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)

Systemic sclerosis is a systemic disease that is characterized by tissue fibrosis, small-vessel vasculopathy, and an autoimmune response associated with autoantibodies. We performed serological analysis of cDNA expression library (SEREX) to identify autoantibodies associated with systemic sclerosis. We identified 4 clones that react with sera of patients with SSc but not with those of healthy donors. These clones are phosphoglycerate mutase, centromere autoantigen C, U1 small nuclear ribonucleoprotein, and DNA binding protein B (dbpB). We chose to study autoantibody to DNA binding protein B. Immunoreactivity against recombinant dbpB was detected in 40.5% (15/37) of patients with SSc, 14.6% (6/41) of patents with systemic lupus erythematosus, 6.7% (1/15) of patients with rheumatoid arthritis, 0% (0/12) of patients with Sjogren syndrome, and 5.9% (1/17) of patients with polymyositis/dermatomyositis. The frequency of anti-dbpB was significantly higher in the SSc patients (15/37, 40.5%) compared to the healthy controls (3/41, 7.3%, p=0.0005 by chi(2) test). Eleven patients (11/20, 55%) with the diffuse cutaneous type of SSc had anti-dbpB and 4 patients (4/17, 23.5%) with the limited cutaneous type had anti-dbpB. The presence of anti-dbpB was significantly associated with the diffuse cutaneous type (p=0.00003 by chi(2) test). This is the first report to suggest that autoantibody to dbpB can be used as a serologic marker of systemic sclerosis.
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PMID:Autoantibody to DNA binding protein B as a novel serologic marker in systemic sclerosis. 1245 73

Cross-reactions of anti-human chorionic gonadotropin-beta (HCG-beta) antibody elicited by HCG-beta based antifertility vaccines with other autoantigens may occur due to identical or homologous protein subsequences. I have detected hitherto unreported identity of HCG-beta sequence with tetrapeptides of PECAM-1, galactosyl transferase-associated protein kinase, insulin receptor-related receptor and carboxypeptidase E. A predicted potential epitope of C-terminal peptide (CTP) of HCG-beta was identical to a tetrapeptide stretch of MCSF-1. The first 30 residue stretch of CTP was found to have yet unknown homologies of more than 56% with many auto-antigens including 60.1% with centromere protein C. The last 30 residue stretch of CTP was found for the first time to have 61.4-65.4% homology with subsequences of autoantigens SP-100, PM-SCL, D1 (64 kDa), lupus KU (p86), small nuclear ribonucleoprotein-associated proteins N, B and B', major centromere autoantigen B, centromere protein C, and dihydrolipoamide acetyl transferase component E2 of pyruvate, respectively.
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PMID:Predictions of Immunological Cross-Reactions of C-Terminal Peptide of Human Chorionic Gonadotropin beta-Chain Based Contraceptive Vaccine with Autoantigens. 1268 22

Anti-Sm antibodies are found in greater than 30% of the patients with systemic lupus erythematosus (SLE) and are diagnostic of SLE. The Sm autoantigens are the small nuclear ribonucleoprotein (snRNP) common core proteins. The seven core proteins, B, D1, D2, D3, E, F and G, shared by a majority of the snRNP particles, form a heptamer ring approximately 20 nm in diameter, with the snRNA passing through the center. The Sm epitopes are distributed on the outside surface of the ring. A repeated proline rich motif with homology to an Epstein bar nuclear antigen in the B protein and a gly-arg-gly motif including a symmetrical dimethylarginine post translational modification in the B, D1 and D3 proteins are major Sm epitopes. The anti-Sm response has features typical of an antigen driven immune response. SnRNP proteins share several characteristics with other autoantigens including their assembly into ribonucleoprotein particles, homologies to known viral proteins, presence of post translational modifications, a high abundance and great stability and the presence of repeated motifs. Current work on the snRNP particles is attempting to identify the features that predispose the common core proteins to become autoantigens in vulnerable individuals.
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PMID:The anti-Sm immune response in autoimmunity and cell biology. 1296 73

A subset of lupus patients with severe nephritis and anti-nRNP reactivity produces autoantibodies primarily against two major epitopes of the nRNP A (also known as U1A) protein. These sequences span amino acids 44-56 (A3) and amino acids 103-115 (A6). These two epitopes represent structurally different regions of the protein, as both epitopes are located on the surface, but the A6 epitope is functionally masked in vivo by binding between nRNP A and the U1 RNA. Rabbits were immunized with either the A3 or A6 peptides constructed on a branching polylysine backbone. Rabbits immunized with each of these peptides first developed antibodies directed against the peptide of immunization. With boosting, the immune response of rabbits immunized with the A3 peptide spread to other common antigenic regions of nRNP A. These regions of nRNP A bound by A3 immunized rabbits are very similar to common epitopes in human systemic lupus erythematosus. These A3 immunized rabbits also develop antibodies to common antigenic regions of nRNP 70K, nRNP C, Sm B/B', and Sm D1 proteins, as well as clinical symptoms of systemic lupus erythematosus such as leukopenia and renal insufficiency. On the other hand, rabbits immunized with the A6 peptide only develop antibodies to the peptide of immunization. Anti-A3, but not anti-A6, antibodies are capable of immunoprecipitating native small nuclear ribonucleoprotein complexes. Immunization with the A3 peptide of nRNP A (a surface epitope), but not the A6 peptide (masked), induces an extensive, varied immune response against multiple small nuclear ribonucleoprotein autoantigens similar to that seen in human systemic lupus erythematosus.
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PMID:Structural availability influences the capacity of autoantigenic epitopes to induce a widespread lupus-like autoimmune response. 1498 8

