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

B lymphocyte chemoattractant (BLC/CXCL13) is ectopically and highly expressed in the target organs such as the thymus and kidney in aged (NZB x NZW)F1 (BWF1) mice, a murine model for SLE. Ectopic expression of BLC/CXCL13 was attributed to mature myeloid DCs infiltrating in the target organs. DCs were also increased in the peripheral blood in aged BWF1 mice and differentiated into BLC/CXCL13-producing DCs in the presence of TNF-alpha or IL-1beta, but not IFN-alpha or IFN-gamma. BLC/CXCL13 expression in mature myeloid DCs was confirmed in bone marrow derived-DCs generated in vitro in the presence of GM-CSF and TNF-alpha. B1 cells expressed higher level of CXCR5 and migrated towards BLC/CXCL13 much better than B2 cells. B1 cells failed to home to the peritoneal cavity and preferentially recruited to the target organs in aged BWF1 mice developing lupus nephritis. B1, but not B2 cells possessed a potent antigen presenting activity in allo-MLR and activated autologous thymic CD4 T cells in the presence of IL-2. CXCR5+ CD4 T cells were also increased in aged BWF1 mice and they enhanced IgG production by B1 cells in vitro. These results suggest a possible involvement of aberrant B1 cell trafficking in activation of autoreactive CD4 T cells and autoantibody production in the target organs during the development of lupus, providing a new insight for the pathogenesis of B1 cells in lupus.
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PMID:Aberrant B1 cell trafficking in a murine model for lupus. 1712 21

T cells from patients with systemic lupus erythematosus (SLE) have high levels of cAMP response element modulator (CREM)-alpha which bind to the interleukin (IL-2) promoter and limit IL-2 production. In this case-controlled study, we show that CREM-alpha mRNA levels were higher in T cells from patients with SLE than controls while CREB mRNA levels did not differ between the two groups. CREM-alpha mRNA levels did not correlate with clinical characteristics, disease activity or treatment. Nevertheless, there was a trend for patients on high doses of corticosteroids to have low levels of CREM-alpha mRNA. The discovery of specific non-toxic medications that block the expression of CREM-alpha may prove useful in reversing the aberrant T cell function in SLE.
Lupus 2006
PMID:CAMP response element modulator a expression in patients with systemic lupus erythematosus. 1721 88

Systemic lupus erythematosus (SLE) is characterized by overactive B cells that differentiate into autoantibody-forming cells, aberrant T cell function that provides helping B cells produce autoantibodies, and overproduction of proinflammatory cytokines. However, immunodysregulation in lupus pathogenensis remains incomplete. We examined mitogen-stimulated production of proinflammatory cytokines, cell proliferation, T cell activation, and T cell apoptosis in vitro in pristane-induced lupus BALB/c mice compared to normal mice. LPS-stimulated production of IL-6 and IL-10 by splenocytes and macrophages from pristane-induced lupus mice were remarkably up-regulated compared to normal mice, whereas production of macrophage TNF-alpha was significantly down-regulated. Moreover, in vitro production of IL-2, IL-6, IL-10 and IFN-gamma by Con A-stimulated splenocytes, cell proliferation in LPS- or Con A-stimulated- thymocytes and splenocytes, and expression of CD69+CD4+ T cells in Con A-stimulated splenocytes were greatly increased in cells derived from pristane-induced lupus mice compared to normal mice. In addition, splenic T cells and CD4+ T cells in thymocytes from pristane-induced lupus mice were more resistant than nonautoimmune normal cells to Con A-induced apoptosis. Our findings indicate that immunoregulatory abnormalities of T cells and hyperreactivity of B cells in the in vitro immune responses in pristane-induced lupus mice may explain some of lupus pathogenesis.
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PMID:Immunoregulatory abnormalities of T cells and hyperreactivity of B cells in the in vitro immune response in pristane-induced lupus mice. 1736 41

