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)

SLE and mixed connective tissue disease (MCTD) are characterized by the presence of high titers of autoantibodies against uridine-rich RNA-small nuclear ribonucleoprotein (snRNP) Ag. Because the presence of such snRNP-reactive autoantibodies has recently been shown to be associated with polymorphisms of HLA, this study was undertaken to determine whether snRNP-reactive T cells could be identified and characterized from patients. PBMC were stimulated with affinity-purified snRNP Ag and cloned by limiting dilution in the presence of rIL-2 and rIL-4, snRNP-reactive human T cell clones were generated from three patients and two healthy blood donors who possessed disease-associated HLA genotypes. The cell surface phenotype of clones determined by flow cytometry was CD3+, CD4+, CD45RO+, TCR V alpha beta+. TCR V beta analysis, performed using V beta-specific primers and polymerase chain reaction, revealed that the T cell lines generated were clonal; a limited number of TCR V beta genes were expressed among the clones tested. All clones tested by mAb blocking of Ag-induced proliferation were restricted by HLA-DR. Several T cell clones were identified that were specific for B'/B or D polypeptides. These results demonstrate that snRNP-reactive T cells can be isolated from SLE and MCTD patients in vitro, and that Ag-driven expansion of such T cells could play a role in the immunopathogenesis of these diseases in vivo.
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PMID:Human T cell clones reactive against U-small nuclear ribonucleoprotein autoantigens from connective tissue disease patients and healthy individuals. 824 79

The U1 small nuclear ribonucleoprotein (sn-RNP) particle, which consists of the U1 small RNA and multiple polypeptides, is a central target of the autoimmune response in systemic lupus erythematosus. Autoantibodies to the individual proteins of the U1 snRNP typically co-occur in patients with systemic lupus erythematosus, an observation reconciled by postulating that the intact RNA-protein complex serves as the autoimmunogen and that snRNP-specific autoreactive T cells are necessary for autoantibody production. In this study, we demonstrated that normal mice did not develop antibody responses following immunization with purified self (murine) snRNPs. However, when such mice were coimmunized with self snRNPs in conjunction with the human (foreign) U1 snRNP A protein, they developed autoantibodies directed against individual proteins of the U1 snRNP, in addition to anti-A antibodies; we have previously shown that such mice develop snRNP-specific, autoreactive T cells. Intact snRNPs as a co-immunogen were a prerequisite for antibody expansion, since this response was abrogated by disruption of snRNP particles with pancreatic RNase prior to immunization. These findings indicate that autoreactive helper T cells can drive autoantibody production to the individual proteins of snRNP particles and that such autoantibody responses may require the presence of intact snRNP particles that possess intrastructural B-cell and helper-T-cell determinants. These results also suggest that induction of an immune response to one component of an autoantigenic snRNP complex, possibly through priming with molecular mimics, can induce the diversification of autoantibodies that is characteristic of that found in patients with systemic lupus erythematosus.
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PMID:Role of intermolecular/intrastructural B- and T-cell determinants in the diversification of autoantibodies to ribonucleoprotein particles. 826 62

Antibodies against U small nuclear ribonucleoprotein (snRNP) particles are a common finding in the sera of humans with SLE and in certain strains of mice with murine lupus. It is likely that Th cells are important in amplifying this autoantibody response. The focus of this work was to investigate events that might initiate autoimmune B and T cell response in non-autoimmune mice to native snRNP particles. Mice that were immunized and boosted with native mouse snRNPs failed to produce any detectable specific anti-snRNP antibody or T cell responses, suggesting that these autoreactive cells were deleted from the repertoire or were anergic to stimulation with this self Ag. In contrast, immunization with native foreign (human) snRNPs elicited both T cells and cross-reactive anti-snRNP antibodies; the latter predominantly were directed toward the A protein of the U1 snRNP. When mice were immunized with human and mouse snRNPs together in adjuvant, T cells specific for mouse snRNPs could be elicited. The results of these experiments suggested that the mechanism of breaking T cell tolerance to self snRNPs was dependent on the ability of cross-reactive B cells to process and present these autoantigens. To address this hypothesis, B cells purified from mice immunized with recombinant human A protein were transferred into naive mice. Upon boosting with native mouse snRNPs, autoreactive CD4+ T cells specific for mouse Ags, and not cross-reactive with human snRNPs, were observed. These studies support a model of molecular mimicry whereby autoantigen-presenting B cells are generated by foreign cross-reactive determinants that can, in turn, elicit an autoimmune T cell response.
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PMID:B cells process and present lupus autoantigens that initiate autoimmune T cell responses. 830 Nov 45

