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)

Susceptibility to systemic lupus erythematosus (SLE) is known to be governed by genes in the HLA region of the 6th chromosome. From previous studies it has not been possible to distinguish between the effects of null genes for the complement component C4 and HLA-DR3, because of the marked linkage disequilibrium between DR3 and a null allele of C4A (C4A QO) in caucasoid populations. We report here an immunogenetic study of 44 cases of SLE, selected because they were DR3 negative. Eighteen of the 30 Caucasoid cases (60%) had extended HLA haplotypes with a C4 null allele, compared with 22 of 60 (37%) of a control panel of 60 DR3 negative normal Caucasoid subjects. This difference is significant (chi 2 = 4.41; 0.05 greater than P greater than 0.01). Of 14 non-caucasoid patients analysed, 10 had a C4 null allele. It is concluded that the null alleles of the C4 A and B genes are themselves directly responsible for conferring susceptibility to SLE.
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PMID:Family study of the major histocompatibility complex in HLA DR3 negative patients with systemic lupus erythematosus. 350 48

Genes in the major histocompatibility complex code for three major groups of glycoproteins, now referred to as classes I, II, and III. Susceptibility to some autoimmune diseases and to systemic lupus erythematosus is associated with the presence of particular haplotypes of genes in these three classes. An attempt has been made to correlate these finding on the basis of the observation that different polymorphic forms of complement component C4 show varying efficiencies of complement activation. It is suggested that susceptibility to these diseases will be related to the varying efficiency of complement cell lysis and of immune aggregate dissolution by complement. This in turn will depend on the strength of interaction of the different polymorphic forms of C4 with other proteins (some also polymorphic) in the scheme of activation and inactivation of complement. Such an arrangement would lead to preferential association of certain alleles of C2, C4 and factor B and possibly also of class I and II antigens as potential targets of complement reaction.
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PMID:Complement polymorphism, the major histocompatibility complex and associated diseases: a speculation. 667 72

Circulating immune complexes (C.I.C.) were investigated in 244 patients with various skin diseases and 100 healthy subjects. C.I.C. were detected by the PEG-C4 assay, firstly proposed by Digeon et al. using the precipitation by polyethylene glycol (PEG 3,5 p. 100) and the determination by laser nephelometry of complement component C4 in sera and in precipitates. The percentage of C4 precipitated and of positive subjects were significantly increased in numerous cutaneous diseases: systemic lupus erythematosus, scleroderma, pemphigus, bullous pemphigoid, dermatitis herpetiformis, psoriasis, contact dermatitis and lichen planus. Two cases of dermatomyositis, 3 cases of post herpetic erythema multiformis and 2 cases of Kaposi-Juliusberg syndroma were also positives but no definite conclusion can be given because of the few patients tested. On the contrary, the values of precipitated C4 are normal in most cases of atopic dermatitis (the method does not detect IgE-C.I.C.) scabies, porphyria cutanea tarda, cutaneous epithelioma and discoid lupus. In chronic urticaria and in mycosis fongoides the mean values of precipitated C4 are significantly increased but the number of positive subjects is low and the significance of these results is uncertain because of the wide range of the values. The results of the present study are compared with the literature data. The value of C.I.C. determination in determining the evolutivity of skin diseases and their possible role in pathogenesis are discussed.
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PMID:[Circulating immune complexes in skin disease patients. Study and literature data (author's transl)]. 730 15

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

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

Mouse complement component C4 exists in two isoforms, C4 and a protein with expression restricted to male animals called sex-limited protein (Slp). Although Slp is about 95% homologous to C4, it is generally believed to be non-functional, at least in conventional haemolytic complement assays. In a previous study, however, we showed that Slp is haemolytically active in a C1-inhibitor (C1INH)-regulated, EDTA-resistant mouse complement activation pathway. To study other possible implications of this finding, we generated constitutively expressing Slp-transgenic mice. The transgene was crossed into otherwise Slp-deficient C57Bl/6J and NZB mice. Members of the third backcross generation of C57Bl/6J mice were tested for functional Slp and classical and alternative complement pathway activities (CH50 and AP50 levels, respectively). Slp-transgenic C57Bl/6J mice showed enhanced CH50, but normal AP50 levels when compared with non-transgenic littermates. To discover a possible protective role for Slp in spontaneous systemic lupus erythematosus (SLE) in NZBxNZW (NZBxW) mice, the third backcross generation of Slp-transgenic NZB mice was mated with NZW mice and the development of SLE in the female offspring was followed. In these introductory experiments, Slp-transgenic NZBxW animals presented with a significantly extended life span. Our results imply that Slp is a mouse complement component with functions which partially resemble some of those of human C4A.
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PMID:Sex-limited protein: in vitro and in vivo functions. 1036 Dec 25

Contrary to infective anticardiolipin (aCL) antibodies, autoimmune aCL antibodies react with phospholipids (PL) mainly via binding to the plasma glycoprotein cofactor beta2-Glycoprotein I (beta2GPI). While there is a well-documented link between the risk of thrombosis and the presence of beta2GPI-dependent anticardiolipin antibodies, the pathological impact of other antiphospholipid antibodies is less clear. By means of cardiolipin affinity-chromatography, we isolated and identified 3 CL-binding proteins, complement component C4, complement factor H and a kallikrein-sensitive glycoprotein, and tested for the presence of autoantibodies against these proteins in patients with antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and other autoimmune diseases. High titers of autoantibodies to C4 as compared to age- and sex-matched healthy controls were present in 3 of 26 patients with APS, and weak titers were found in 2 of 26 patients with SLE and in none of 26 patients with other autoimmune diseases. Autoantibodies to complement factor H were found in 4 APS, 3 SLE and none of the other autoimmune patients. Autoantibodies to kallikrein-sensitive glycoprotein were detected in 6 APS patients, 1 SLE patient, and 1 patient with another autoimmune disease. A close relationship between these antibodies was found, suggesting their origin from a common macromolecular complex. However, no relationship with anti-beta2GPI antibodies was found, with the three patients with higher levels of autoantibodies having a low titer of anti-beta2GPI antibodies. In conclusion, some patients with APS harbor circulating antibodies to other CL-binding proteins which might be useful to further characterize these patients.
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PMID:Some patients with antiphospholipid syndrome express hitherto undescribed antibodies to cardiolipin-binding proteins. 1120 89

