Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas is a 43 kDa glycoprotein molecule which is involved in inducing apoptosis in both B and T lymphocytes. In the murine MRL/Ipr-Ipr model of systemic lupus erythematosus (SLE), the lymphoproliferation (lpr) mutation results in defective transcription of the gene that codes for the Fas protein. MRL mice which carry the homozygous recessive Ipr mutation develop a severe early-onset genetically predetermined autoimmune syndrome characterised by high IgG and autoantibody levels and a diffuse proliferative immune complex-mediated glomerulonephritis. Interest in the importance of Fas in SLE has risen with the observation that 60% of human subjects with lupus have elevated levels of the soluble Fas receptor in their serum and that the abnormal presence of this molecule may protect lymphocytes from undergoing apoptosis. In this review the importance of Fas in autoimmune pathogenesis is discussed.
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PMID:Lupus in the Fas lane? 874 2

Thrombospondin is a multifunctional 450 kD glycoprotein which may be secreted into the extracellular matrix by a wide variety of cells. Occasional foci of immunoreactive thrombospondin have previously been demonstrated within normal human glomeruli. A specific polyclonal antibody directed against thrombospondin 1 was used to examine the distribution of this regulatory glycoprotein in renal biopsies from patients with a variety of renal diseases, including rapidly progressive glomerulonephritis associated with circulating antibodies to neutrophils, active or quiescent systemic lupus erythematosus, and membranous nephropathy, together with normal renal tissue. The results demonstrated the marked up-regulation of thrombospondin expression in acutely inflamed renal tissue with strongly positive, predominantly extracellular staining of glomerular crescents, although cytoplasmic staining of epithelial cells was also seen, indicating that these cells may contribute to thrombospondin accumulation at these sites. Occasional segmental mesangial staining was seen in cases of active lupus and rapidly progressive glomerulonephritis, while some focal interstitial staining around peritubular capillaries was seen in all renal tissue examined. These results suggest that thrombospondin may play an important role in the regulation of cellular recruitment, proliferation, and function in crescentic glomerulonephritis.
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PMID:Expression of the multifunctional extracellular matrix protein thrombospondin in crescentic glomerulonephritis. 877 23

Hydroxychloroquine (HCQ) and chloroquine (CQ) are well absorbed (0.7-0.8 bioavailability) when given orally. Severe malnutrition (such as kwashiorkor) effects absorption but diahrrea does not. Both HCQ and CQ have prolonged half-lives, between 40 and 50 days, and low blood clearance (e.g. hydroxychloroquine's blood clearance is 96 ml/min). There is great variability of blood concentrations with an eleven-fold range of drug concentrations found after similar doses in RA patients. Protein binding ranges between 30 and 40% with binding to both albumin and alpha, glycoprotein. There is differential binding and metabolism of the (R) and (S) stereoisomers. Both drugs bind strongly to pigmented tissues but also bind to mononuclear cells, muscles, etc. There is stereo-selective excretion of both drugs and 40-50% of the drug is excreted renally. Between 21 and 47% is excreted unchanged. There is a suggestion of concentration response and concentration toxicity relationships with decreased morning stiffness as HCQ concentrations increase and increased EKG abnormalities as CQ concentrations become higher, but further testing is required. Pharmacokinetic interaction studies are limited. Potentially important kinetic interactions have been documented for d-penicillamine and cimetidine but have not been found for aspirin, ranitidine or imipramine.
Lupus 1996 Jun
PMID:Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. 880 4

F1 hybrids of New Zealand black (NZB) and New Zealand white (NZW) mice are a model of human systemic lupus erythematosus. These mice develop a severe immune com-plex-mediated nephritis, in which antinuclear autoantibodies are believed to play the major role. We used a genetic analysis of (NZB x NZW)F1 x NZW backcross mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin, which overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein, gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a distal chromosome 4 locus, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production.
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PMID:Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice. 887 26

