLE patients independently of the two risk haplotypes. C4A gene deletions, but not silent C4AQ0 alleles, were increased in SLE patients and neither C4BQ0 alleles nor C4B gene deletions were increased. The observed frequencies of homozygosity and heterozygosity for the two haplotypes and the frequencies of homozygotes for C4AQ0 and C4A deletions did not differ from the expected values, indicating that the risk for SLE is conveyed by single allele effects. In conclusion, there are two MHC-linked susceptibility factors for Caucasian SLE patients carried by the haplotypes B7-DR2 and B8-DR3. The results argue against C4Q0 alleles being the decisive factors increasing susceptibility to SLE.
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PMID:Major histocompatibility complex haplotypes and complement C4 alleles in systemic lupus erythematosus. Results of a multicenter study. 140 Oct 69

The metabolism of the C4 allotypes C4A3,B1 and C4A3,BO was studied in five healthy control subjects and six patients with active immunological disease (five with systemic lupus erythematosus and one with rheumatoid arthritis). The specific aim was to identify any differences in the metabolism of C4A and C4B gene products that may be linked to their documented functional differences in vitro. The fractional catabolic rate of C4A3,B1 in patients was significantly greater than that of C4A3,BO (3.98 +/- 1.37 versus 3.31 +/- 0.85%/h; mean +/- s.d.; P less than 0.05) but there was no difference in control subjects (1.95 versus 1.99%/h). The extravascular:intravascular (EV:IV) distribution ratio of C4A3,B1 was also greater in both patients (1.19 +/- 0.36 versus 0.97 +/- 0.35; P less than 0.01) and controls (0.43 +/- 0.11 versus 0.31 +/- 0.13; P = 0.01). We conclude that C4B1 was catabolized more rapidly than C4A3 in patients with pathological complement activation but not in control subjects. This difference could reflect the relatively greater extravascular distribution (i.e. EV:IV ratio) of C4B at sites of immune complex deposition or, alternatively, different rates of catabolism of inactive C4 isotypes (iC4b).
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PMID:Differences in the metabolism of C4 isotypes in patients with complement activation. 253 15

The inhibition of immune precipitation is mediated by the classical complement pathway. We report here that the rate of precipitate formation depends on the genetic form of human C4 present during immune precipitation. C4A3 is more effective than C4B1 in its capacity to inhibit the rate of immune precipitate formation in serum and in serum-free reaction mixtures containing C1 and C4. Immune precipitates form within seconds after antigen is mixed with antibody, and the activation of the classical pathway is known to occur within seconds after C1 binds to antibody molecules. The covalent deposition of C4b on immune complexes is an essential step in the inhibition of immune precipitate formation, and if any of the reactions that lead to covalent C4b deposition become limiting, the rate of immune precipitation could exceed the complement system's inhibitory capacity. Hence, the inhibition of this rate may be an important function underlying the complement-mediated processing of immune complexes, and a decreased ability of the complement system to mediate this process in the presence of C4B1, in contrast to C4A3, could explain, at least in part, the association between the C4A-null phenotype and autoimmune diseases such as systemic lupus erythematosus.
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PMID:C4-mediated inhibition of immune precipitation and differences in inhibitory action of genetic variants, C4A3 and C4B1. 318 Jul 39

Human complement component C4 is encoded by two structurally distinct loci in the major histocompatibility complex (MHC) class III region. The two isotypes, C4A and C4B, differ at only four residues in the C4d fragment, but C4 constitutes the most polymorphic of the complement components. It is not known, however, whether the regions involved in the regulation of C4 expression also display polymorphic variation. By using the technique of DNase I hypersensitivity mapping, we established that the only area of transcriptional activity for C4 in the hepatocyte cell line, HepG2, occurs approximately 500 base pairs upstream of the transcriptional start site. This region was found to be remarkably constant in sequence when analyzed in the context of differing MHC haplotypes including HLA B57, C4A6, C4B1, DR7, which has been correlated with reduced expression of the C4A isotype. Similarly, polymerase chain reaction followed by single-strand conformation polymorphism analysis failed to demonstrate any promoter polymorphisms in 103 individuals comprising 52 systemic lupus erythematosus patients and 51 healthy controls.
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PMID:DNase I hypersensitivity mapping and promoter polymorphism analysis of human C4. 775 31