This is the first study describing recombinant human antibody fragments directed to the U1 RNA-associated A protein (U1A). Three anti-U1A antibody fragments (Fab) were isolated from a semi-synthetic human Fab library and one anti-U1A single-chain variable fragment (scFv) was isolated from a library which was derived from the IgG-positive splenic lymphocytes of an autoimmune patient. Competition studies with autoantibodies against the U1 small nuclear ribonucleoprotein (snRNP) particle from patients with systemic lupus erythematosus (SLE) and SLE-overlap syndromes revealed that U1A binding of these antibody fragments can be inhibited by about 40% of the patient sera. All antibody fragments recognized the native U1 snRNP in immunoprecipitation assays. Two of three Fab clones as well as the scFv clone derived from the repertoire of an autoimmune patient use the same heavy chain germ-line gene DP-65. Epitope mapping revealed that these three clones appear to recognize an identical epitope domain present on the C-terminal RNP motif of the U1A protein. The DP-65 heavy chain gene is used in less than 1% of the B cells in healthy individuals, while three out of four anti-U1A antibody fragments use this gene. This points to a restricted VH gene usage in the case of U1A, suggesting that the DP-65 heavy chain has a natural shape complementarity to the U1A protein.
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PMID:Characterization of human variable domain antibody fragments against the U1 RNA-associated A protein, selected from a synthetic and patient-derived combinatorial V gene library. 860 31

Autoantibodies to U1 RNA occur frequently in sera from patients with SLE and SLE-overlap syndromes. These autoantibodies have been previously shown to recognize major epitopes on stem-loops II and IV of U1 RNA. To further define these recognition sites, in vitro RNA selection was performed to identify the individual nucleotides which form the antibody binding site. Serum autoantibodies were used in this procedure to select synthetic variants from a library of RNA oligomers with a central region of 25 degenerate nucleotides in a linear context. A consensus sequence was derived from the autoantibody-selected RNA ligands that corresponded to a region of stem-loop II. It contained six continuous nucleotides (U63-C64-C65,-A66-X-U68) and one presumed discontinuous nucleotide (U79). In vitro selection of RNA ligands from simpler sublibraries consisting of oligomers with random loops and fixed U1 stem II sequences yielded no consensus sequence, suggesting that autoimmune recognition occurs independent of loop nucleotides. Competition assays confirmed the specificity of these binding reactions. The structural nature of this autoimmune U1 RNA epitope is compatible with a model of autoantibody production based on stimulation by native small nuclear ribonucleoprotein particles.
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PMID:In vitro RNA selection of an autoimmune epitope on stem-loop II of U1 RNA. 861 52

The Ul small nuclear ribonucleoprotein (snRNP), a complex of nine proteins with Ul RNA, is a frequent target of autoantibodies in human and murine systemic lupus erythematosus (SLE). Anti-Sm antibodies recognizing the B'/B, D, E, F, and G proteins of Ul snRNPs are highly specific for SLE, and are nearly always accompanied by anti-nRNP antibodies recognizing the Ul snRNP-specific 70K, A, and/or C proteins. Previous studies suggest that human anti-nRNP antibodies recognize primarily the U1-70K and Ul-A proteins, whereas recognition of Ul-C is less frequent. We report here that autoantibodies to U1-C are more common in human autoimmune sera than believed previously. Using a novel immunoprecipitation technique to detect autoantibodies to native Ul-C, 75/78 human sera with anti-nRNP/ Sm antibodies were anti-Ul-C (+). In striking contrast, only 1/65 anti-nRNP/Sm (+) MRL mouse sera of various Igh allotypes was positive. Two of ten anti-nRNP/Sm (+) sera from BALB/c mice with a lupus-like syndrome induced by pristane recognized Ul-C. Thus, lupus in MRL mice was characterized by a markedly lower frequency of anti-U1-C antibodies than seen in human SLE or pristane-induced lupus. The results may indicate different pathways of intermolecular-intrastructural diversification of autoantibody responses to the components of Ul snRNPs in human and murine lupus, possibly mediated by alterations in antigen processing induced by the autoantibodies themselves.
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PMID:Distinctive immune response patterns of human and murine autoimmune sera to U1 small nuclear ribonucleoprotein C protein. 864 56

