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)

The contribution of genetic factors in the reduction in erythrocyte CR1 levels observed in hydralazine (Hz) induced systemic lupus erythematosus (SLE) was investigated by determining the frequency of a HindIII restriction fragment length polymorphism (RFLP) in the CR1 gene. This RFLP is associated with quantitative erythrocyte CR1 expression. Individuals who have developed SLE as a reaction to Hz therapy, consanguinous relatives of the Hz-SLE patients, controls who had been treated with Hz without any adverse reaction, and the consanguinous relatives of these controls were included in this study. No difference was found in the frequency of occurrence of the alleles associated with CR1 expression between the Hz-SLE patients and the control groups (P greater than 0.2). Individuals from the Hz-SLE group who were homozygous for the 7.4 kb 'high expressor' allele had lower mean levels of erythrocytes CR1 (564 +/- 65) than the corresponding homozygous subgroups within the Hz-SLE relative group (774 +/- 46), the Hz control group (756 +/- 80) and the Hz control relatives group (825 +/- 66). In addition, 50% of the Hz-SLE patients in the 'high expressor' subgroup who had less than 500 CR1 per erythrocyte had elevated levels of circulating immune complexes. This study suggests that individuals who are genetically low expressors of erythrocyte CR1 are not predisposed to developing SLE in response to Hz therapy, and that in a subgroup of genetically 'high expressors', low CR1 levels are associated with elevated levels of circulatory immune complexes.
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PMID:CR1 polymorphism in hydralazine-induced systemic lupus erythematosus: DNA restriction fragment length polymorphism. 257 71

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which affected erythrocytes (E) are abnormally sensitive to lysis by autologous complement. Affected E from patients with PNH (PNH-E) are deficient in an E membrane regulatory protein of complement, decay-accelerating factor (DAF). Because a functional defect in a second membrane regulatory protein of complement, CR1 (C3b receptor), has also been hypothesized, severely affected PNH-E (type III PNH-E) were tested for abnormalities in CR1 by four methods. E from two patients with 100% type III PNH-E had 3201 and 6783 sites per cell for binding of 125I-labeled rabbit polyclonal F(ab')2 anti-CR1. These values fall within the normal range of CR1 antigenic sites per cell (1267 to 7915, mean = 5,014 +/- 155 SEM) established by assaying the E from 113 healthy donors. The Ka of CR1 on type III PNH-E for 125I-labeled C3b dimer was 2.06 X 10(7) M-1, and the Ka values for the binding of the same ligand to the E from two healthy individuals were 2.45 X 10(7) M-1 and 1.58 X 10(7) M-1. In an assay designed to measure the capacity of human E (Eh) to accelerate the decay of the classical C3 convertase deposited on 1 X 10(7) bystander sheep E (EAC1gp,4bh,2agp), the half-life (t 1/2) of this convertase was diminished from 18.1 min (range 15.2 to 22.9) to 8.1 min (range 7.4 to 8.5) by the addition of 1 X 10(7) normal Eh, to 6.2 min by 100% type III PNH-E, and to 7.5 min by Eh pretreated with an IgG fraction of human antiserum directed against the D antigen of the Rh system. In contrast, Eh (t 1/2 = 7.4) pretreated with a saturating dose of F(ab')2 anti-CR1, and CR1-deficient Eh (less than 10 CR1 molecules/E) from a patient with systemic lupus erythematosus, showed a loss of convertase decay-accelerating capacity to t 1/2 = 11.6 and t 1/2 = 12.4, respectively. Type III PNH-E pretreated with anti-CR1 demonstrated a total loss of their decay-accelerating capacity (t 1/2 = 19.9). In an assay of I cofactor activity, soluble C3b was rapidly converted to iC3b by purified I plus Eh or type III PNH-E, whereas CR1-deficient Eh exhibited less than 5% the I cofactor activity of normal Eh.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Normal function of CR1 on affected erythrocytes of patients with paroxysmal nocturnal hemoglobinuria. 257 50

We isolated the IgM fraction from the plasma of an SLE patient with high titer anti-dsDNA antibodies and prepared soluble IgM/dsDNA immune complexes (IC) that fixed C and captured sufficient C3b to bind to human E via their C3b/C4b receptor, CR1 (immune adherence, IA). We used specific 125I-labeled mAb to IgM, C3b, and IgG to measure the stoichiometries of these C-opsonized IC. They contained 10 to 60 C3b and 10 to 30 IgM per PM2 dsDNA, had no detectable IgG, and the vast majority of the C3b was bound to the IgM, and not to the dsDNA. These stoichiometries are in contrast to those we observed for comparable E-bound IC prepared with IgG anti-dsDNA antibodies (100 to 200 C3b, and 200 to 500 IgG). Our results help explain the greater lability of the IgM IC with respect to IA as evidenced by their plasma-mediated release from human E (presumably due to factor I), and confirm previous predictions of a lower density of "packing" of IgM on dsDNA, compared to IgG. The detailed stoichiometry of C3b capture by the IgM IC (typically 1.5 to 3 C3b per IgM) suggests that individual IgM molecules with multiple C3b facilitate IC binding to clusters of CR1. Finally, comparison of the IgM/dsDNA IC with other IgM IC which have been investigated with respect to C activation, and review of the proposed mechanism by which IgM activates C, suggests that the nature of the Ag plays a fundamental role in determining whether or not an IgM IC can activate C and participate in IA.
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PMID:Quantitative analyses of C3b capture and immune adherence of IgM antibody/dsDNA immune complexes. 258 11