There is increasing evidence that the TCR can have significant plasticity in the range of Ags that a single receptor can recognize. Although it has been proposed that such TCR plasticity might contribute to autoimmunity, there have been few studies examining this possibility in either animal models or human disease. In the present study, we examined human T cell clones that were generated against two structurally dissimilar proteins, U1-70 kDa and Smith-B, that are physically associated in the U1-small nuclear ribonucleoprotein complex and that are frequent targets of autoantibodies and T cells in the same lupus patient. We found that the TCR from all clones isolated had substantial sequence homology within their complementarity-determining region 3. We molecularly cloned and expressed individual TCR/A and TCR/B genes in a TCR-negative human cell line J.RT3-T3.5. We then examined the interaction between the TCR and U1-70 kDa and Smith-B antigenic peptides. We found that there was plasticity or degeneracy of the TCR reactive with these lupus autoantigens in that two structurally dissimilar lupus autoantigenic peptides could stimulate a single TCR. These studies support an important role of plasticity of the TCR in the development of human autoimmunity.
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PMID:Cloned human TCR from patients with autoimmune disease can respond to two structurally distinct autoantigens. 1500 2

T cells that recognize nucleoproteins are required for the production of anti-dsDNA Abs involved in lupus development. SmD1 83-119 (a D1 protein of the Smith (Sm) proteins, part of small nuclear ribonucleoprotein) was recently shown to provide T cell help to anti-dsDNA Abs in the NZB/NZW model of lupus. Using this model in the present study, we showed that high dose tolerance to SmD1 (600-1000 microg i.v. of SmD1(83-119) peptide/mo) delays the production of autoantibodies, postpones the onset of lupus nephritis as confirmed by histology, and prolongs survival. Tolerance to SmD1 83-119 was adoptively transferred by CD90+ T cells, which also reduce T cell help for autoreactive B cells in vitro. One week after SmD1 83-119 tolerance induction in prenephritic mice, we detected cytokine changes in cultures of CD90+ T and B220+ B cells with decreased IFN-gamma and IL-4 expression and an increase in TGFbeta. Increased frequencies of regulatory IFN-gamma+ and IL10+ CD4+ T cells were later detected. Such regulatory IL-10+/IFN-gamma+ type 1 regulatory T cells prevented autoantibody generation and anti-CD3-induced proliferation of naive T cells. In conclusion, these results indicate that SmD1 83-119 peptide may play a dominant role in the activation of helper and regulatory T cells that influence autoantibody generation and murine lupus.
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PMID:Intravenous injection of a D1 protein of the Smith proteins postpones murine lupus and induces type 1 regulatory T cells. 1549 37

Among anti-nuclear antibodies, anti-Sm and anti-RNP antibodies are of the utmost importance in clinical practice. Anti-Sm antibodies are directed against 7 proteins (B/B', D1, D2, D3, E, F, G) that constitute the common core of U1, U2, U4 and U5 small nuclear ribonucleoprotein (snRNP) particles; B/B', D1 and D3 are more frequently targeted. Anti-RNP antibodies react with proteins (70 Kd, A, C) that are associated with U1 RNA and form U1snRNP. Anti-Sm and anti-RNP antibodies are directed towards both discontinuous and linear epitopes which are either contained in the protein sequence or are post-translationally modified. The assays to detect anti-Sm and anti-RNP antibodies are counterimmunoelectrophoresis (CIE), immunoblot, and ELISA, based on purified or recombinant proteins or synthetic peptides. Anti-Sm antibodies are detectable in a percentage of SLE patients comprised between 5 and 30%; they are more prevalent in blacks and because of their high specificity for SLE have been included in the serological criteria for diagnosing the disease.Anti-RNP are detectable in 25-47% of SLE patients; high titers of anti-RNP antibodies are diagnostic of mixed connective tissue disorder (MCTD). The measurement of anti-Sm and anti-RNP antibodies is more important in the diagnosis of SLE than in the follow-up of patients. However, anti-RNP antibodies are more prevalent in patients with Raynaud's phenomenon and are associated with milder renal involvement. On the contrary, anti-Sm antibodies are associated with the severity and the activity of renal involvement. The specificity of anti-Sm antibodies, together with epidemiological data, suggest that Epstein-Barr virus infection has the potential to induce anti-Sm antibodies by molecular mimicry.Anti-nuclear antibodies, a hallmark of the systemic autoimmune diseases, include several populations of antibodies with different specificities. Among them, anti-Sm and anti-RNP antibodies are of the utmost importance in clinical practice; in research, the study of the mechanisms inducing their production has opened up new perspectives and helped to elucidate the pathogenesis of autoimmune disorders.
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PMID:Anti-Sm and anti-RNP antibodies. 1580 5

