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)

Resistance to the anticoagulant effects of activated protein C (APC) is now considered the most prevalent cause of inherited thrombophilia. The great majority of patients with activated protein C resistance (APCR) have a missense mutation in the factor V molecule (factor V Leiden, FVR506Q) resulting in defective inactivation of factor Va due to a loss of an APC cleavage site. The diagnosis of APCR has been based upon the inability of APC to prolong the activated partial thromboplastin (aPTT) clotting time in subjects with APCR. However, this assay has a number of deficiencies which limit its general use. We have evaluated a newly described one-stage tissue factor dependent factor V coagulation assay for APCR in 117 patients and controls and compared the results of this assay in a blinded manner to a polymerase chain reaction (PCR) based assay for the molecular defect of factor V Leiden. 43% (50/117) of the patients studied were receiving coumadin or heparin, or had a lupus anticoagulant. The tissue factor dependent factor V assay had 100% specificity and sensitivity for factor V Leiden and successfully predicted a homozygous state in the three documented homozygotes. The PCR-based assay for factor V Leiden resulted in a single false positive assay due to a silent A to C transition at nucleotide 1692 resulting in the loss of the Mnl restriction endonuclease cleavage site. The single-stage tissue factor dependent factor V assay is a highly sensitive and generally applicable assay for APCR.
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PMID:Evaluation of a tissue factor dependent factor V assay to detect factor V Leiden: demonstration of high sensitivity and specificity for a generally applicable assay for activated protein C resistance. 894

The present study investigated the expressed number of CR1 on erythrocytes (E) in relationship of the CR1 density genotype from 46 patients with systemic lupus erythematosus (SLE) and 47 healthy volunteers. The CR1 genotype was determined by a method based on polymerase chain reaction (PCR) amplification of the genomic DNA fragment of 1.8 kb separated by HindIII endonuclease digestion and agarose gel electrophoresis. Our data supported the earlier results that the number of binding sites/E for monoclonal anti-CR1 decreased among SLE patients compared with normal individuals having the same alleles for the CR1/E density. At the same time the novelty of our recent results was that the decreased expression of CR1 on E correlated significantly with kidney involvement in patients homozygous for the CR1/E high density allele (HH). These data suggest that the deficiency of the detectable number of CR1 on erythrocytes is acquired in this SLE population.
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PMID:CR1 density polymorphism and expression on erythrocytes of patients with systemic lupus erythematosus. 916

Campylobacter fetus subspecies fetus rarely causes celluitis associated with bacteremia in debilitated hosts. We have identified this infection in two patients with systemic lupus erythematosus and in one with liver cirrhosis. All three patients had eaten raw beef, liver, or improperly cooked pork before the manifestations of the illness. C. fetus subspecies fetus was recovered from blood and feces from the three patients. This organism was also isolated from a subcutaneous aspirate of the cellulitis lesion in one patient. DNA macrorestriction endonuclease profiles analyzed by pulsed field gel electrophoresis differed for the isolates from the three patients but were identical for the blood and fecal isolates or the aspirate and fecal isolates from each patient. These findings suggest that cellulitis associated with bacteremia arises from ingestion of C. fetus subspecies fetus organisms and that clinicians and microbiologists should be aware of this infection in debilitated hosts.
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PMID:Campylobacter fetus subspecies fetus cellulitis associated with bacteremia in debilitated hosts. 970 72

We have investigated the molecular basis of selective and complete C1s deficiency in 2-year-old girl with complex autoimmune diseases including lupus-like syndrome, Hashimoto's thyroiditis, and autoimmune hepatitis. This patient's complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, and undetectable levels of C1s Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of genomic DNA by PCR followed by direct sequence analysis revealed a homozygous nonsense mutation in the C1s gene exon XII at codon 534, caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction site for endonuclease Fok-1 created by the mutation to detect this mutation in the genomic DNA of seven healthy family members. Four additional heterozygotes for the mutation were identified in two generations. Our data characterize for the first time the genetic defect of a selective and complete C1s deficiency in a Caucasian patient.
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PMID:Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases. 1139 May 18

