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)

Major histocompatibility complex (MHC) haplotypes, including HLA-A, -B, -C and -DR and complotypes (BF, C2, C4A and C4B) were determined in a large family with inherited C4 deficiency. The propositus, a 12-year-old girl with complete C4 deficiency and SLE, had the MHC haplotypes HLA-A2,Cw3,-B40,-DR6,BFS,C2C,C4AQO,C4ABQO inherited from her father and HLA-A30,-B8,-DR3,BFF1,C2C,C4AQO,C4BQO from her mother. These haplotypes were identified in several of the healthy relatives, who were thus shown to be carriers of C4 deficiency. Most of the other haplotypes found in the family were not considered to be unusual in the general population. The complete absence of C4 in the patient was confirmed by studies of Chido and Rodgers antigens in the plasma and on the erythrocytes, the absence of plasma C4d fragments and by studies of C4 chain antigens by immunoblotting technique. The results of the genetic analysis, together with the findings in other cases of C4 deficiency, supports the possibility that complete C4 deficiency in itself predisposes to development of SLE without contribution of other MHC gene products.
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PMID:C4 allotypes and HLA-DR antigens in the family of a patient with C4 deficiency. 393 50

The fourth component of complement (C4) in man, is coded for by two separate but closely linked loci (C4A and C4B) within the major histocompatibility region (MHC), on the short arm of chromosome 6. Like class I and II loci of this region, the C4 genes are highly polymorphic with more than 30 alleles, including null alleles, assigned to the two loci. This extensive polymorphism, based mainly on electrophoretic mobility, provides a useful marker for studies of disease susceptibility. Several disorders, including systemic lupus erythematosus and type I diabetes, show associations with C4 phenotypes. We have used the technique of Southern with a C4 specific probe to examine the genomic DNA of individuals typed for C4 by protein electrophoresis. We have identified 10.7 and 3.8 kilobase (kb) BglII restriction fragments in each of 9 unrelated individuals with a C4A6 allele, and in none of 22 unrelated individuals in whom this allele was not expressed. This clear correlation of restriction fragment length polymorphism with C4 phenotype provides a precise basis for analysis of C4 polymorphism. It is likely to be of value in clinical investigations of autoimmune disease.
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PMID:Correlation between a DNA restriction fragment length polymorphism and C4A6 protein. 631 64

The families of 29 patients with systemic lupus erythematosus and 42 normal subjects were studied to determine the inheritance of the HLA-A, B, C, and DR antigens and also the complement polymorphisms for C2, C4A, C4B, and Bf, which are encoded in the same region of the sixth chromosome. Null (silent) alleles for C4A, C4B, or C2 were found in 24 of the 29 (83%) patients compared with 18 of the 42 (43%) normal controls. HLA-DR3 was present in 20 (69%) of the patients and seven out of 39 (18%) of the normal controls. There was strong linkage disequilibrium between DR3 and the null alleles for C4A and C4B. The data did not permit the relative contributions of DR3 and null factors of C4A and C4B as genetic risk factors to be distinguished. The known association of systemic lupus erythematosus with uncommon inherited and acquired deficiencies of complement components suggests, however, that the presence of null alleles for C4A and C4B, as well as C2, found in most of the patients, is relevant to their genetic susceptibility to this disease.
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PMID:Family study of the major histocompatibility complex in patients with systemic lupus erythematosus: importance of null alleles of C4A and C4B in determining disease susceptibility. 640 49

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

Although null alleles of complement C4 genes (C4A*Q0 and C4B*Q0) are frequent in the normal population, the occurrence of two null alleles on the same chromosome is very rare and therefore complete C4 deficiency is exceptional. We describe a 16-year-old North African boy who presented with systemic lupus erythematosus with renal involvement and persistent undetectable classical pathway activity and C4 protein and hemolytic activity in plasma, with normal C3 levels. Similar complement abnormalities were observed in his healthy 12-year-old brother. Complete C4 deficiency was documented in the two brothers by investigation of the family and the lack of C4A and C4B bands upon phenotyping of C4. Southern blot analysis of the C4/CYP21 gene organization in the family indicated that the deficiency resulted from a deletion of the C4B/CYP21A genes associated with nonexpression of a C4A gene. The double-null haplotype was found to be associated with homozygous A2 B17 C2C BFF C4 AQ0 BQ0 DR7 HLA haplotype. Thus, similar C4 deficiencies with HLA identity may lead to different clinical presentations.
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PMID:Complete inherited deficiency of the fourth complement component in a child with systemic lupus erythematosus and his disease-free brother in a north African family. 781 56

The complement system is an important part of non clonal or innate immunity that collaborates with acquired immunity to kill pathogens and to facilitate the clearance of immune complexes. The complement is made up of 20 distinct plasma proteins and 9 different membrane proteins. Three components, factor B, C2 and C4 (with 2 isotypes), are coded by polymorphic HLA-linked genes and are sometimes referred to as class III antigens, inherited as compact units called complotypes. The C4 genes are the most polymorphic, including a common null allele (Q0) at both the C4A and C4B loci. Other polymorphic complement factors (not linked to HLA) are C3 (2 common alleles), C6 and C7 (closely linked, with 3 and 2 alleles, respectively). A certain degree of polymorphism has also been described for complement receptors and membrane control proteins. No differences in functional activity are usually detected among different alleles. Immune-mediated diseases are associated with C4Q0, in particular: systemic lupus erythematosus and discoid-systemic lupus erythematosus, insulin-dependent diabetes mellitus, liver cirrhosis, celiac disease and IgA/IgG4 deficiency. Even if optimal HLA markers do become available, genetic counselling is usually not the ultimate goal for dealing with most of the HLA-associated common diseases, although their study could help to better delineate disease pathogenesis.
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PMID:Polymorphism of the complement components in human pathology. 794 94

