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)

Covalent attachment of activated complement C3 (C3d) to antigen links innate and adaptive immunity by targeting antigen to follicular dendritic cells (FDC) and B cells via specific receptors CD21 and CD35. Recent characterization of knockout mice deficient in complement components C3, C4, or the receptors CD21 and CD35 as well as biochemical studies of the CD21/CD19/Tapa-1 coreceptor on B cells have helped to elucidate the mechanism of complement regulation of both B-1 and B-2 lymphocytes. Interestingly, natural antibody of the adaptive immune system provides a major recognition role in activation of the complement system, which in turn enhances activation of antigen-specific B cells. Enhancement of the primary and secondary immune response to T-dependent antigens is mediated by coligation of the coreceptor and the B cell antigen receptor, which dramatically increases follicular retention and B cell survival within the germinal center. Most recent evidence suggests that complement also regulates elimination of self-reactive B cells, as breeding of mice that are deficient in C4 or CD21/CD35 with the lupus-prone strain of lpr mice demonstrates an exacerbation of disease due to an increase in autoantibodies.
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PMID:The role of complement and complement receptors in induction and regulation of immunity. 959 41

The role of complement in the maintenance of self-tolerance has been examined in two models: an immunoglobulin transgenic model of peripheral tolerance and a lupus-like murine model of CD95 (Fas) deficiency. We find that self-reactive B lymphocytes deficient in complement receptors CD21/CD35 or transferred into mice deficient in the complement protein C4 are not anergized by soluble self-antigen. In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease. These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus.
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PMID:A critical role for complement in maintenance of self-tolerance. 984 93

The density of CR1, the C3b/C4b receptor (CD35), on erythrocytes (E) (CR1/E) is genetically determined. However, the broad distribution of CR1/E within a given genotype suggests that other genetic elements might contribute to the regulation of CR1/E. In some pathological conditions, including systemic lupus erythematosus (SLE), AIDS and hemolytic anemia, CR1 deficiency parallels the severity of the disease. When compared to healthy individuals, an accelerated decrease in CR1/E in these patients has been demonstrated, but other mechanisms interfering with CR1 density regulation during erythropoiesis might also contribute. In exceptional circumstances, CR1/E can be dramatically decreased in healthy individuals by the effect of a regulatory gene, In(Lu), that switches off various surface molecules on E, the structure genes of which are located on four different chromosomes, suggesting a transcription regulatory role for In(Lu) gene products. The hypothesis that products of this gene could physiologically regulate the surface density of all these molecules has been tested by determining Lub density on E (Lub/E) using quantitative flow cytometry. Lub antigenic sites were then compared to CR1/E among healthy individuals of the different CR1 density phenotypes, SLE patients with and without CR1 deficiency, and an exceptional SLE patient totally lacking CR1/E and reticulocytes. No quantitative relationship was found between CR1 and Lub expression in either normal or pathological conditions. These data establish that In(Lu) products are not involved in normal or pathological CR1 density regulation.
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PMID:No quantitative relationship between CR1 and Lutheran expression on erythrocytes: In(Lu) gene product is not a common regulator of CR1 expression on erythrocytes. 1034 58

