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 characteristic finding of high levels of circulating immune complexes in patients with the autoimmune connective tissue diseases systemic lupus erythematosus (SLE) or scleroderma has raised the possibility that these patients may have a primary defect in immune complex clearance. The Fc receptor for IgG (Fc gamma R) plays a central role in the phagocytosis of antibody complexes. We have analysed Fc gamma R (type II) RFLPs identified in TaqI- and MspI-restricted genomic DNA and found that their distribution in SLE and scleroderma did not differ significantly from controls. Hybridization with specific regions of the Fc gamma RII cDNA clone indicate that part of the Fc gamma RII alpha locus is duplicated in some individuals. A further Fc gamma RII gene has recently been identified (Fc gamma RII alpha'). This gene shows greater than 95% homology with Fc gamma RII alpha and may thus be the candidate gene for the apparent alpha duplication seen in some individuals. It is possible that an individual may possess one, two, three or four TaqI Fc gamma RII alpha/alpha' alleles, correlating with incidence and numerical heterogeneity in Fc gamma RII alpha and alpha'. The physiological effects of this numerical heterogeneity remain to be investigated.
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PMID:Fc gamma RII restriction fragment length polymorphism (RFLP): analysis in systemic lupus erythematosus and scleroderma and evidence of an alpha gene duplication. 167 Oct 5

By flow cytometry analysis we could show a decreased expression of Fc gamma receptor type III (Fc gamma RIII) on granulocytes of a patient with systemic lupus erythematosus (SLE). Therefore, we constructed a leukocyte cDNA library from this patient with the aim of investigating this defect on the molecular level. Using an Fc gamma RIII cDNA probe we isolated 15 Fc gamma RIII cDNA clones, which were all characterized by sequencing. Our sequence data revealed that the patient was heterozygous for Fc gamma RIII (NA-1/NA-2). Only clone 5 (NA-2) was a full-length cDNA clone. In contrast to the wild-type Fc gamma RIII the signal sequence is mutated, lacking the hydrophobic region essential for co-translational transport across the endoplasmic reticulum membrane. The predicted transport defect leading to the lack of membrane expression could be confirmed by immunofluorescence staining after expression of this cDNA clone in BHK cells. The cDNA clones 6 and 8 (NA-1) lack the first 45 bp of the signal sequence, but considering the flow cytometry data the signal sequence must be functional allowing the membrane expression of this receptor allele. The part of the cDNA sequence of all isolated clones coding the mature Fc gamma RIII is identical to the wild-type sequence. Therefore, we conclude that the decreased expression of Fc gamma RIII on granulocytes of this SLE patient is due to the transport defect of one of the receptor alleles.
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PMID:Molecular basis of IgG Fc receptor III defect in a patient with systemic lupus erythematosus. 182 62

The receptor for the Fc portion of IgG (Fc gamma R) is involved in the slow clearance of immune complexes. To perform this role it must be cross-linked by IgG bound in its extracellular domains. It has been suggested that defective Fc gamma R-mediated clearance of immune complexes may play a role in the pathogenesis of autoimmune connective tissue disorders. We have sequenced DNA encoding the second extracellular domain of Fc gamma RII alpha in six patients with SLE, to investigate whether point mutations may be responsible for encoding a defect in the IgG binding capacity of the receptor. We were able to identify the point mutation which discriminates high and low responder genotypes but found no other change from the published DNA sequence for this region.
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PMID:Fc gamma RII alpha: sequencing of the ligand binding domain in systemic lupus erythematosus patients. 183 76

We demonstrate, using a recombinant truncated Fc gamma RII molecule as a probe, the presence of anti-Fc gamma R antibodies in several strains of autoimmune mice. Affinity chromatography on a truncated Fc gamma R column of pooled sera from aged NZB females resulted in isolation of 16 micrograms of IgM per ml of serum, approximately 2% of the total IgM; no anti-Fc gamma R IgM was found in sera from C58/J mice. Mice with high titers of anti-Fc gamma R IgM also had anti-Fc gamma R IgG. Affinity-purified anti-Fc gamma R IgG bound to Fc gamma R-bearing cells. A good correlation was found between the presence of anti-Fc gamma R Ig and impaired phagocytosis of immune complexes in autoimmune strains such as NZB or NZB/NZW F1. Sera with high titers of anti-Fc gamma R Ig from NZB and motheaten mice inhibited the binding of soluble immune complexes. Furthermore, BXSB, a lupus-prone mouse strain that does not produce anti-Fc gamma R Ig, shows normal macrophage binding and phagocytosis of immune complexes. A set of four IgM mAbs that bind to Fc gamma R was identified. These antibodies were polyspecific; some were directed against DNA, and others recognized a wide variety of antigens including histones, thyroglobulin, and transferrin, but all anti-Fc gamma R IgM antibodies effectively inhibited the binding of IgG1 anti-DNP/DNP20BSA complexes to J774 macrophages. The role of anti-Fc gamma R Ig in autoimmunity remains to be established. It may act to crosslink and activate Fc gamma Rs on neutrophils, macrophages, NK, and mesangial cells, or it may desensitize Fc gamma R function of Fc gamma R-bearing cells.
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PMID:Autoimmune mice make anti-Fc gamma receptor antibodies. 213 98