IL-2 gene expression in activated T-cells is initiated by chromatin remodeling at the IL-2 proximal promoter and conversion of a transcriptional repressor into a potent transcriptional activator. A purine-box regulator complex was purified from activated Jurkat T-cell nuclei based on sequence-specific DNA binding to the antigen receptor response element (ARRE)/nuclear factor of activated T-cells (NF-AT) target DNA sequence in the proximal IL-2 promoter. ARRE DNA-binding subunits were identified as NF90, NF45 and systemic lupus erythematosis autoantigens, Ku80 and Ku70. Monoclonal antibodies to Ku80, Ku70 and NF90 specifically inhibit constitutive and inducible ARRE DNA-binding activity in Jurkat T-cells. Ku80, Ku70 and NF90 bind specifically to the IL-2 gene promoter in vivo, as demonstrated by chromatin immunoprecipitation. Activation of Jurkat T-cells and mouse primary spleen cells induces binding of Ku80 and NF90 to the IL-2 promoter in vivo, and decreases binding of Ku70 to the IL-2 promoter in vivo, and these dynamic changes are inhibited by immunosuppressants cyclosporin A and triptolide. Dynamic changes in binding of Ku80, Ku70 and NF90 to the IL-2 proximal promoter in vivo correlate with chromatin remodeling and transcriptional initiation in activated T-cells.
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PMID:Dynamic binding of Ku80, Ku70 and NF90 to the IL-2 promoter in vivo in activated T-cells. 1738 50

Regulatory T cell deficiency is evident in patients with lupus, but the casual [corrected] relationship and underlying mechanism leading to Treg deficiency are unclear. We analyzed the Treg profile, induction and functions of Treg in a lupus mouse model. A characteristic age-dependent biphasic change of Treg frequency was observed in the MRL/lpr mice, which developed a spontaneous lupus-like disease. After an early increase, Treg frequency in the peripheral lymphoid organs rapidly declined with age. Functionally, Treg from both young and old MRL/lpr mice were fully competent in suppressing the wild-type MRL/+ T effector cell (Teff) responses. Adoptive transfer of MRL/+ Treg markedly suppressed clinical disease in the MRL/lpr mice. We demonstrated that the reduced Treg frequency was a result of insufficient peripheral Treg expansion due to defective MRL/lpr Teff in IL-2 production, and the associated defects in dendritic cells, which could be fully restored by exogenous IL-2. In the absence of IL-2, MRL/lpr Teff but not MRL/lpr Treg were highly responsive to IL-15 and could expand rapidly due to enhanced IL-15R expression and IL-15 synthesis. These findings thus provide a clear causal relationship and immunological mechanism underlying Treg deficiency and systemic autoimmunity.
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PMID:Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: roles of IL-2 versus IL-15. 1846 74

Previous studies have shown that treatment of ovariectomized females with 17-beta estradiol (E2) accelerates the development of autoimmunity in the (NZBxNZW)F(1) murine lupus model. Treatment with estrogenic organochlorine pesticides (OCPs) such as chlordecone produces a similar effect. Although it is reasonable to postulate that the effects of chlordecone and related OCPs on autoimmunity are due to their estrogenic effects, this has not been clearly demonstrated. The objective of this study was to compare effects of chlordecone and E2 on splenic T lymphocyte parameters plausibly related to autoimmunity; specifically, on T-cell phenotype and functions. Ovariectomized (NZBxNZW)F(1) mice were treated for 6 weeks with implanted sustained-release pellets containing chlordecone or E2 at dosing rates shown previously to significantly shorten time to onset of disease. E2, but not chlordecone, increased the percentage of activated and memory CD4 T-cells, and reduced naive CD4 T-cells. E2 also elevated CD25 and glucocorticoid-induced TNF receptor (GITR) levels in CD4 T-cells, an effect not shared by chlordecone. On the other hand, both chlordecone and E2 increased Bcl-2 expression in CD4 T-cells and reduced CD4 T-cell apoptosis without affecting their proliferation. Although both treatments increased TNF-alpha and IL-2 secretion by CD4 T-cells, only chlordecone increased secretion of IFN-gamma and GM-CSF. E2, but not chlordecone, increased IL-10 secretion. These observations indicate that although it is considered an estrogenic OCP, chlordecone exerts effects on splenic T-cells that are different in a number of ways from E2.
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PMID:Comparison of chlordecone and estradiol effects on splenic T-cells in (NZBxNZW)F(1) mice. 1895 62