Decreased binding capacity of the erythrocyte complement receptor (RBC CR1) in systemic lupus erythematosus (SLE) may contribute to abnormal handling of circulating immune complexes in these patients. Decreased numbers of RBC CR1 have been reported in SLE, but, since binding is a function of both receptor number and receptor binding kinetics, we measured kinetic parameters for the interaction of complement (C) containing [3H]DNA:anti-DNA immune complexes (IC) with normal control (NC) and SLE RBC. Experiments were performed at five temperatures ranging from 7-37 degrees C. The parameters measured included: (1) the maximum quantity of DNA:anti-DNA:C which could bind per RBC, S; (2) the association rate constant, ka, for the binding of DNA:anti-DNA:C to RBC; (3) the dissociation rate constant, kd, for the dissociation of bound DNA:anti-DNA:C IC from RBC; (4) the steady-state constant, Kss (ka/kd); and (5) the energies of activation for association, Eaa, and dissociation, Ead. Although the relative amount of bound DNA:anti-DNA:C per RBC was significantly decreased in SLE patients compared to NC (P less than 0.001), the mean values for Kss, ka, kd, Eaa and Ead did not differ significantly between the two groups. These data suggest the following: (1) RBC CR1 binding and dissociation of DNA:anti-DNA:C are consecutive reactions resulting in steady-state concentrations of free and RBC-bound IC; (2) at steady-state times, the ratio of RBC bound to unbound DNA:anti-DNA:C are governed by kinetic factors; (3) since the binding kinetics of SLE and NC RBC are not significantly different, the decreased binding activity described by other investigators can only be due to a decreased number of CR1 per RBC; and (4) values for Eaa and Ead suggest that the rate-determining steps in IC association with and dissociation from RBC involves making and breaking of hydrogen bonds.
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PMID:A kinetic study of erythrocyte-DNA/anti-DNA immune complex association and dissociation reactions in systemic lupus erythematosus. 278 31

The role of genetic factors in controlling CR1 quantitative expression on erythrocytes (E) of patients with systemic lupus erythematosus (SLE) was reexamined by determining the temporal stability of CR1 numbers and the frequency of a CR1 genomic restriction fragment length polymorphism (RFLP). The mean number of binding sites/(E) for Yz-1 monoclonal anti-CR1 correlated with the number of sites for polyclonal anti-CR1 that had been determined 2 to 4 yr previously in 18 normal persons (p less than 0.001), 18 patients (p less than 0.001), and 28 relatives (p less than 0.001), indicating that CR1 sites/E was a stable characteristic in all three groups. The mean number of Yz-1 sites/E was 281 +/- 34 (+/- SEM) in 28 probands with SLE and 457 +/- 21 in 93 relatives, both determinations being less than that for 100 normal persons, 553 +/- 21 (p less than 0.002). Thirty-six patients and 51 normal individuals were also assessed for the presence of the 7.4 kb and 6.9 kb HindIII CR1 allelic restriction fragments that correlate with high and low expression, respectively, of CR1 on E. The distribution of patients differed from normal (p less than 0.05), with a smaller proportion being homozygous for the 7.4 kb allele. In addition, the mean numbers of Yz-1 sites/E for patients and relatives who were homozygous (p less than 0.02) and heterozygous (p less than 0.05) for the 7.4 kb allele were significantly lower than those for normal persons matched for the HindIII RFLP, suggesting the existence of additional heritable factors that decrease CR1 expression. The stability over time of the CR1 deficiency among patients, the finding of decreased CR1 number among an expanded group of relatives, the altered frequency among patients of CR1 alleles defined by the HindIII RFLP, and the decreased expression of CR1 on E among patients and relatives compared with normal individuals having the same HindIII RFLP indicate a role for genetic factors in CR1 deficiency in SLE.
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PMID:Deficiency of the C3b/C4b receptor (CR1) of erythrocytes in systemic lupus erythematosus: analysis of the stability of the defect and of a restriction fragment length polymorphism of the CR1 gene. 288 67

