Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD4+CD25+ regulatory T cells (Treg) are of critical importance for the maintenance of tolerance. The kidney is frequently involved in autoimmune diseases, such as lupus erythematosus or glomerulonephritis (GN). Therefore, the therapeutic efficacy of Treg in a T cell-dependent murine model of experimental anti-glomerular basement membrane (anti-GBM) GN was tested. Transfer of 1 x 10(6) CD4+CD25+ T cells (day -1) into mice that were previously immunized with rabbit IgG (day -3) and subsequently received an injection of anti-GBM rabbit serum (day 0) significantly attenuated the development of proteinuria when compared with animals that received an injection of 1 x 10(6) CD4+CD25- T cells (control group). Treg injection induced a dramatic decrease of glomerular damage as well as a marked decrease of CD4+ T cell, CD8+ T cell, and macrophage infiltration. Of note, deposition of immune complexes was not prevented by Treg, showing that Treg rather inhibited cell-mediated organ damage than priming of the humoral immune response. Accordingly, a significant reduction of IFN-gamma, TNF-alpha, and TGF-beta1 mRNA in kidneys from animals that received Treg injection was observed. Tracking of enhanced green fluorescence protein-transgenic Treg revealed a predominant migration to secondary lymphoid organs with a significant increase of regulatory T cells (CD4+CD25+CD69-CD45RB(low)) in the lymph nodes. In contrast, enhanced green fluorescence protein-and FoxP3-positive cells by reverse transcription-PCR and CD4+CD25+CD69-CD45RB(low) T cells by flow cytometry in the kidney of nephritic animals were not detected. This report provides first evidence that Treg are potent suppressors of anti-GBM GN. Treg therefore might be of therapeutic value for the treatment of severe GN in humans.
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PMID:CD4+CD25+ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice. 1582 6

In the course of the disease, a wide variety of cytokines is dysregulated, many of which likely influence systemic lupus erythematosus (SLE) autoimmunity and/or lupus tissue inflammation. Proinflammatory cytokines in particular, such as TNF, IL-6, IL-18 or IFN-gamma, may play a major role in propagating the inflammatory processes responsible for tissue damage. These cytokines are overexpressed both systemically and locally, and preliminary results from open-label trials and/or animal studies suggest potential benefits of blocking either of these inflammatory mediators. Since new therapeutic agents may soon offer many ways to influence the process, controlled clinical trials following open-label safety studies are of central importance to arrive at optimized therapies for SLE patients.
Lupus 2005
PMID:Anti-cytokine therapy in systemic lupus erythematosus. 1580 94

Natural killer T (NKT) cells are a subset of T cells that share properties of natural killer cells and conventional T cells. They are involved in immediate immune responses, tumor rejection, immune surveillance and control of autoimmune diseases. Most NKT cells express both an invariant T cell antigen receptor and the NK cell receptor NK1.1, and are referred to as invariant NKT cells. This invariant T cell receptor is restricted to interactions with glycolipids presented by the non-classical MHC, CD1d. These NKT cells rapidly produce high levels of interleukin (IL)-2, IFN-gamma, TNF-alpha, and IL-4 upon stimulation through their TCR. Most also have cytotoxic activity similar to NK cells. NKT cells are involved in a number of pathological conditions, and have been shown to regulate viral infections in vivo, and control tumor growth. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma.
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PMID:Natural killer T cells: rapid responders controlling immunity and disease. 1583 65

Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the role of specific genes in lupus, we have examined the effects of single gene deletions on mercury-induced autoimmunity. Deficiency of certain genes abrogated induction of autoimmunity, while absence of others had little effect. The most interesting observations were obtained with genes related to interferon-gamma. Genes involved in upregulation of IFN-gamma expression did not significantly influence autoimmunity whereas absence of IFN-gamma or IFN-gamma receptor led to greatly reduced autoantibody responses and immunopathology. Absence of IRF-1, a gene expressed in response to IFN-gamma, resulted in selective retention of anti-chromatin autoantibodies demonstrating that specific defects in signaling pathways and gene expression subsequent to IFN-gamma/IFN-gamma receptor interaction influence specific disease parameters. These studies show that single gene deletions can have various outcomes ranging from no effect, suppression of one or more features of disease, to suppression of all features of disease, and that all three outcomes can be observed in the IFN-gamma pathway. IFN-gamma influences the expression and function of other lupus relevant genes such as IL-6 and beta2microglobulin, therefore the effects of these gene deletions on disease expression may also reflect responses downstream of IFN-gamma function.
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PMID:Immunology and genetics of induced systemic autoimmunity. 1599 75