Various nuclear proteins are the major targets of autoimmune responses in various rheumatic disorders. In particular, autoantibodies directed against a 68-kDa protein associated with the (U1) RNA-containing small nuclear ribonucleoprotein complexes typically occur in sera of patients with mixed connective tissue disease and related rheumatic disorders, such as systemic lupus erythematosus, and therefore are very useful as a serological marker. For establishing powerful immunoassays, it was necessary to generate recombinant human P68 antigen as the antigenic target. In this study we demonstrated that the cDNA coding for the full-length human P68 antigen could not be expressed by a traditional bacterial vector system due to a putative inhibitory sequence designated as inhibitory sequence X which is located between the autoreactive domains C' and D' of the human P68 antigen. The construction of corresponding hybrid plasmids carrying two functional and independent gene blocks indicated the trans-active function of the inhibitory sequence X, which could be localized by expression studies of various deletion constructs. Comparable Northern blot analysis clearly demonstrated that the inhibitory sequence X could act on the translation of the P68 mRNA. After excision of the inhibitory sequence X a dramatic increase in the production of recombinant human P68 antigen was observed.
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PMID:Identification of an inhibitory element within the human 68-kDa (U1) ribonucleoprotein antigen. 874 26

Immunoblot analysis of sperm protein from several species revealed the presence of polypeptides recognised by anti-Sm sera obtained from patients with systemic lupus erythematosus. Immunoreactive polypeptides in human, bull, mouse and rat sperm were identified as protein B', B and D as compared with the Sm polypeptides of HeLa cells. In the sperm of rooster, the teleost fish Cyprinus carpio and the mussel Choromytilus chorus, the immunoreactive polypeptide profile was more complex. To ascertain the sperm origin of the Sm antigens, immunolocalisation with anti-Sm serum was carried out. The results demonstrated that in all the species studied staining was confined to the sperm nucleus, confirming that some polypeptides of the small nuclear ribonucleoprotein complex are present in the gamete.
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PMID:Nuclear Sm antigens in the sperm of different organisms. 878 81

Using HEp-2 cells as a substrate, we developed a method to quantitate antinuclear antibodies (ANA) by comparing the green fluorescence intensity of unknown samples with that of calibrated standards. Intensity was then converted to international units per milliliter by reference to a standard curve. This method is accurate and precise around the cutoff for positively (5 to 10 IU/ml) and therefore provides a reliable screening test for active, untreated systemic lupus erythematosus. Furthermore, the method can identify sera likely to contain autoantibodies commonly detected in ANA-positive sera (SS-A, SS-B, Sm, small nuclear ribonucleoprotein, Scl-70, and double-stranded DNA).
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PMID:Precise quantitation of antinuclear antibodies on HEp-2 cells without the need for serial dilution. 880 99

Lupus anti-DNA may have higher homology with germline than those from normal subjects. However, in NZB/NZW mice, bacterial DNA is more antigenic than mammal DNA, which could indicate an antigen-driven origin. High-affinity antibodies to double-stranded DNA cross-react with small nuclear ribonucleoprotein and ribosomal P proteins. These cross-reactive anti-DNA may penetrate live cells. Antibodies to ribosomal P proteins are associated with neuropsychiatric, renal, and hepatic lupus involvement. IgG antibodies to (H2A-H2B)-DNA complexes antedate procainamide-induced lupus. Autoantibodies to some La/Ro peptides in a mother indicates that her children may develop neonatal lupus and determine who will have congenital heart block. Perinuclear antineutrophil cytoplasmic antibodies are present in 25% of systemic lupus erythematosus patients without correlation with anti-DNA or disease activity. Different antiphospholipid antibodies require different protein cofactors for reactivity. Those to anionic phospholipids require beta 2-glycoprotein I, whereas anti-phosphatidylethanolamine antibodies require kininogen or its binding protein. Antibodies to phospholipid-free beta 2-glycoprotein I are associated more strongly with clinical antiphospholipid syndrome than are antiphospholipid antibodies.
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PMID:Autoantibodies in systemic lupus erythematosus. 894 42


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