In 1990, three groups simultaneously reported that putative IgG antibodies to anionic phospholipids were either not directed to phospholipids or at least required beta 2-glycoprotein-I (beta 2-GP-I) for reactivity in vitro. During the same year, our group described a patient with "idiopathic' hemolytic anemia with serum and erythrocyte-bound IgM antibodies to phosphatidylcholine later found to be independent of beta 2-GP-I for antigen recognition. Lately, the field has been expanded considerably with: (1) the description of other potential antigens such as prothrombin for some lupus anticoagulants, (2) the finding of crossreactivity between some antiphospholipid antibodies (aPL) with thrombomodulin, (3) the presence of serum antibodies to beta 2-GP-I (anti-beta 2-GP-I) in patients with SLE and thromboses, (4) the findings that the clinical manifestations of APS in SLE patients associate more strongly with anti-beta 2-GP-I than with aPL, (5) our finding of a group of SLE patients with the clinical manifestations of APS, with negative serum aPL, but with positive anti-beta 2-GP-I, (6) the description of a group of patients with the clinical manifestations of APS, without serum aPL, without serological nor clinical evidence of any autoimmune disease, but with IgG anti-beta 2-GP-I, and (7) the observation that serum anti-phosphatidylethanolamine antibodies detected in some patients with APS require kininogen (alone or complexed with the kininogen-binding protein), prekallikrein and/or factor XI for in vitro reactivity. Thus, there are antibodies that may be considered true aPL; other "aPL' require a protein cofactor for their detection in vitro, at least in the case of beta 2-GP-I it would appear that their epitope is present on the protein proper not on the phospholipid, hence these are pseudo aPL, and a third group of related anti-cofactor autoantibodies that are directed to the protein in the absence of phospholipid. Clearly, the term "antiphospholipid syndrome' has become obsolete. We propose the term "Antiphospholipid/Cofactor Syndromes' to cull the various syndromes.
Lupus 1996 Oct
PMID:The concept and classification of antiphospholipid/cofactor syndromes. 890 61

The 'lupus anticoagulant' phenomenon is the best documented functional effect of antiphospholipid (aPL) antibodies, occurring either by inhibition of the prothrombinase and/or Factor X activation reactions. Understanding the mechanism by which aPL antibodies inhibit phospholipid dependent coagulation reactions may yield important clues about their 'thrombogenic effects' in vivo. We conducted a series of studies to determine the specificity, diversity, and mechanism by which aPL antibodies inhibit phospholipid dependent reactions. Results showed that purified immunoglobulins with lupus anticoagulant and anti-cardiolipin activities were absorbed by negatively charged phospholipids and both activities were recovered from the phospholipid-antibody precipitate. Purified aPL antibodies inhibited the prothrombinase reaction in a plasma free system in which beta 2-glycoprotein 1 (beta 2-GP1) was absent. Affinity purified aPL antibodies had 25-50 times the inhibitory activity of immunoglobulin preparations. The phospholipid binding proteins, beta 2-GPI and placental anticoagulant protein I (PAP I), independently inhibited the prothrombinase reaction, and when these proteins were combined with aPL, inhibition of the prothrombinase reaction was additive. Antibodies of syphilis had no inhibitory effect, partially accounted for by lack of specificity for phosphotidylserine (PS). Although aPL antibodies inhibited the protein C activation reaction, there was no correlation of these activities with inhibition of the prothrombinase reaction. Together, these results show that aPL exert their effects by interaction with negatively charged phospholipids, in particular phosphotidylserine, but lack of correlation between inhibition of the prothrombinase and protein C activation reactions, suggests that the nature of the coagulation protein is also important.
Lupus 1996 Oct
PMID:Functional effects of anticardiolipin antibodies. 890 63

The precise target of marker autoantibodies in the antiphospholipid syndrome (APS) has been controversial. Recently, the theory that surface-bound beta 2 glycoprotein I (beta 2 GPI) presents a normally encrypted autoepitope and that antibodies to beta 2 GPI (anti-beta 2 GPI) are associated with APS, has been prominent. The literature has been searched from 1990 to 1995 (inclusive) to find studies in which: (1) anti-beta 2 GPI antibodies were measured and, (2) adequate clinical data describing the patients were included. These conditions were met in four studies, from August 1992 to December 1995, in which patient samples ranged from 15 to 39 cases, the total of the four studies being 90 cases. Applying the diagnostic criteria of > or = 2 clinical manifestations of APS, 65 cases had APS while 25 did not. For the group with APS, 58/65 (89 percent) were anti-beta 2 GPI (+); among those who did not meet the criteria, 11/25 (44 percent) were anti-beta 2 GPI (+) (p < 0.0001). The presence of either the primary (1 degree) or secondary (2 degrees) form of APS made no difference in association with anti-beta 2 GPI; 13/16 (81 percent) patients with 1 degree APS and 45/49 (92 percent) with 2 degrees APS had anti-beta 2 GPI. The presence of lupus anticoagulant (LAC) did not predict APS: 25/58 (38 percent) APS (+) cases were LAC (+); 11 APS (-) were all LC (+) (p < 0.0001). IgG anticardiolipin also showed a closer association with APS absence (25/25 cases; 100 percent) than with APS presence (40/65; 62 percent, p < 0.0001). These data support the contention that anti-beta 2 GPI antibodies are closely associated with APS and that their measurement may facilitate the diagnosis.
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PMID:The association of antibodies to beta 2 glycoprotein I with the antiphospholipid syndrome: a meta-analysis. 899 56

