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)

It has previously been reported that the expression of the complement receptors, CR1 on erythrocytes and blood leucocytes and CR2 on B cells, is reduced in patients with SLE, and that the reduced expression of CR1 on erythrocytes is related to disease activity. We have earlier demonstrated that normal B cells are capable of activating the alternative pathway (AP) of complement in a CR2-dependent fashion. In this study we have investigated whether disturbances in this activity may be related to the altered phenotype of SLE B cells. Flow cytometry was used to measure expression of complement receptors and regulatory proteins on B cells from SLE patients, as well as the deposition of C3 fragments occurring in vivo or after in vitro AP activation. We have confirmed, for a proportion of the patients studied, reduced expression of CR1 and CR2 on B cells, and shown a consistency between low CR2 expression and reduced in vitro AP activation in the presence of homologous, normal serum. In addition, the B cells, like erythrocytes, bear raised levels of in vivo-deposited C3dg, but not C3b fragments, compared with normal B cells. The erythrocytes from SLE patients were unable to inhibit in vitro AP activation by B cells in homologous serum. Finally, we demonstrated an inverse relationship between SLE disease activity index (SLEDAI) and the expression of complement receptor 2 (CR2) on SLE B cells. Thus, determination of CR2 on B cells may emerge as an additional laboratory tool in the assessment of SLE activity.
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PMID:Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE). 762 93

Abrogation of peripheral tolerance in transgenic mice that express a uniform B-cell receptor may create a powerful tool to examine the molecular mechanisms that underlie the autoimmune response in B cells. Here we report that processes that induce a systemic lupus erythematosus-like syndrome in normal mice, namely chronic graft vs host reaction, trigger systemic autoimmunity in a well-established transgenic mice model of B cell receptor peripheral tolerance. The induction of graft vs host reaction in mice that carry both a rearranged B cell Ag receptors specific for hen egg lysozyme and expressing chronically circulating hen egg lysozyme Ag resulted in induction of high and sustained levels of circulating anti-hen egg lysozyme autoantibodies and glomerulonephritis with proteinuria. This was associated with marked changes in expression of cell-surface proteins, such as CD23 and complement receptor 2. B cells from the graft vs host-induced mice could proliferate in vitro in response to self-Ag, and upon stimulation with anti-IgD demonstrated rapid phosphotyrosine phosphorylation of specific proteins, which could not be induced in the anergic double transgenic B cells. Conversely, loss of tolerance was not associated with a higher induction in the level of Syk kinase phosphorylation following stimulation with anti-IgD. Taken collectively, these data establish that 1) processes that induce a systemic lupus erythematosus-like syndrome in normal mice can abrogate peripheral tolerance in transgenic mice expressing self-tolerized B cells, and that 2) loss of tolerance in this model is associated with marked changes in surface expression of B cell coreceptors as well as with selective changes in IgD-induced signaling by discrete tyrosine-phosphoproteins, but not Syk kinase.
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PMID:Induction of autoimmunity in a transgenic model of B cell receptor peripheral tolerance: changes in coreceptors and B cell receptor-induced tyrosine-phosphoproteins. 1055 51

The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4(-/)- mice. This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2(-)(/)- mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4(-)(/)- but not Cr2(-)(/)- mice. C4(-)(/)-, but not Cr2(-)(/)-, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.
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PMID:Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2. 1106 82

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

B cells from patients with systemic lupus erythematosus (SLE) display increased responses following cross-linking of the surface antigen receptor. We explored the possibility that the increased responses are at least partially due to simultaneous cross-linking of the complement receptor 2 (CR2). To this end, we stimulated fresh B cells from SLE patients with an anti-IgD antibody conjugated to the Epstein-Barr virus gp350 protein, which binds to CR2, and recorded the free intracytoplasmic calcium response during the first 10 min. Despite the fact that SLE B cells were found to express half as many surface CR2 as normal B cells, both peak responses and the percentage of responding cells were significantly increased in the former. These observations suggest that regulatory molecules such as CR2 are involved in the increased B cell responses in SLE patients. We propose that certain immune complexes that circulate in the sera of SLE patients that have anti-surface immunoglobulin specificities and are decorated with natural ligands of CR2, such as C3d, elicit and promote B cell overactivity.
Lupus 2002
PMID:Engagement of complement receptor 2 on the surface of B cells from patients with systemic lupus erythematosus contributes to the increased responsiveness to antigen stimulation. 1209 May 64

Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease. Genetic factors are thought to contribute to its pathogenesis. There have been numerous recent advances in the study of murine and human lupus genetics. In well-defined experimental transgenic or gene-knockout mouse models, the development of lupus-like disease has implicated specific genes and pathways in the disease pathogenesis. Linkage analyses have mapped multiple susceptibility loci and disease suppressive loci using inbred strains of mice that spontaneously develop lupus-like disease. Elegant genetic dissection and function studies have led to the recent identification of two murine candidate susceptibility genes, Ifi202 (encoding an interferon-inducible protein) and Cr2 (encoding complement receptors 1 and 2). In human lupus, case- control studies have established associations of SLE with certain major histocompatibility class II alleles, complement deficiencies, and polymorphisms of Fc gamma receptor genes, a complement-related gene, and cytokine genes. During the past several years, linkage analyses using SLE multiplex families have provided many chromosomal regions for further exploration of susceptibility genes. Six regions exhibiting significant linkage to SLE are promising. Studies are underway to fine map these linked regions and to identify the genes in the susceptibility regions. An understanding of the genes involved in the development of lupus should provide targets for more focused therapy in lupus.
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PMID:An update on genetic studies of systemic lupus erythematosus. 1212 89

