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 study of 30 patients with systemic lupus and of 153 relatives failed to show any differences in HLA and TCR beta haplotype frequencies between patients and relatives. A significant interaction between TCR V beta and HLA-DR/DQ genes in the response to the peptide U1-RNP A 35-58 was demonstrated.
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PMID:[Immunogenetics of systemic lupus: adequacy between HLA molecules class II and the germinal genes of antigen receptor of T-lymphocytes favours the production of various antibodies]. 800 72

The monoclonal nonspecific suppressor factor (MNSF) is a lymphokine produced by a murine T cell hybridoma capable of suppressing Ab production by LPS-stimulated B cells. The existence of a human counterpart of MNSF, designated as the human nonspecific suppressor factor (hNSF), was likely because the anti-MNSF mAb (MO6) recognizes a similar suppressive activity in supernatants of Con A-stimulated human PBMC. By using the MO6 mAb, we investigated the presence of hNSF in the ascitic fluid of a patient with SLE. A small amount of cross-reactive hNSF was isolated from concentrated ascitic fluid fractionated with the MO6-affinity column, and a specific anti-hNSF mAb (P2) was produced. The hNSF eluted from the P2-affinity column could suppress up to 80% of the PWM-induced IgG production of human PBMC in a dose-dependent manner, even when added in late culture periods. Moreover, hNSF could inhibit proliferation of PBMC triggered by either PWM or Con A, which also implies an effect on T cells. On SDS-PAGE, the isolated hNSF resolved as a single peak of about 66 kDa and probably represents an aggregate of hydrophobic subunits. On reverse-phase HPLC, the bioactivity could be recovered from a single peak at 18.3 min. The suppression of IgG production induced by hNSF could be partly neutralized by preincubation with an anti-TCR-alpha mAb, whereas an anti-TCR-beta did not have any effect. Anti-TCR-alpha could also directly bind to the isolated nNSF, demonstrating some serologic relationship, as has been reported for several Ag-specific suppressor systems.
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PMID:Isolation and characterization of a human nonspecific suppressor factor from ascitic fluid of systemic lupus erythematosus. Evidence for a human counterpart of the monoclonal nonspecific suppressor factor and relationship to the T cell receptor alpha-chain. 813 68

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 production of pathogenic anti-DNA autoantibodies in mice with lupus nephritis is dependent on special autoimmune Th cells that can also transfer the disease into preautoimmune mice. In previous work, these pathogenic Th cells were cloned and their TCR beta-chains were sequenced to reveal a recurrent motif of anionic residues in their CDR3 loops. Accordingly, approximately half of the Th clones were found to be specific for nucleosomal Ag that contain cationic residues. Herein, we analyzed the TCR alpha-chain repertoire of 15 of these pathogenic Th clones and found them to be heterogeneous, even among the nucleosome-specific Th clones. Most of these autoimmune TCR alpha-chains contained anionic residues in their CDR3 in addition to cationic residues. Therefore, these pathogenic Th clones of lupus probably recognize epitopes with mixed charge runs that are derived from autoantigens, such as histone-DNA complexes. Interestingly, the V alpha gene segments used by 10 of these Th clones derived from the (SWR x NZB)F1 lupus mice differed from previously reported sequences indicating that they were new members or alleles of the respective V alpha gene family. One of the Th clones used a gene from an entirely new murine V alpha gene family, identified here as V alpha 23, which consisted of approximately two members that were conserved among strains with different V alpha haplotypes. Knowledge of the primary structure of the TCR expressed by these pathogenic Th clones of lupus would help in the analysis of their antigenic specificities and also would be essential for studying their regulation in transgenic mice carrying these autoimmune TCR genes.
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PMID:T cell receptor alpha-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice. 830 Nov 46