The benefit of high-dose, pulse intravenous methylprednisolone (IVMP) for some patients with active lupus nephritis would appear paradoxical, since active nephritis is associated with profound abnormalities in Fc gamma receptor function, and several studies have demonstrated that glucocorticoids decrease monocyte Fc gamma receptor expression and phagocytic function. To resolve this paradox, we investigated the possibility that pulse IVMP might enhance monocyte Fc gamma receptor function in patients with systemic lupus erythematosus (SLE). Circulating immune complex (CIC) levels, Fc gamma receptor-mediated clearance, and Fc gamma receptor-dependent monocyte function were analyzed in 23 SLE patients before and after pulse IVMP (1 gm daily for 3 days). A biphasic response in CIC levels, determined by a staphylococcal protein A binding assay, was observed. Initially, CIC levels increased within 2-4 hours after the first dose of pulse IVMP and then decreased by 50% within 24-48 hours after the completion of therapy. Fc gamma receptor-mediated binding and phagocytosis of IgG-sensitized erythrocytes (EA) by monocytes in vitro were significantly enhanced 24 hours after the final dose of pulse IVMP (pre-IVMP versus post-IVMP 43 +/- 14% versus 53 +/- 12% EA rosettes, P less than 0.01; 3.00 +/- 1.04 versus 3.99 +/- 1.30 EA ingested/monocyte, P less than 0.01). In contrast, there was no change in the phagocytosis of an Fc gamma receptor-independent probe, neuraminidase-treated erythrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High-dose, pulse intravenous methylprednisolone enhances Fc gamma receptor-mediated mononuclear phagocyte function in systemic lupus erythematosus. 252 82

Abnormalities in host mechanisms for the handling of immune complexes (IC) may promote both tissue deposition of pathogenic complexes and interaction of complexes with other immunocompetent cells. Although immune adherence of complexes to erythrocytes may be decreased in patients with autoimmune disease, the significance of this decrease for overall immune complex handling is unclear since many IC release rapidly from the erythrocytes. Little is known about the role of complement receptors in IC uptake by phagocytes. In contrast, the observations of defective Fc gamma receptor-mediated uptake of IgG ligand-coated erythrocytes (one model for erythrocyte-bound complexes) by fixed tissue macrophages in SLE patients demonstrate the role of Fc gamma receptors in the uptake of these complexes. Although partly acquired and related to disease activity in SLE, the Fc-mediated clearance defect may also have a genetic component. Inherited differences in Fc gamma function may reflect structural polymorphisms of the involved Fc receptors. The emerging picture of Fc gamma receptor structural diversity - several different receptor families (Fc gamma RI, Fc gamma RII and Fc gamma RIII) each with different isoforms, the potential for different glycoforms and cell anchoring mechanisms, and allelic variations within the isoforms - provides the basis for structure/function relationships which have clear implications for autoimmune diseases with abnormal Fc receptor function.
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PMID:The role of Fc gamma receptors in mononuclear phagocyte system function. 253 76

Human receptors for IgG (Fc gamma R) play important roles in the immune response. Expression of the human Fc gamma RII gene may be relevant in immune complex related disorders such as systemic lupus erythematosus and Sjogren's syndrome. We have used spot blot analysis of dual laser-sorted human chromosomes to localize the Fc gamma RII gene to human chromosome 1. Spot blot analysis of sorted derivative chromosomes sublocalized the gene to the chromosome 1 long arm (1q12----q25.1). This subchromosomal localization involved reassigning a reciprocal chromosome translocation breakpoint. We also identified Xmn I and Taq I Fc gamma RII polymorphic restriction sites that arose before the races diverged. These common Xmn I and Taq I polymorphisms are predicted to be informative for segregation analysis with human diseases in 85% of all matings.
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PMID:The polymorphic Fc gamma receptor II gene maps to human chromosome 1q. 256 86