Deficiency of complement component C4 is considered playing a role in the genetic predisposition for systemic lupus erythematosus (SLE). The purpose of this study was to characterize the genomic alterations of the C4 and CYP21 genes in 40 caucasoid patients with SLE by C4 allotyping and by RFLP analysis. Nineteen patients (47.5%) carried C4A null alleles and eight patients (20.0%) C4B null alleles. SLE patients had more frequent C4A null alleles (47.5%) than healthy individuals (20%) (chi 2 = 10.75; P < 0.005). The commonest molecular alteration in the patients with C4A null alleles was a large gene deletion affecting both C4A and CYP21A genes. However, among the patients with C4A null alleles, 16.7% persons had no detectable C4A deletion. The non-expression of C4A gene might be due to defects at various levels of gene expression (i.e. transcription and translation). Among the patients with C4B null alleles, 62.5% persons had no detectable gene lesion, whereas 37.5% showed a C4B deletion including both C4B/CYP21A or C4B/CYP21B genes. Duplication of the C4B gene was not rare in SLE patients, as we found 15.0% of the patients with a heterozygous C4B/CY21A gene duplication. The patients typed as having C4B gene homoduplication (B1,1) demonstrated two long C4B loci, whereas heteroduplication (B1,2) displayed two short loci, therefore the type of C4B gene duplication may be related to the gene length. In conclusion, C4 deficiencies observed in 26 of the 40 SLE patients studied were very heterogeneous. In every case, the gene alteration affected both C4 and CYP21 genes.
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PMID:Complement component C4 deficiencies and gene alterations in patients with systemic lupus erythematosus. 809 58

We report a follow-up of our previous study of HLA markers in 118 unrelated patients: 49 with definite systemic lupus erythematosus (SLE) (group 1), 32 with definite or probable SLE and chronic biologically false positive (CBFP) seroreactions for syphilis (group 2), and 37 CBFP reactors (group 3). Definite SLE was confirmed in 28 (90.3%) of the patients in group 2, equally in HLA B8- and HLA B7-positive patients. Three of the CBFP reactors developed SLE, two (40%) out of five HLA B8-positive as compared to one (6.6%) out of 15 HLA B7-positive CBFP reactors (P = 0.07). Fourteen patients died (groups 1 and 2). Eight of the 24 HLA B8-positive patients died in contrast to one of the 20 HLA B7-positive patients (P < 0.02). Of the CBFP reactors, 70.9% had complement C4 null alleles as compared to 47.9% in controls (P = 0.05) and 50% had C4A null alleles as compared to 17.8% in controls (P < 0.05). C4B null alleles were found in 28.6% (28.6% in controls, P is not significant). The null alleles for C4A were not solely in a linkage disequilibrium with the HLA B8 DR3 haplotype. CBFP reactors with C4A null alleles had a higher risk of developing SLE, lupus-like disease or symptoms such as photosensitivity, cutaneous vasculitis and/or autoantibodies than did those with no C4A null alleles (P < 0.02).
Lupus 1993 Apr
PMID:HLA antigens and complement C4 allotypes in patients with chronic biologically false positive (CBFP) seroreactions for syphilis: a follow-up study of SLE patients and CBFP reactors. 833 39

A report is presented of a family with selective partial C4-deficiency in 3 members, two of whom suffer from systemic lupus erythematosus (SLE). C4-allotyping showed the presence of one "silent gene" for the C4B-locus (C4BQO) in these three cases. Presumably it is not the reduced C4-content per se that plays the essential role in the pathogenesis of familial SLE, but the combination of the C4BQO-allele with the HLA-DR2, which was also present in all three affected persons. However, it is of practical relevance that strikingly low C4-levels in comparison with the C3-levels in patients with early onset of SLE should initiate an investigation of the whole family. Furthermore, the C4-level in this form of familial SLE is not a suitable parameter for ganging disease activity on follow-up control investigations.
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PMID:[Familial lupus erythematosus with partial C4 deficiency]. 833 99

Immunoassays using C4 monoclonal antibodies were developed to quantitate C4A, C4B and total C4 in the serum of healthy controls and patients with systemic lupus erythematosus (SLE). Mean C4A or C4B levels were reduced when a single C4A*Q0 or C4B*Q0 gene was present; however, total C4 levels showed considerable overlap with and did not differ significantly from the non-C4 null groups in either patients or controls. Black patients with SLE without active disease, as well as black controls, had higher levels of C4B and consequently total C4 than whites. Ten patients with SLE studied serially showed that C4A and C4B levels changed proportionally during changes in disease activity. Thus, it may be more important to consider race and disease activity rather than C4 null gene status when assessing C4 levels in patients with lupus.
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PMID:Complement component C4A and C4B levels in systemic lupus erythematosus: quantitation in relation to C4 null status and disease activity. 804 42


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