This study examines the responses of lupus-prone NZB, (NZB x NZW) F1, BXSB, MRL-lpr/lpr and control mice (H-2 and Mls matched) to in vivo administration of the superantigen staphylococcal enterotoxin B (SEB). Two weeks after i.v. administration of 500 micrograms SEB, CD4+V beta 8+ lymph node T cells were deleted equivalently by lupus-prone and control mice. However, IE+ strains deleted a greater proportion (47% to 77%) of their CD4+V beta 8+ cells than did IE- strains (24% to 27%). CD8+V beta 8+ cells were deleted less than CD4+V beta 8+ cells by injection of 500 micrograms SEB. IE- strains failed to delete CD8+V beta 8+ cells, whereas six of seven IE+ strains deleted > 25% of their CD8+V beta 8+ cells. IE+ MRL-lpr/lpr mice showed some impairment in deletion: they failed to delete CD8+V beta 8+ cells at all doses of SEB and had reduced deletion of CD4+V beta 8+ cells at low doses of in vivo SEB (10 and 50 micrograms). Peripheral expansion of the intrathymically deleted V beta 7 TCR family was not observed in lupus-prone mice 2 wk after 500 micrograms in vivo SEB. In vitro restimulation with SEB of mice previously injected with 500 micrograms SEB demonstrated anergy in T cells from all strains, including the IE- and MRL-lpr/lpr. This result contrasts with previous reports of tolerance defects in lupus-prone strains using B cell read-out assays as measures of tolerance. The present study demonstrates that there is no global defect in peripheral T cell deletion or anergy in lupus-prone mice to the superantigen SEB. Although additional Ag would need to be studied, these experiments raise the possibility that some reported tolerance defects in lupus-prone strains may reflect excessive B cell responses to relatively normal T cell signals.
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PMID:Studies of T cell deletion and T cell anergy following in vivo administration of SEB to normal and lupus-prone mice. 841 93

To investigate the possibility that non-alpha beta T cell-dependent mechanisms can induce systemic autoimmune disease, and to address the roles of alpha beta T cells in murine lupus, we analyzed lupus-prone MRL mice congenitally deficient in alpha beta T cells. Surprisingly, TCR-alpha-/- MRL mice developed several characteristics of human systemic lupus erythematosus, including hypergammaglobulinemia, autoantibodies against DNA and small nuclear ribonucleoproteins, and immune deposits in kidneys. These results, which contrast with past studies concluding that MRL autoimmunity requires CD4+ alpha beta T cells, demonstrate that non-alpha beta T cell-dependent mechanisms are capable of inducing lupus phenomena, and further suggest that MRL disease may consist of both alpha beta T cell-independent and alpha beta T cell-dependent mechanisms.
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PMID:Murine lupus in the absence of alpha beta T cells. 862 47

MRL-lpr/lpr mice develop a distinctive immunologic disease characterized by accumulation of unusually large numbers of T cells in the peripheral lymphoid organs. Most of the accumulating T cells express an alpha beta-TCR but are peculiar in that they express neither CD4 nor CD8 co-ligands. Concurrent with lymphoaccumulation of such double negative (DN) T cells, MRL-lpr/lpr mice develop a lethal systemic lupus erythematosus-like autoimmune syndrome. This study focuses on the role of MHC class I molecules in this latter pathologic process. Highly backcrossed class I molecule-deficient MRL and MRL-lpr mice carrying a functionally defective allele of the gene beta 2-microglobulin (B2m) were produced. Class I deficient MRL-lpr/lpr mice demonstrated a substantial reduction in DN T cells, confirming other reports indicating that most DN T cells arise from progenitors positively selected on MHC class I molecules. Significantly, class I-deficient MRL-lpr/lpr mice also demonstrated a diminution of every autoimmune disease indicator analyzed including hypergammaglobulinemia; autoantibodies including anti-DNA, anti-Smith antigen, and rheumatoid factor; and glomerulonephritis. The results indicate that class I-dependent T cells are crucial not only for the development of DN T cells, but for multiple features of the MRL-lpr/lpr systemic lupus erythematosus syndrome. Moreover, the pattern of hypergammaglobulinemia suggests that the requirement for MHC class I proteins is restricted temporally to later stages of the disease.
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PMID:beta2-microglobulin dependence of the lupus-like autoimmune syndrome of MRL-lpr mice. 864 44