The disease course of a complete C4-deficient patient in the U.S. was followed for 18 years. The patient experienced multiple episodes of infection, and he was diagnosed with systemic lupus erythematosus at age 9 years. The disease progressed to WHO class III mild lupus nephritis and to fatal CNS vasculitis at age 23 years. Immunochemical experiments showed that the patient and his sibling had complete absence of C4A and C4B proteins and were negative for the Rodgers and Chido blood group Ags. Segregation and definitive RFLP analyses demonstrated that the patient and his sibling inherited two identical haplotypes, HLA A2 B12 DR6, each of which carries a defective long C4A gene and a defective short C4B gene. PCR and DNA sequencing revealed that the mutant C4A contained a 2-bp insertion in exon 29 at the sequence for codon 1213. The identical mutation was absent in the mutant C4B. The C4B mutant gene was selectively amplified by long range PCR, and its 41 exons were completely sequenced. The C4B mutant had a novel single C nucleotide deletion at the sequence for codon 522 in exon 13, leading to frame-shift mutation and premature termination. Thus, a multiplex PCR is designed by which known mutations in C4A and C4B can be elucidated conveniently. Among the 28 individuals reported with complete C4 deficiency, 75-96% of the subjects (dependent on the inclusion criteria) were afflicted with autoimmune or immune complex disorders. Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus.
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PMID:The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes. 1213 86

Mice lacking the classical complement component C4 (C4(-/-)) were evaluated for autoreactivity because classical complement deficiencies are major risk factors for human systemic lupus erythematosus (SLE). Naive, 6-month-old C4(-/-) mice have significantly more IgM anti-double-strand DNA antibodies than C4(+/+) controls. By 9 months, IgG anti-dsDNA antibodies are increased and this spontaneous autoreactivity is evident across a mixture of genetic backgrounds. C4(+/-) heterozygous mice also develop autoantibodies, reminiscent of the high incidence of partial C4 deficiency observed in human SLE. Kidneys of C4(-/-) mice have glomerular immune complexes, but progressive renal disease is not apparent in unmanipulated animals. Nonetheless, splenic B cells from C4(-/-) and not C4(+/+) mice as young as 3 months can be triggered to secrete IgM anti-dsDNA antibodies in vitro, before autoantibody titers are significantly elevated in vivo. These findings suggest that C4 normally helps prevent early stages of autoimmune disease and that C4 deficiency predisposes to abnormal regulation of autoreactive B cells.
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PMID:Anti-DNA autoreactivity in C4-deficient mice. 1220 52

The complement component C4 is encoded by two genes: C4A and C4B on human chromosome 6p in the major histocompatibility complex (MHC). Most studies have linked the deficiencies in C4 with systemic lupus erythematosus (SLE) in Angio-Irish, North American, Black American, Mexican American, Australian and Japanese populations. Null alleles at either locus (C4AQ0 or C4BQ0) are relatively common in Americans occurring at the C4A and C4B loci in approximately 10% and 16% of normal individuals, respectively. In the present study, we extensively examined the possible association between homozygous C4Q0 and SLE in a large cohort of Thai populations diagnosed as SLE and further attempted to identify the genetic basis of C4Q0. One hundred and eighteen cases of SLE patients and 145 matched controls were genotyped by touchdown PCR. The results confirmed the previous studies that 5.93% (7/118) of C4 null genes: 2.54% (3/118) of C4AQ0 and 3.39% (4/118) of C4BQ0 were found in SLE patients. In contrast to other studies, we found no cases of C4 null genes in normal control (0 from 145 samples). To further investigate the genetic basis of C4 deficiency, all genomic DNAs were also analyzed for 2-bp (TC) insertion at codon 1213 in exon 29 which is a common mutation in many C4A null genes and a novel 1-bp deletion (C) at codon 522 in exon 13 that is common in most C4B null genes. Both mutation results in a flame-shift mutation and premature stop codon using sequence specific primers PCR (SSP-PCR) and direct sequencing. The results showed that there was 2-bp insertion in exon 29 of mutant C4B gene in one SLE patient carrying C4AQ0. There was no 2-bp insertion in exon 29 of both C4A and C4B genes in normal individual and the rest of SLE patients. All patients with C4AQ0 exhibited more than 5 ACR criteria including malar rash, oral ulcers, renal disorder, immunological disorder, anti-nuclear antibody, without hematological disorder. In contrast, all of C4BQ0 SLE patients showed 5 or 6 ACR criteria including hematological disorder, malar rash, oral ulcers, renal disorder, immunological disorder and anti-nuclear antibody. A patient who possesses C4AQ0 and 2-bp insertion in exon 29 of mutant C4B showed 9 ACR criteria but no discoid rash and hematological disorder. In conclusion, both C4AQ0 and C4BQ0 are the strong predisposing factors for SLE in Thais. It was supported by the absence of either C4A or C4B deletion in healthy control. We suggested that the different racial and genetic backgrounds could alter the thresholds for requirement of C4A or C4B protein levels in immune tolerance and regulation.
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PMID:Complete deficiencies of complement C4A and C4B including 2-bp insertion in codon 1213 are genetic risk factors of systemic lupus erythematosus in Thai populations. 1599 80


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