The purpose of this study was to evaluate whether vitamin D receptor (VDR) genes BsmI polymorphisms were markers for susceptibility to or severity of systemic lupus erythematosus (SLE) in Chinese patients in Taiwan. The study included 47 Chinese patients with SLE. In addition, 90 unrelated, healthy individuals living in central Taiwan served as control subjects. Each polymorphism was detected as a result of polymerase chain reaction (PCR)-based restriction analysis. A PCR product length was determined to be 580bp (BB) whereas two fragments of 405 and 175bp were determined to be excisable lengths (bb) by BsmI endonuclease. The relationship between Bsm polymorphisms and clinical manifestations of SLE was evaluated. We found that BB was significantly more common and bb less common in SLE than in control group (chi2 = 54.2, P < 0.0001). In addition, the frequency of B allele was also significantly more common in patients with SLE than in the healthy control subjects (chi2 = 38.7, P < 0.0001), giving an odds ratio of 7.14 (95% confidence interval 3.53-14.4). In the SLE patients, we did not detect any associations of VDR genotype with the clinical, laboratory profiles, or lupus nephritis (chi2 = 2.34, P = 0.3). This study indicated an increased distribution of VDR BB genotype and B allelic frequencies in the Chinese SLE patients in Taiwan. However, there were no associations between the frequency of VDR allelic variations and clinical manifestations, laboratory profiles, or lupus nephritis.
Lupus 2002
PMID:Association of vitamin D receptor gene BsmI polymorphisms in Chinese patients with systemic lupus erythematosus. 1189 16

Uteroglobin (UG) is a multifunctional protein with anti-inflammatory/immunomodulatory properties. The UG gene is located on the long arm of chromosome 11 (11q12.3-q13.1) in a region linked to some immune disorders. A guanine-adenine substitution at position 38 (A38G) has been found in the noncoding region of exon 1 that is significantly correlated with an increased risk of developing immune-mediated diseases. Recently an experimental model of UG knockout mice showed that in mice, UG deficiency causes severe glomerulopathy with mesangial deposition of IgA-fibronectin complexes. To detect the presence of polymorphisms in the UG coding sequence, the DNA of 109 patients with IgA nephropathy (IgAN), and 32 patients with systemic lupus erythematosus (SLE) were tested for the nucleotide sequence of all three UG exons by heteroduplex analysis. We detected heterozygous DNA only for exon 1 due to the A38G substitution, as confirmed by sequencing. We tested for A38G polymorphism, by restriction endonuclease digestion (Sau96I), both in SLE patients and in IgAN patients. Twenty patients with either membranous nephropathy (12) or focal and segmental glomerular sclerosis and 120 healthy subjects served as controls. Compared with both healthy controls and non-IgA control patients, the frequency of the 38A allele was significantly higher in SLE patients (38 of 64 alleles versus 89 of 240 alleles, p = 0.002, and versus 7 of 40 alleles, p < 0.001). IgAN patients showed an allelic distribution similar to both control groups. A subgroup of 18 IgAN patients undergoing renal replacement therapy because of end-stage renal disease showed a significant increase in 38A allele frequency (5 of 36 38G alleles versus 31 of 36 38A alleles, p < 0.001). UG is an immunomodulatory agent that is able to (a) inhibit the activity of several phospholipase A2 (PLA2s), (b) interfere with the function of both neutrophils and monocytes, and (c) prevent immune recognition, perhaps by masking surface antigens. This could account for the role this molecule plays in SLE. The A38G polymorphism is located within a region corresponding to the rat minimal promoter that proved to be important in the transcriptional regulation of UG. Although the significance of any alterations in the UG exon 1 noncoding region in humans has yet to be clarified, initial evidence suggests that it may alter the control of immune response and of inflammation.
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PMID:Polymorphism of the uteroglobin gene in systemic lupus erythematosus and IgA nephropathy. 1200 94

The risk of cardiovascular disease (CVD) in SLE patients is very high. It is therefore surprising that IL-10 has been discussed both as pathogenic in SLE and as an atheroprotective cytokine. In contrast, TNF is believed to be atherogenic and we recently reported that raised activity in the TNF-system is implicated in SLE-related CVD. Twenty-six (aged 52 +/- 8 years) female patients with SLE and a history of CVD (myocardial infarction, angina, stroke or claudication) were compared with 26 age-matched SLE patients without CVD (SLE controls) or 26 age-matched population controls. The -1087IL-10 gene polymorphism was determined by PCR with restriction endonuclease mapping. Serum IL-10 and TNF-levels were determined by ELISA. The A allele frequency of -1087IL-10 gene in SLE/CVD was higher than in SLE controls (0.62 versus 0.42, p < 0.05). Ten (38%) of 26 SLE/CVD exhibited IL-10 AA genotype compared with five (19%) of 26 SLE controls. Serum IL-10 and TNF-levels were raised in SLE/CVD compared with SLE controls or population controls (p < 0.001). Furthermore, in SLE/CVD, a significantly reduced IL-10:TNF ratio was observed in patients with IL-10 AA genotype compared with AG or GG genotype (0.56 versus 0.77 versus 1.24, p < 0.05). In SLE controls and population controls, individuals with IL-10 GG genotype tended to have higher IL-10:TNF ratio. In conclusion, the A-1087IL-10 allele which has been reported to cause a lower capacity for IL-10 production could contribute to CVD in SLE. Furthermore, the IL-10 AA genotype is associated with reduced ratio of atheroprotective to atherogenic cytokines in SLE patients with CVD.
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PMID:The A-1087IL-10 allele is associated with cardiovascular disease in SLE. 1553 Sep 17