The use of mAbs to abrogate costimulatory interactions has attracted much attention with regard to prevention and modulation of adverse (auto)immune-like reactions. However, the role of costimulatory molecules and possible therapeutic use of Ab-treatment in drug-induced immunostimulation is poorly elucidated. In the present studies, we show that CD28/CTLA-4-CD80/CD86 costimulatory interactions differently regulate drug-induced type 1 and type 2 responses to an identical bystander Ag, TNP-OVA, in BALB/c mice using the reporter Ag popliteal lymph node assay. The antirheumatic drug D-Penicillamine, which may induce lupus-like side-effects, stimulated type 2 responses against TNP-OVA, characterized by the production of IL-4 and TNP-specific IgG1 and IgE. These responses were abrogated in CD80/CD86-deficient mice and in wild-type mice that were treated with anti-CD80 and anti-CD86, or CTLA-4-Ig. Anti-CTLA-4 intensively enhanced the D-Penicillamine-induced effects. In contrast, the type 1 response (IFN-gamma, TNF-alpha, IgG2a) to TNP-OVA induced by the diabetogen streptozotocin still developed in the absence of CD80/CD86 costimulatory signaling. In addition, it was demonstrated that coadministration of anti-CD80 and anti-CD86 mAbs slightly enhanced streptozotocin-induced type 1 responses, whereas the CTLA-4-Ig fusion protein completely abrogated this response. In conclusion, different drugs may stimulate distinct types of immune responses against an identical bystander Ag, which are completely dependent on (type 2) or independent of (type 1) the CD28/CTLA-4-CD80/CD86 pathway. Importantly, the effects of treatment with anti-CD80/CD86 mAbs and CTLA-4-Ig may be considerably different in responses induced by distinct drugs.
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PMID:Differential requirement for CD28/CTLA-4-CD80/CD86 interactions in drug-induced type 1 and type 2 immune responses to trinitrophenyl-ovalbumin. 1614 16

The development and progression of systemic lupus erythematosus (SLE) is strongly associated with complement activation and deposition. To characterize the role of C5a and its receptor (C5aR) in SLE, C5aR-deficient mice were backcrossed nine generations onto the lupus-like MRL(lpr) genetic background. Evidence is presented that C5aR modulates both renal injury and T cell responses in MRL(lpr) mouse. C5aR-deficient MRL(lpr) mice had prolonged viability, with a mean survival time of 33.0 wk compared with 22.6 wk in control mice. Renal injury was also attenuated in the C5aR-/- MRL(lpr) mice. At 20 wk of age C5aR-/- MRL(lpr) mice had a complete absence of glomerular crescents and marked reductions in glomerular hypercellularity. There was no difference in the degree of glomerular C3 deposition; however, IgG deposits were reduced in the C5aR-/- MRL(lpr) mice. The reduction in glomerular injury was also associated with a four-fold decrease in renal CD4+ T cell infiltrates. Whereas there were modest differences in total IgG anti-dsDNA antibody titers, C5aR-deficient mice had 3.5-fold higher levels of IgG1 and 15-fold lower levels of IgG2a anti-dsDNA antibody titers compared to controls. The differences in anti-dsDNA IgG subclasses were associated with reduced CD4+ Th-1 responses in the C5aR-/- MRL(lpr) mice, including diminished production of IL-12p70, IFN-gamma, and increased expression of the Th-2 transcription factor GATA-3. These findings indicate that the C5aR plays a major role in modulating complement-dependent renal injury and T helper cell Th-1 responses in the MRL(lpr) mouse.
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PMID:C5a receptor deficiency attenuates T cell function and renal disease in MRLlpr mice. 1620 26

Excessive T helper cell function is a hallmark of systemic lupus erythematosus and abnormalities of T helper cytokine profiles have been implicated in loss of immune tolerance, increased antigenic load, defective B cell suppression and a variety of clinical manifestations. Here, we emphasize the importance of T helper 1-type (i.e., IFN-gamma) with respect to T helper 2-type (i.e., IL-4) cytokines in promoting the pathogenesis of lupus nephritis focusing on the critical role of IL-18, a major T helper 1 differentiation factor. IL-18 is overexpressed in patients with lupus nephritis along with higher INF-gammaand lower IL-4 production as compared to non-nephritic lupus patients. We hypothesize a pathogenic model where both the onset and aggravation of nephritis are promoted by an imbalance of immune response towards a T helper 1 cytokine predominance due to IL-18 up-regulation. In contrast, a T helper 2-skewed cytokine profile may possibly prevent the development of renal disease. In this context, IL-18 represents a novel marker of lupus nephritis and its measurement may be helpful in the assessment of patients.
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PMID:Th1 cytokines in the pathogenesis of lupus nephritis: the role of IL-18. 1621 93

Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-gamma and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ-lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a 'butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis.
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PMID:Systemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strains. 1622 14

MRL/MpJ-Tnfrsf6lpr (MRL-Faslpr) mice develop a spontaneous T cell-dependent autoimmune disease that shares features with human lupus, including fatal nephritis, systemic pathology, and autoantibodies (autoAb). The inducible co-stimulator (ICOS) is upregulated on activated T cells and modulates T cell-mediated responses. To investigate whether ICOS has an essential role in regulating autoimmune lupus nephritis and the systemic illness in MRL-Faslpr mice, ICOS null (-/-) MRL Faslpr and ICOS intact (+/+) MRL-Faslpr strains (wild-type [WT]) were generated and compared. It was determined that in ICOS-/- MRL-Faslpr as compared with the WT strain, (1) there is a significant reduction in circulating IgG and double-stranded DNA autoantibody isotype titers, and (2) there is an amplification of the frequency of intrarenal T cells generating IFN-gamma and TNF-alpha in ICOS-/- versus WT mice. Of note, eliminating ICOS in the MRL-Faslpr strain does not alter renal pathology or function. Despite the reduction in circulating IgG and autoantibody isotypes (G1, G2a, and G2b), the amount of these IgG isotypes depositing in kidneys is similar. Furthermore, the systemic illness (skin, salivary and lacrimal glands, lungs, lymphadenopathy, and splenomegaly) is equivalent in ICOS-/- MRL-Faslpr and WT mice. These findings highlight the danger of relying on individual parameters, such as quantitative serum Ig levels and T cell functions, as prognostic indicators of lupus.
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PMID:Inducible co-stimulator null MRL-Faslpr mice: uncoupling of autoantibodies and T cell responses in lupus. 1629 36

We investigated in vivo the relationship between the degree of peripheral blood lymphocyte apoptosis and circulating dendritic cells (DC) as well as the immunological status in 45 patients with systemic lupus erythematous (SLE). Apoptosis was detected by phosphatidylserine externalization and assays to detect caspase activation. The total DC count (tDC) and their myeloid, mDC1 (BDCA1+) and mDC2 (BDCA3+), and plasmacytoid, pDC (BDCA3+), subtypes were assessed. Moreover, several immunological parameters, such as complement proteins, interferons (IFN), tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-6 levels were assessed. There were no significant differences in both the intensity of apoptosis and DC counts between active and inactive SLE as well as between untreated patients and those treated with steroids. The incidence of lymphocyte apoptosis correlated positively with T-cell count, both T-helper (p=0.004) and cytotoxic T cells (p=0.001), but not with B or natural killer (NK) cells. The intensity of apoptosis enhanced along with the increase in complement C3 (p=0.016) and decrease in IFN-gamma (p=0.040) levels. The apoptotic cell count correlated with tDC (p=0.031), mDC1 (p=0.007), and pDC (p=0.039) counts. Both tDC and mDC1 counts correlated positively with antinuclear antibody (ANA) titers (p=0.017 and 0.032, respectively). Moreover, tDC correlated with C4 (p=0.039) and pDC with both C3 (p=0.032) and C4 (p=0.007) levels. The DC counts correlated inversely with IFN-gamma (tDC, p=0.038; mDC1, p=0.009), IL-6 (mDC2, p=0.031), or serum IgG levels (tDC, p=0.006; mDC1, p<0.001; mDC2, p=0.001). We found a positive correlation between lymphocyte apoptosis and peripheral blood DC count as well as the level of complement proteins in patients with SLE. The enhanced lymphocyte apoptosis was accompanied by the decrease in concentration of some cytokines, such as IFN-gamma or IL-6, as well as serum IgG level. This finding may reflect pathogenetic events during development of the disease, which include a persistent signal derived from circulating apoptotic lymphocytes, mobilizing the complement system, and attracting peripheral blood DC.
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PMID:Peripheral blood lymphocyte apoptosis and circulating dendritic cells in patients with systemic lupus erythematosus: correlation with immunological status and disease-related symptoms. 1643 61


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