CR1 (CD35, the C3b/C4b receptor) is a widely distributed membrane glycoprotein with a unique cluster conformation on the surface of erythrocytes (E). CR1 on E is responsible for the transport of immune complexes (IC) to liver and spleen. As a cofactor of the C3b cleavage by factor I, CR1 is also a potent inhibitor of C activation and inflammation. In some diseases (systemic lupus erythematosus, hemolytic anemia, AIDS, etc.) an acquired low level of CR1 on E has been observed, leading to an impaired clearance of IC. The aim of this study was to design a heterofunctional molecule that will bind to E and restore a normal or a supranormal CR1 density on E that could mimic the unique distribution pattern of CR1 on normal E. For that purpose a new multimerizing system based on the properties of the C-terminal part of the alpha-chain of the C4 binding protein (C4bp) was used. We first produced a multimeric soluble CR1 that proved to be a better inhibitor of in vitro C activation than the monomeric form of CR1, then a heteromultimeric molecule made of CR1 and single-chain Fv anti-Rh(D) valences able to attach E and providing E with as much as a 10-fold increase in CR1 density with the same CR1 distribution pattern as native E. CR1/single-chain Fv anti-Rh(D)-treated E were able in vitro to attach as many opsonized IC as native E. These data open the way for future use of multimeric and heteromultimeric forms of soluble recombinant CR1 as therapy of IC diseases.
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PMID:A soluble recombinant multimeric anti-Rh(D) single-chain Fv/CR1 molecule restores the immune complex binding ability of CR1-deficient erythrocytes. 1064 Jul 68

This report is devoted to methodologies used in analyzing the C3b/C4b receptor (CR1, CD35) on erythrocytes (E), its soluble form, the CRI structural or allotype polymorphism, and CR1 density polymorphism. In primates E CR1 serves as the main system for processing and clearance of complement opsonized immune complexes (IC). CR1 copy numbers decrease with aging of E in normal individuals. Erythrocyte CR1 is also decreased in pathological conditions such as systemic lupus erythematosus (SLE), HIV infection, certain hemolytic anemias, and many other conditions featuring immune complexes. Consequently, CRI on E has an important physiological role in immune complex handling and has interesting alterations in disease.
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PMID:The C3b/C4b receptor (CR1, CD35) on erythrocytes: methods for study of the polymorphisms. 1069 35

The major murine systemic lupus erythematosus (SLE) susceptibility locus, Sle1, corresponds to three loci independently affecting loss of tolerance to chromatin in the NZM2410 mouse. The congenic interval corresponding to Sle1c contains Cr2, which encodes complement receptors 1 and 2 (CR1/CR2, CD35/CD21). NZM2410/NZW Cr2 exhibits a single nucleotide polymorphism that introduces a novel glycosylation site, resulting in higher molecular weight proteins. This polymorphism, located in the C3d binding domain, reduces ligand binding and receptor-mediated cell signaling. Molecular modeling based on the recently solved CR2 structure in complex with C3d reveals that this glycosylation interferes with receptor dimerization. These data demonstrate a functionally significant phenotype for the NZM2410 Cr2 allele and strongly support its role as a lupus susceptibility gene.
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PMID:Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein. 1172 39

Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis or dermatitis and the presence of antinuclear autoantibodies is associated with deficiencies of complement factors of the classical activation pathway. Results accumulated over the past few years with the use of complement gene deficient mice made it possible to update the conventional hypothesis for this association in regard to the etiology of the disease, whereby the early events leading to induction of autoimmunity can be explained by various functions of complement. As a conclusion, a new model for the etiology of the SLE based on the reduced elimination of apoptotic cells, the increased uptake of IgM containing immune complexes into the spleen and the CD21/CD35 dependent B cell toleration in the periphery demonstrates the importance of complement in the prevention of autoimmunity whereas the inflammatory reactions occurring in later stages of the disease are relatively independent from complement. The results obtained with complement deficient mice contribute to a better understanding of tolerance-inducing mechanisms and offers the option to develop new therapeutic procedures for autoimmune diseases.
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PMID:The association between systemic lupus erythematosus and deficiencies of the complement system. 1203 Apr 27