Fc gamma receptor-dependent mononuclear phagocyte system (MPS) clearance of opsonized erythrocytes is prolonged in healthy adults with the class II alloantigens HLA-DR2, DR3, or DQw1, despite normal receptor-specific Fc ligand binding by monocytes in these groups. To investigate the basis for the MPS dysfunction, we determined the phagocytic capacity of blood monocytes from 66 disease-free adults and analyzed the data according to the HLA type of the subjects. The data demonstrate decreased phagocytosis of IgG-sensitized erythrocytes (EA) by monocytes from HLA-DR2, DR3, or DQw1-positive subjects compared with normals without these B cell alloantigens (2.87 +/- 0.83 erythrocytes/monocyte vs 3.87 +/- 1.05, p less than 0.004; 3.01 +/- 0.94 vs 3.87 +/- 1.05, p less than 0.02; 3.18 +/- 0.89 vs 3.87 +/- 1.05, p less than 0.02, respectively). Because HLA-DR2 and DQw1 are in linkage disequilibrium, we compared EA phagocytosis in subjects with DQw1 alone to normals without HLA-DR2, DR3, or DQw1. Among subjects positive only for DQw1, no significant decrease in phagocytosis could be seen (3.46 +/- 0.95 vs 3.87 +/- 1.05, p = NS). To determine whether these differences represented an Fc receptor-specific dysfunction or a more generalized decrease in phagocytic activity, we compared the quantitative phagocytosis of EA with that of neuraminidase-treated erythrocytes (EN), which is Fc receptor independent and beta-glucan receptor mediated. No segregation of phagocytic capacity for EN by HLA class II phenotypes could be demonstrated (DR2, 2.68 +/- 1.30 erythrocytes/monocyte; DR3, 2.95 +/- 1.30; DQw1, 2.84 +/- 1.15; others, 3.06 +/- 1.14). Our data indicate that the decrease in phagocytosis by blood monocytes from normal individuals with HLA-DR2 or DR3, the class II alloantigens associated with systemic lupus erythematosus and other autoimmune diseases, is specific for the Fc receptor-mediated process. This alteration of Fc receptor function among immunogenetically defined individuals may contribute to their predisposition to autoimmune disease. These differences may also apply to other Fc receptor-initiated cellular functions.
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PMID:Altered phagocytosis by monocytes from HLA-DR2 and DR3-positive healthy adults is Fc gamma receptor specific. 300 7

The binding of 125I-labelled anti-bovine serum albumin (BSA)-BSA immune complexes (IC), giving a final molar antibody to antigen ratio of 1:1, to monocytes isolated from 18 patients with systemic lupus erythematosus (SLE) and from 10 normal healthy donors was quantitatively investigated. The degradation of the bound IC by the same monocytes was kinetically determined at the same time. The assays were performed on monocyte monolayers. Scatchard plots at 4 degrees C demonstrated that monocytes from patients with active SLE expressed a mean Fc gamma receptor (FcR) number that was 22% higher than that of the controls, although this did not reach statistical significance. The FcR number of normal monocytes and the degradation rate of anti-BSA-BSA complexes by the same cells showed a positive correlation. At the same time, the digestion of anti-BSA-BSA complexes by monocytes of SLE patients with active disease was prolonged, despite their enhanced FcR-ligand binding. The dissociation of FcR-ligand binding and FcR-mediated degradation suggests that the IC degradation is controlled by altered biochemical mechanisms in the monocytes of SLE patients.
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PMID:Defective immune complex degradation by monocytes in patients with systemic lupus erythematosus. 378 86

We asked whether binding of human immunoglobulin (Ig)G antibody reacting with Raji cells could be distinguished from binding of IgG immune complexes. Using a standard Raji assay employing 125I-IgG goat anti-human Fc gamma, we found that digestion of Raji cells with pronase reduced by 95% their ability to bind complement-fixed aggregated human gamma globulin and complement-fixed tetanus toxoid-antitetanus toxin complexes. However, binding at 37 degrees C of IgG from the sera of 16 patients with systemic lupus erythematosus (SLE) to pronase-digested Raji cells was reduced much less consistently and extensively (9-100% reduction; mean reduction of 51%). In more detailed studies of two SLE sera, sucrose density gradient centrifugation showed that greater than 50% of the IgG binding to undigested Raji cells sedimented in the 7S region. Pepsin digestion of immunoglobulin fractions from four SLE sera caused a reduction in SLE IgG binding to undigested Raji cells when detected with 125I anti-Fc gamma, but an increase when binding was detected with 125I-anti-Fab, suggesting that substantial SLE IgG can bind through F(ab')2 regions. Binding of IgG from SLE sera was not directed at neoantigenic sites induced by pronase digestion because binding activity was adsorbed with undigested cells as readily as with digested cells. Moreover, sera from 10 SLE patients that had negative Raji assays contained no IgG that bound to pronase-digested Raji cells. We conclude that much of the IgG bound at 37 degrees C to Raji cells from the sera of many patients with SLE does not represent immune complexes but is probably antibody directed toward sites on the Raji cell.
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PMID:Raji cell assay for immune complexes. Evidence for detection of Raji-directed immunoglobulin G antibody in sera from patients with systemic lupus erythematosus. 699 84


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