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies to certain cellular macromolecules, such as the small nuclear ribonucleoprotein particles (snRNPs), which had been considered to be passive targets of the autoimmune response. SLE is also characterized by the increased expression of type I interferon (IFN), which appears to be associated with the development and severity of disease. Here, we show that specific, highly conserved RNA sequences within snRNPs can stimulate Toll-like receptors (TLRs) 7 and 8 as well as activate innate immune cells, such as plasmacytoid dendritic cells (pDCs), which respond by secreting high levels of type I IFN. SLE patient sera containing autoantibodies to snRNPs form immune complexes that are taken up through the Fc receptor gammaRII and efficiently stimulate pDCs to secrete type I IFNs. These results demonstrate that a prototype autoantigen, the snRNP, can directly stimulate innate immunity and suggest that autoantibodies against snRNP may initiate SLE by stimulating TLR7/8.
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PMID:Immune stimulation mediated by autoantigen binding sites within small nuclear RNAs involves Toll-like receptors 7 and 8. 1633 Aug 16

Autoreactive B cells are the source of pathogenic autoantibodies (autoAb) in systemic lupus erythematosus (SLE). Previous studies have demonstrated that anti-small nuclear ribonucleoprotein particles (snRNP) B cells from normal background mice tolerize T cells in the periphery and do not secrete autoAb. In this study, we examined whether these anti-snRNP B cells can be activated for autoAb production by the engagement of Toll-like receptors (TLR). Anti-snRNP B cells proliferated vigorously and secreted abundant anti-snRNP autoAb upon exposure to CpG or polyriboinosinic polyribocytidylic acid [poly (I:C)] in vitro. In addition, the costimulatory molecules CD80 and CD86 were up-regulated. While both anti-snRNP B cells and wild-type B cells produced similar levels of IL-6 and IL-10, anti-snRNP B cells secreted predominately IFN-gamma in response to CpG or poly (I:C) stimulation. Furthermore, we showed that in vivo engagement of TLR stimulated immature anti-snRNP B cells to further differentiate and produce autoAb and form germinal centers. The activated anti-snRNP B cells became expanded and migrated into the T-B cell interface. Moreover, TLR engagement directly or indirectly activated autoreactive B cells via a CD4 T cell-independent manner. These results provide in vitro and in vivo evidence that BCR/TLR co-engagement promotes the activation of anti-snRNP B cells for autoAb production.
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PMID:Toll-like receptor engagement stimulates anti-snRNP autoreactive B cells for activation. 1681 Jun 34

Autoantibody response against the small nuclear ribonucleoprotein (snRNP) complex is a characteristic feature of systemic lupus erythematosus. The current investigation was undertaken to determine whether activation of SmD-reactive T cells by synthetic peptides harboring T cell epitopes can initiate a B cell epitope spreading cascade within the snRNP complex. T cell epitopes on SmD were mapped in A/J mice and were localized to three regions on SmD, within aa 26-55, 52-69, and 86-115. Immunization with synthetic peptides SmD(31-45), SmD(52-66), and SmD(91-110) induced T and B cell responses to the peptides, with SmD(31-45) inducing the strongest response. However, only SmD(52-66) immunization induced T cells capable of reacting with SmD. Analysis of sera by immunoprecipitation assays showed that intermolecular B cell epitope spreading to U1RNA-associated A ribonucleoprotein and SmB was consistently observed only in the SmD(52-66)-immunized mice. Surprisingly, in these mice, Ab responses to SmD were at low levels and transient. In addition, the sera did not react with other regions on SmD, indicating a lack of intramolecular B cell epitope spreading within SmD. Our study demonstrates that T cell responses to dominant epitope on a protein within a multiantigenic complex are capable of inducing B cell responses to other proteins within the complex. This effect can happen without generating a good Ab response to the protein from which the T epitope was derived. Thus caution must be taken in the identification of Ags responsible for initiating autoimmune responses based solely on serological analysis of patients and animals with systemic autoimmune disorders.
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PMID:A SmD peptide induces better antibody responses to other proteins within the small nuclear ribonucleoprotein complex than to SmD protein via intermolecular epitope spreading. 1727 66


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