Antiphospholipid antibody syndrome (APS) is one of the most important causes of thrombophilia, presenting most often as venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. Both the lupus anticoagulant and anticardiolipin antibody are associated with APS. The mechanism of the prothrombotic state is not understood, but may involve beta-2 glycoprotein 1 (a naturally occurring anticoagulant), platelet aggregation, the protein C pathway, or endothelial cell function. The current treatment recommendation, after a venous or arterial thrombosis, is high-intensity, long-term warfarin therapy.
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PMID:Pathogenesis and treatment of the antiphospholipid antibody syndrome. 901 59

"Antiphospholipid" antibodies (aPL) are a heterogenous group of autoantibodies with clinical importance because of their association with thrombotic events, both venous and arterial. Traditionally, aPL have been assayed using phospholipid-dependent tests and are classified as lupus anticoagulants and anticardiolipin antibodies (ACA), based on the method of detection. Most antibodies associated with the aPL syndrome and detected in standard assays are actually directed against two phospholipid-binding plasma proteins, beta 2 glycoprotein I and prothrombin. These antibodies can also be detected in immunoassays (ELISA) utilizing purified protein antigens, in the absence of phospholipids. The main advantage of beta 2 GPI-ELISA compared with conventional cardiolipin-ELISA appearing from initial clinical studies is greater specificity for the aPL syndrome, due to (i) ignorance of "authentic" ACA that interact directly with cardiolipin; (ii) detection of species specific anti-beta 2 GPI antibodies poorly reactive with bovine beta 2 GPI in the cardiolipin-ELISA. Other proteins proposed as target antigens of aPL are protein C, protein S, annexin V, high- and low-molecular weight kininogens, the latter being involved in the binding of antibodies to phosphatidylethanolamine. The possibility that particular autoantibodies (or combinations of autoantibodies) explain the observed clinical spectrum of the aPL syndrome is attractive, but much remains to be learned about their pathogenicity and origin in order to improve diagnosis and therapy.
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PMID:[New targets of antiphospholipid antibodies]. 916 56

We have studied target platelet antigens in 22 patients with lupus anticoagulants and a primary antiphospholipid syndrome in order to determine whether any specificities of platelet autoantibodies are correlated with thromboembolism, and if these antibodies cross-react with phospholipids, which would suggest their role in the development of thromboembolic disease. Platelet counts were median 203 x 10(9)/l, range 100-298 x 10(9)/l. Platelet antibodies were found in six thrombocytopenic patients and in further nine patients. All these 15 patients had antibodies against GPIIb/ IIIa, five patients against GPIb/IX, and six patients against GPIV. Anti-GPIb/IX and -GPIV occurred only in combination with anti-GPIIb/IIIa antibodies. There was no correlation between the presence of detectable platelet antibodies or any of their glycoprotein specificity and thrombocytopenia or the history of a thromboembolic disease. Eluates from platelets contained only GPIIb/IIIa reactivities, but neither anti-GPIb/IX nor anti-GPIV. None of the eluates contained lupus anticoagulant activity. In one case, the platelet eluates contained anti-GPIIb/IIIa and anticardiolipin IgG antibodies. These results suggest that in patients with a primary antiphospholipid syndrome the presence of platelet autoantibodies neither indicate a risk for thromboembolic disorder nor have lupus anticoagulant activity.
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PMID:Specificities of platelet autoantibodies in patients with lupus anticoagulants in primary antiphospholipid syndrome. 920 Sep 97


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