Systemic lupus erythematosus is an autoimmune disease characterized by autoantibody production against nuclear Ags. Recent studies suggest that the Cr2 gene, which encodes for complement receptor (CR)1 and CR2, is important in disease susceptibility. Because the precise disease phenotype related to this gene, in isolation or in relation to other genetic loci, is not known, we analyzed C57BL/6 mice with a targeted mutation in Cr2 (C57BL/6.Cr2(-/-)) with or without a concomitant mutation in Fas (C57BL/6.lpr Cr2(-/-)). The Cr2(null) mutation in a C57BL/6.lpr background markedly increases the serum concentrations of IgG1 and IgG2b and the levels of antinuclear and anti-dsDNA Abs as compared with C57BL/6.lpr controls. There is also a trend for higher concentrations of IgG2a and IgG3. In contrast, isolated deficiencies in either these CRs or Fas have a limited effect in the production of anti-dsDNA Abs. Moreover, the Cr2(null) mutation does not affect other disease manifestations. These findings demonstrate that abnormalities in CR1 and CR2 may be linked to the production of autoantibodies by modifying the effect of other systemic lupus erythematosus susceptibility genes. Phenotypic expression of other disease manifestations need additional Cr2-independent genetic factors.
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PMID:A role for the Cr2 gene in modifying autoantibody production in systemic lupus erythematosus. 1213 88

B cell complement receptors have been shown to be important in the generation of normal humoral immune responses, and they likely also participate in the development of autoimmunity. Complement component and receptor deficiencies have been associated with SLE in both animal models and patients with disease. Recent data suggest that Cr2 is a lupus susceptibility gene in the NZM2410 mouse model for lupus, as it generates complement receptors that are structurally and functionally altered. Complement deficiency may result in autoimmune disease because of the inability to appropriately clear immune complexes or apoptotic cells or by the impaired generation of C3-coated autoantigens for CR1/CR2. In turn, CR1/CR2 may participate in the maintenance of B cell tolerance by lowering the threshold for negative selection of autoreactive B cells, by targeting autoantigen to FDCs in secondary lymphoid organs, or by regulating autoreactive T cell function. The effect of CR2 has not been dissected from that of CR1 in the animal studies performed to date. Furthermore, the effects of CR1/CR2 dysfunction or partial deficiency, which are found in the NZM2410 mouse model and in patients with SLE respectively, have not been delineated from those of complete deficiency, which has been studied in several animal models of autoimmunity and tolerance. Although CR1/CR2 dysfunction or deficiency may confer only a modest phenotype in isolation, it is likely that when combined with other disease susceptibility genes it will result in a fully penetrant end-stage disease phenotype. Understanding the mechanisms by which these receptors participate in the maintenance of B cell tolerance will be critical in developing appropriate therapeutic interventions for patients with autoimmune diseases such as SLE.
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PMID:Role of complement in the development of autoimmunity. 1240 51

The complement system is comprised of a number of serum and membrane-bound proteins that play an important role in the elimination of foreign microorganisms while protecting the host organism from complement-related damage. Complement has also been shown to participate in the generation of normal humoral immune responses to foreign antigens. Recent studies suggest that the functions of complement may be extended to include the maintenance of B cell tolerance. Complement receptor 2 (CR2/CD21) has been implicated in lupus susceptibility in both humans and animal models of disease. Located primarily on B cells and follicular dendritic cells, CR2 binds C3 degradation products that have become covalently bound to antigen or immune complexes in the process of complement activation. The mechanism by which CR2 might regulate B cell reactivity to autoantigens has not been elucidated, but may involve direct effects on B cell tolerance or indirect effects on T cell tolerance.
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PMID:Complement and autoimmunity. 1449 71

Complement receptor 2 (CR2/CD21) plays a major role in the immune response by linking innate and adaptive immunity to foreign pathogens and proteins. In addition, several lines of evidence strongly support a role for CR2 in the maintenance of tolerance to self-antigens. Both the absence of CR2 expression (along with the alternatively spliced gene product CR1) and the presence of a dysfunctional CR2 protein are tightly associated with the development of autoreactivity to nuclear antigens. Altered levels of expression of CR2 in patients with systemic lupus erythematosus support a clinically relevant role for this phenotype. Several possible mechanisms could underlie the loss of self-tolerance related to CR2, but the effect is most likely related to the failure of one or more specific checkpoints that limit autoreactivity during B cell development and immune reactions.
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PMID:Complement receptor 2 and autoimmunity. 1471 74


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