Complement component C4 is an important protein of the classical, or antibody-mediated pathway of complement activation. Human C4 is located within the central region of the major histocompatibility complex on chromosome 6. Partial C4 deficiency has been associated with an increased susceptibility to immune complex disease. The strongest association with partial C4 deficiency is with systemic lupus erythematosus (SLE) and has been shown in most racial groups studied. Interestingly, Caucasian population studies have demonstrated an increased prevalence of C4A null alleles in SLE patients, in particular in association with the haplotype HLA-A1, B8, BfS, C4AQ0, C4B1, DR3. To investigate whether the C4 gene on this haplotype had any structural irregularities which may explain disease association, we sequenced the entire C4B gene from this haplotype. The results revealed that the gene encoded on the disease-associated haplotype carried major structural differences (when compared to C4A3) at the exonic level only in the C4d region. A high degree of conservation in both the 5' and 3' untranslated regions imply that disease associations will not be due to differential C4 expression as a result of regulatory differences between C4 genes. It appears likely that protein clearance mechanisms may account for the altered levels of C4 seen between different isotypes.
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PMID:Comparative analysis of the disease-associated complement C4 gene from the HLA-A1, B8, DR3 haplotype. 885 88

An individual's major histocompatibility complex (MHC) ancestral haplotype (AH) is the clearest single determinant of susceptibility to MHC associated immunopathological disease, as it defines the alleles carried at all loci in the MHC. However, the direct effects of any of the 150-200 genes that constitute the MHC are difficult to determine since recombination only occurs at defined hotspots. This review concerns the 8.1 AH (HLA-A1, C7, B8, C4AQ0, C4B1, DR3, DQ2), which is carried by most Caucasians with HLA-B8. It is associated with accelerated human immunodeficiency virus (HIV) disease, and susceptibility to insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus, dermatitis herpetiformis, common variable immunodeficiency and IgA deficiency, myasthenia gravis and several other conditions. We have mapped susceptibility genes for HIV, IDDM and myasthenia gravis to the central MHC between HLA-B and the tumour necrosis factor or complement genes. Here we consider which of the remaining 8.1-associated diseases are more closely associated with HLA-DR3 and/or DQ2. Several candidate genes in the central MHC have the potential to modulate immune or inflammatory responses in an antigen-independent manner, as is seen in studies of cultured cells from healthy carriers of the 8.1 AH. Hence these genes may act as a common co-factor in the diverse immunopathological conditions associated with the 8.1 AH.
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PMID:The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. 1031 67

The genes coding for the two components of complement 4 (C4), C4A and C4B, are located within the major histocompatibility complex (MHC) on the short arm of chromosome 6. Several studies have shown that deficiency of C4A is associated with systemic lupus erythematosus (SLE), rheumatoid arthritis and scleroderma. A large deletion covering most of the C4A gene and the 21-hydroxylase-A (21-OHA) pseudogene found on the extended haplotype B8-C4AQ0-C4B1-DR3 is estimated to account for approximately two-thirds of C4A deficiency in Caucasian SLE patients. Detection of this C4A null allele has been technically difficult due to the high degree of homology between C4A and C4B, with protein analysis and restriction fragment length polymorphism (RFLP) analysis using Southern blotting being the only approaches available. In this study, a long PCR strategy was used to rapidly genotype for the C4A deletion through specific primer design. The methodology makes use of the unique sequence of the G11 gene upstream of C4A and the sequence of a 6.4 kb retrotransposon, the human endogenous retrovirus HERV-K(C4), which is present in intron 9 of C4A but absent in the case of the deletion.
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PMID:Long PCR detection of the C4A null allele in B8-C4AQ0-C4B1-DR3. 1103 17