CD4+ T cells play a crucial role in the development of lupus in MRL-lpr/lpr mice: incomplete deletion/silencing of self-reactive CD4+ T cells leads to T cell activation, which causes both polyclonal B cell activation and T cell infiltration of multiple organs. Furthermore, anti-CD4 antibody therapy ameliorates disease and prolongs survival. Because CD4 is normally involved in both tolerance induction and T cell activation, we questioned whether signaling through CD4 was normal among T cells in this strain. For this purpose, signal transduction in CD4+ T cells derived from MRL-lpr/lpr and normal mice were compared, using an autoreactive CD4+ T cell clone and freshly isolated CD4+ T cells derived from mice of varying ages. Tyrosine phosphorylation was similar among MRL and normal CD4+ T cells after cross-linking with either anti-TCR antibody or anti-CD3 antibody, and following co-culture with Con A. In constrast, cross-linking of surface CD4 resulted in deficient tyrosine phosphorylation of cellular proteins in MRL T cells. By comparison, lck protein expression in MRL CD4+ T cells was found to be lower than normal. However, following stimulation with Con A, lck enzyme activity, as detected by autophosphorylation of lck, was comparable in MRL and normal T cells. The observed differences were present in the autoreactive T cell clone as well as in T cells isolated from both pre-diseased and diseased mice, and they could not be explained by variation in surface density of CD4. These results raise the possibility that abnormal signaling through CD4 may contribute to impaired tolerance and expansion of autoreactive T cells exhibited in MRL-lpr/lpr mice.
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PMID:Abnormal signal transduction through CD4 leads to altered tyrosine phosphorylation in T cells derived from MRL-lpr/lpr mice. 891 30

Activation-induced cell death (AICD) plays an important role in the regulation of the immune response by eliminating preactivated and potentially autoreactive cells. To elucidate possible abnormalities of AICD in human systemic lupus erythematosus (SLE), we studied AICD in activated T cells from patients with SLE and normal controls. CD3-mediated cell death was determined in short-term T cell lines by flow cytometry using propidium iodide staining and analysis of DNA subdiploid peak populations. It was found to be significantly lower in T cells from SLE patients compared to cells from normal controls. Anti-Fas mAb-mediated cell death was similar in SLE and control cell lines. CD3-mediated AICD could be blocked in control and SLE T cell lines by an IgG anti-Fas mAb. Indirect immunofluorescence analysis showed statistically significantly less intracellular TNF-alpha in SLE T cells than in control cells. These data show that activated T cells from patients with SLE are relatively resistant to a TCR-mediated death stimulus although they display intact anti-Fas mAb-mediated cell death. Defective antigen-mediated cell death can contribute to increased numbers of activated autoreactive cells in lupus patients.
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PMID:Defective CD3-mediated cell death in activated T cells from patients with systemic lupus erythematosus: role of decreased intracellular TNF-alpha. 893 8

Murine lupus predominantly requires alpha beta T cells, which provide pathogenic help for autoantibody production and immune complex-associated end-organ disease. Autoantigen-specific, pathogenic alpha beta T cells have been isolated from some lupus-prone mice, but a requirement for such T cells in disease has not been clearly demonstrated. To address alpha beta T cell specificity in murine lupus, lupus-prone mice were generated that contained only a single population of alpha beta T cells of foreign specificity by generating anti-pigeon cytochrome c (AND) TCR transgenic TCRalpha -/- TCRbeta -/- MRL/Mp-lpr/lpr (MRL/lpr) mice, which lacked the ability to express endogenous TCRalpha or -beta genes. These AND alpha beta T cells induced hypergammaglobulinemia and autoantibody production, as seen in serum Ig, anti-DNA, anti-small nuclear ribonucleoprotein (snRNP) and rheumatoid factor titers, but failed to promote the development of lymphadenopathy or pathogenic immune-complex disease, as assayed by cutaneous, renal, and salivary gland lesions. Thus, antigen-nonspecific alpha beta T cell help can promote generalized autoimmunity, but autoantigen-specific alpha beta T cells are required to cause overt disease.
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PMID:Induction of nonpathologic, humoral autoimmunity in lupus-prone mice by a class II-restricted, transgenic alpha beta T cell. Separation of autoantigen-specific and -nonspecific help. 895 66


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