IL-2 plays a key role in setting the balance between immunity and tolerance. This cytokine has a dual role as the regulator of the two main phases of the immune response (proliferative and suppressive). Likewise, activation induced cell death and the induction and maintenance of regulatory T cells are the tolerance mechanisms regulated by IL-2, which convey the link between IL-2 abnormalities and the development of autoimmune disorders, such as systemic lupus erythematosus (SLE). Particularly, in SLE murine models and in humans, deficiency in IL-2 synthesis and activity has been proven. Diverse signaling pathways abnormalities (TCR, NF-kappaBeta, NF-AT) have been involved in the IL-2 transcriptional dysregulation displayed by T cells from SLE patients, and its functional relevance as part of the physiopathogenic scheme has been shown. Aberrant expression and activity of multiple IL-2 transcriptional factors, such as c-fos, and predominantly, CREM and CREB have been involved in this immune dysregulation. Diverse alterations in signaling kinases and phosphatases (PKA, PP2A, CAMKIV) and the modulation by epigenetic mechanisms have been related to the altered CREM/pCREB index. The synergic effect of multiple abnormalities in the transcriptional factors previously mentioned has been shown to be of functional relevance in lupus.
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PMID:Interleukin 2 and systemic lupus erythematosus: beyond the transcriptional regulatory net abnormalities. 1926 52

In this study, hypoproliferation and defects of effectors and cytokines in CD4(+) and CD8(+) T-cells via ICOS costimulation were found in active SLE patients, relative to normal individuals and RA patient controls. Exogenous IL-2 can partially reverse those defects. In addition, low level of ERK phosphorylation in ICOS-mediated signaling pathway was discovered in lupus CD4(+) and CD8(+) T-cells. When blocked with ERK-specific chemical inhibitor PD98059, cell proliferation and IL-2 production via ICOS costimulation from both CD4(+) and CD8(+) T-cells will be severely inhibited. These findings confirmed the dysfunction of both CD4(+) and CD8(+) T-cells after ICOS costimulation in lupus patients and most importantly pointed out that impairment of ERK activation might be one of the critical factors involved in ICOS-mediated IL-2 and T-cell hypoproliferation in active SLE.
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PMID:Defects of mitogen-activated protein kinase in ICOS signaling pathway lead to CD4(+) and CD8(+) T-cell dysfunction in patients with active SLE. 1937 99

In animal models of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), the proportion of CD45RC T cell subsets is important for disease susceptibility. Their human counterparts are, however, functionally ill defined. In this report, we studied their distribution in healthy controls (HC), AAV patients and in Systemic lupus erythematous (SLE) patients as disease controls. We showed that CD45RC expression level on human CD4 and CD8 T cells identifies subsets that are highly variable among individuals. Interestingly, AAV patients exhibit an increased proportion of CD45RC(low) CD4 T cells as compared to HC and SLE patients. This increase is stable over time and independent of AAV subtype, ANCA specificity, disease duration, or number of relapses. We also analyzed the cytokine profile of purified CD4 and CD8 CD45RC T cell subsets from HC, after stimulation with anti-CD3 and anti-CD28 mAbs. The CD45RC subsets exhibit different cytokine profiles. Type-1 cytokines (IL-2, IFN-gamma and TNF-alpha) were produced by all CD45RC T cell subsets, while the production of IL-17, type-2 (IL-4, IL-5) and regulatory (IL-10) cytokines was restricted to the CD45RC(low) subset. In conclusion, we have shown that CD45RC expression divides human T cells in functionally distinct subsets that are imbalanced in AAV. Since this imbalance is stable over time and independent of several disease parameters, we hypothesize that this is a pre-existing immune abnormality involved in the etiology of AAV.
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PMID:CD45RC isoform expression identifies functionally distinct T cell subsets differentially distributed between healthy individuals and AAV patients. 1938 Dec 93

Xanthohumol (XN), a prenylated chalcone present in hops (Humulus lupus L.) and beer, exhibits anti-inflammatory, antioxidant and antiproliferative activity, but has not been studied for effects on T cell-mediated immune responses. Here we demonstrate that XN has profound immunosuppressive effects on T cell proliferation, development of IL-2 activated killer (LAK) cells, cytotoxic T lymphocytes (CTLs), and production of Th1 cytokines (IL-2, IFN-gamma and TNF-alpha). The suppression of these cell-mediated immune responses by XN was at, least in part, due to the inhibition of nuclear factor kappa B (NF-kappaB) transcription factor through suppression of phosphorylation of IkappaBalpha, an inhibitor of NF-kappaB.
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PMID:Immunomodulatory activity of xanthohumol: inhibition of T cell proliferation, cell-mediated cytotoxicity and Th1 cytokine production through suppression of NF-kappaB. 1955


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