The stability of CR1 (complement receptor type 1) on ageing erythrocytes in vivo was examined in a group of normal subjects who had been genotyped using a restriction fragment length polymorphism (detected using a cDNA probe for CR1) that correlates with the numerical expression of CR1 on normal erythrocytes (H = allele correlating with high expression, L = low). Erythrocytes were separated into 5 fractions of increasing age on discontinuous Percoll gradients. Mean CR1 numbers on erythrocytes fell from 636 molecules per cell in the first fraction to 384 in the fifth in the HH group and from 478 to 315 in the LL group. There was no difference in the rate of decline of CR1 numbers between the groups. A group of nine SLE patients was also studied in the same way; their genotypes were HH (four) and HL (five). Mean CR1 numbers amongst all of these patients fell from 477 to 232, a faster rate of decline than in a genotypically matched group of normal subjects. There was no difference in the prevalence of the different structural allotypes amongst 30 SLE patients compared with 21 normal subjects. These data provide further evidence that there are enhanced extracellular mechanisms for the removal of CR1 from erythrocytes of SLE patients and do not support the hypothesis that inherited variation in CR1 expression on erythrocytes increases disease susceptibility to SLE.
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PMID:The rate of loss of CR1 from ageing erythrocytes in vivo in normal subjects and SLE patients: no correlation with structural or numerical polymorphisms. 289 64

C3-bearing immune complexes and C3 activation products were detected by using two monoclonal antibodies, one specific for a neoantigenic determinant on C3c and the other for C3d. To quantitate immune complexes, the anti-C3c or anti-C3d antibodies were fixed to microtiter plates and reacted with test plasma. The binding of C3-bearing immune complexes in this plasma was then measured with radioisotope- or enzyme-labeled anti-human IgG. To test for C3 breakdown products, solid-phase monoclonal antibody to the C3d neoantigen was reacted with EDTA-plasma samples, and fixed iC3b or C3d was measured with a polyclonal anti-C3 antibody. Patients with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome, and paracoccidioidomycosis were found to contain immune complexes bearing C3b/iC3b or C3d. In most conditions, there were more C3d-containing immune complexes than C3b/iC3b. Although CR1 (C3b receptors) rapidly converted immune complex-bound iC3b to C3dg/C3d and lupus patients had reduced CR1, no correlation between the state of C3 on circulating immune complexes or levels of immune complexes and CR1 numbers was seen. However, levels of C3-fixing ICs correlated with levels of C3 activation products. This assay system with monoclonal antibodies to neoantigens expressed on activated, but not native, C3 provides sensitive and specific means for detecting and classifying C3-fixing immune complexes and for assessing C3 activation.
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PMID:Monoclonal antibodies against complement 3 neoantigens for detection of immune complexes and complement activation. Relationship between immune complex levels, state of C3, and numbers of receptors for C3b. 293 66

Using an enzyme-linked immunoadsorbent assay, IgG in the plasma and purified IgG from 2 patients with systemic lupus erythematosus (SLE) were found to strongly react with purified C3b receptor (CR1) insolubilized on microtiter plates. The amount of IgG that bound to CR1 in 201 plasma samples from 179 other patients with SLE did not significantly differ from that which bound in 72 control samples from normal individuals. Purified IgG from the patients with anti-CR1 reactivity did not inhibit CR1 function in vitro. The number of CR1 antigenic sites expressed on erythrocytes from both patients was much lower than that observed in a normal population and in the lowest range of the decreased numbers found in patients with SLE. The occurrence of anti-CR1 antibodies in patients with SLE could provide an acquired mechanism for decreased expression of CR1 through antigenic modulation of the receptor on precursor cells and/or alter the function of cells of the immune system bearing C3b receptors.
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PMID:Anti-C3b-receptor (CR1) antibodies in patients with systemic lupus erythematosus. 293 95

The reactivity of glomerular C3b receptors (CR1) measured by the number of sheep erythrocytes bearing C3b (EAC) that adhered to glomeruli in frozen sections, was compared with the reactivity of erythrocyte CR1, which was determined by immune adherence hemagglutination (IAHA), in 22 patients with renal and non-renal diseases. Among seven patients with primary glomerulonephritis whose erythrocytes were positive for IAHA, the reactivity of glomerular CR1 was high in five. In the remaining two, the reactivity of glomerular CR1 was low, accompanied by severe sclerotic glomerular changes. Erythrocytes from five of six patients with systemic lupus erythematosus were IAHA negative, and their glomeruli failed to produce adherence of EAC, even in three cases in which there were no detectable C3 deposits or histopathological changes. In the other nine patients without appreciable glomerular changes, the reactivity of glomerular CR1 was low in three along with negative erythrocyte IAHA, whereas the remaining six exhibited high CR1 reactivity both in glomeruli and on erythrocytes. The results indicate a close correlation between the expression of CR1 in the glomerulus and on erythrocytes.
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PMID:Correlative expression of C3b receptors in the glomerulus and on erythrocytes. 293 97

Erythrocytes from 30 patients suffering from systemic lupus erythematosus (SLE) were tested for CR1 activity by an immune adherence haemagglutination technique. Defective CR1 activity (CR1D) was found in 11 (37%) of the patients on initial testing. On repeat testings, however, CR1 activity often varied from time to time and was shown to be inversely related to serum anti-DNA binding and apparent complement activation in vivo. Two of the 19 patients with normal CR1 activity acquired CR1D during the study. One patient with previously defective CR1 attained normal activity in the course of the study. The increased occurrence of CR1D in patients with SLE is largely or wholly acquired rather than genetically determined.
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PMID:CR1 deficiency in SLE: acquired or genetic? 293 36


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