Systemic lupus erythematosus (SLE) is characterised by the production of autoantibodies against ubiquitous antigens, especially nuclear components. Evidence makes it clear that the development of these autoantibodies is an antigen-driven process and that immune complexes involving DNA-containing antigens play a key role in the disease process. In rodents, DNase I is the major endonuclease present in saliva, urine and plasma, where it catalyses the hydrolysis of DNA, and impaired DNase function has been implicated in the pathogenesis of SLE. In this study we have evaluated the effects of transgenic over-expression of murine DNase I endonucleases in vivo in a mouse model of lupus. We generated transgenic mice having T-cells that express either wild-type DNase I (wt.DNase I) or a mutant DNase I (ash.DNase I), engineered for three new properties - resistance to inhibition by G-actin, resistance to inhibition by physiological saline and hyperactivity compared to wild type. By crossing these transgenic mice with a murine strain that develops SLE we found that, compared to control non-transgenic littermates or wt.DNase I transgenic mice, the ash.DNase I mutant provided significant protection from the development of anti-single-stranded DNA and anti-histone antibodies, but not of renal disease. In summary, this is the first study in vivo to directly test the effects of long-term increased expression of DNase I on the development of SLE. Our results are in line with previous reports on the possible clinical benefits of recombinant DNase I treatment in SLE, and extend them further to the use of engineered DNase I variants with increased activity and resistance to physiological inhibitors.
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PMID:The in vivo expression of actin/salt-resistant hyperactive DNase I inhibits the development of anti-ssDNA and anti-histone autoantibodies in a murine model of systemic lupus erythematosus. 1660 42

Nuclear autoantigens in systemic lupus erythematosus are thought to derive primarily from apoptotic cells, yet there is no direct evidence that interfering with apoptosis impairs the generation of lupus autoantibodies. Here we use a mouse model that lacks the endonuclease caspase-activated DNase (CAD), resulting in an absence of chromatin and nuclear fragmentation during apoptotic cell death. We show that in this mouse, production and release into circulation of chromatin is impaired after exposure to several apoptotic triggers, but that the absence of CAD does not interfere with upstream steps of apoptosis or immune system function. Finally we show that in CAD-mutant mice, impaired lupus autoimmunity is skewed toward known cytoplasmic components, and autoimmunity toward membrane autoantigens is preserved, while autoimmunity toward chromatin and other lupus nuclear targets is severely impaired or absent. We also show, as control, that the induction of experimental autoimmune encephalomyelitis is not affected by the absence of CAD. Thus, our work in vivo strongly suggests that apoptotic molecular steps during cell death generate nuclear autoantigens to sustain the specific autoimmune response in systemic lupus erythematosus.
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PMID:Lack of chromatin and nuclear fragmentation in vivo impairs the production of lupus anti-nuclear antibodies. 1802 44

B lymphocytes from patients with systemic lupus erythematosus (SLE) are characterized by reduced expression levels of membrane CD5. Recent studies from our laboratory have revealed that the level of membrane CD5 is determined by the relative level of two alternative CD5 isoforms; CD5-E1A, which is expressed on the membrane, and CD5-E1B, which is retained in the cytoplasm. Using bisulfite sequencing and methylation-sensitive endonuclease assays we show that the promoter for the alternative CD5-E1B isoform is demethylated in B cells from patients with SLE but not in healthy controls. We go on to show that differential methylation is more pronounced following BCR engagement. As a result of this demethylation, CD5-E1B mRNA is transcribed at the expense of CD5-E1A mRNA transcription. We provide further evidence that production of high IL-6 levels by SLE B cells abrogates the ability of SLE B cells to induce DNA methyl transferase (DNMT1) and then to methylate DNA, an effect that is reversed in the presence of a blocking Ab to the IL-6 receptor. The pattern of demethylation of CpG islands in the CD5-E1B promoter in SLE B cells is similar to those in B cells from healthy controls stimulated in the presence of IL-6, or treated with the methylation inhibitor PD98059. The study reveals that engagement of the BCR with constitutive IL-6 down-regulates the level of membrane CD5, which negatively regulates BCR signaling, in SLE B cells. This altered signaling could, in turn, promote the activation and expansion of autoreactive B cells in SLE patients.
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PMID:IL-6 modulates CD5 expression in B cells from patients with lupus by regulating DNA methylation. 1938 Aug 9


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