The acquired loss of CR1 (CD35) on erythrocytes in specific autoimmune diseases and chronic infections may be due to autoAb against CR1. An ELISA using rCR1 was established to measure antiCR1 IgG autoAb. Plasma containing alloAb to polymorphism on CR1 (Knops blood group Ab) reacted strongly against rCR1 and were used as positive controls. AntiCR1 Ab was found in 3/90 (3.5%) plasma samples from healthy blood donors. The binding of these Ab was not inhibited by high salt concentrations. AntiCR1 Ab were present in the IgG fractions of plasma, and they bound to rCR1 on Western Blot. Affinity chromatography on rCR1-sepharose depleted the plasma of antiCR1, and the acid-eluted fractions contained the antiCR1 Ab. An increased frequency of antiCR1 autoAb was found in patients with SLE (36/78; 46%), liver cirrhosis (15/41; 36%), HIV infection (23/76; 30%) (all P < 0.0001), and in patients with anticardiolipin Ab (4/21; 19%, P < 0.01) multiple sclerosis (7/50; 14%, P < 0.02), and myeloma (autoAb (8/56; 14%, P < 0.02), but not in those with acute poststreptococcal glomerulonephritis (1:32; 3%). Because C1q binds to CR1, antiC1q Ab were analysed in the same patients. There was no correlation between levels of antiC1q and antiCR1 autoAb. In HIV patients, levels of antiCR1 did not correlate with low CR1 levels expressed on erythrocytes or soluble CR1 in plasma. The binding of antiCR1 autoAb to rCR1 fixed on ELISA plates was not inhibited by soluble rCR1 or by human erythrocyte CR1, in contrast to alloAb and one SLE serum, which induced partial blockade. Thus, antiCR1 autoAb recognize mostly CR1 epitope(s) not present on the native molecule, suggesting that they are not directly involved in the loss of CR1. Rather antiCR1 autoAb might indicate a specific immune response to denatured CR1.
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PMID:Autoantibodies against complement receptor 1 (CD35) in SLE, liver cirrhosis and HIV-infected patients. 1251 2

The role of complement in the development and regulation of antibody responses under both healthy and pathological conditions is known for long. Unraveling the elements involved and the molecular mechanisms underlying the events however is still in progress. This review focuses on the role of complement receptors CR1 (CD35) and CR2 (CD21) expressed on B lymphocytes, which interact with ligands generated upon activation of component C3, the major protein of the complement cascade. The binding and possible effects of immune complexes comprising antigen, antibody and complement on B-cell activation are discussed. Results of clinical studies of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis and conclusions drawn from animal models used to investigate various aspects of human diseases are also debated. We discuss similarities regarding the overall structure and certain functions of complement and complement receptors in mice and men however, call the attention to major differences regarding tissue distribution and their role in B-cell functions.
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PMID:Regulation of B-cell activation by complement receptors CD21 and CD35. 1287 Nov 89

Complement receptor 1 (CR1, CD35, C3b/C4b receptor), a polymorphic membrane bound glycoprotein is important both as a complement regulatory protein, and as a vehicle for immune complex clearance. It is differentially expressed on erythrocytes, eosinophils, monocytes, B and T-lymphocytes, dendritic cells and kidney podocytes. It also occurs in the plasma as soluble CR1 (sCR1) and in urine as urinary CR1 (uCR1). Different population studies have either suggested or refuted the functional and physiological significance of genomic (HH, high erythrocyte CR1 expression; HL, intermediate and LL, low expression) polymorphism of CR1 in health and disease. Prevalence of autoimmune disorders like RA, GN and SLE is higher in Asian-Indians compared to the western world. Although several studies from India emphasize the modulation of E-CR1 levels as a key factor in the pathophysiology of glomerulonephritis (GN), none of them, however, provide much information on the role of CR1 gene variance in this context. We, therefore, carried out the study of CR1 polymorphism in 117 normal Indian subjects and 65 patients suffering from glomerulonephritis in order to study its possible association with the disease and E-CR1 levels. This is the first study of its kind in the Indian population, in which, the direct effect of a particular genotype on the E-CR1 levels and its possible association with the disease has been studied simultaneously.
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PMID:Association of complement receptor 1 (CR1, CD35, C3b/C4b receptor) density polymorphism with glomerulonephritis in Indian subjects. 1507 51


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