Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have indicated that the autoimmune phenomenon might be caused by an imbalance of T helper cell (Th) cytokines. We measured the plasma concentrations of three novel proinflammatory cytokines interleukin (IL)-17, IL-18, IL-12 and a key Th2 cytokine IL-4 in patients with systemic lupus erythematosus (SLE) and correlated the ratio of proinflammatory/Th2 cytokines with SLE disease activity index (SLEDAI). Plasma IL-12, IL-17, IL-18 and IL-4 concentrations of 36 SLE patients and 18 sex- and age-matched control subjects were measured by enzyme linked immunosorbent assay. All were significantly higher in SLE patients than control subjects (IL-12, mean+/-s.d. of 166.7+/-84.5 vs 93.5+/-39.2 pg/ml, P<0.001; IL-17, 76.5+/-45.7 vs 37.6+/-35.3 pg/ml, P=0.002; IL-18, 368.7+/-199. 5 vs 141.1+/-47.1 pg/ml, P<0.001; and IL-4, 27.1+/-15.3 vs 17.3+/-7. 2 pg/ml, P<0.05), and IL-18/IL-4 ratio correlated positively and significantly with SLEDAI score (r=0.435, P=0.006). We propose that SLE is characterized by an elevation of both Th1 and Th2 cytokines: the elevation of proinflammatory cytokine IL-12, IL-17 and IL-18 may trigger the inflammatory process in SLE and the elevation of IL-18/IL-4 ratio suggests an imbalance of cytokine profile to mediate the inflammatory response.
Lupus 2000
PMID:Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus. 1103 33

Type I interferons (IFN) (IFN-alpha/beta) are recognized as both inhibitors and effectors of autoimmune disease. In multiple sclerosis, IFN-beta therapy appears beneficial, in part, due to its suppression of autoimmune inflammatory Th cell responses. In contrast, in systemic lupus erythematosus (SLE) triggering of plasmacytoid DC (pDC) Toll-like receptors (TLRs) by autoimmune complexes (autoICs) results in circulating type I IFN that appear to promote disease by driving autoantigen presentation and autoantibody production. To investigate how pDC-derived type I IFN might regulate Th cells in SLE, we examined a model in which sustained pDC stimulation by autoICs is mimicked by pretreating normal human PBMC with TLR9 agonist, CpG-A. Subsequently, PBMC Th cells are activated with superantigen, and APC are activated with CD40L. The role of CpG-A/TLR9-induced type I IFN in regulating PBMC is determined by blocking with virus-derived soluble type I IFN receptor, B18R. In summary, pretreatment with either rhIFN-alpha/beta or CpG-A inhibits PBMC secretion of superantigen-induced IFN-gamma and IL-17, and CD40L-induced IL-12p70 and IL-23. B18R prevents these effects. Data indicate that CpG-A-induced type I IFN inhibit IL-12p70-dependent PBMC IFN-gamma secretion by enhancing IL-10. Our results suggest that in SLE, circulating type I IFN may potentially act to inhibit inflammatory cytokine secretion.
 ...
PMID:Blockade of TLR9 agonist-induced type I interferons promotes inflammatory cytokine IFN-gamma and IL-17 secretion by activated human PBMC. 1705 15

IL-23-dependent IL-17-producing T helper (Th) lymphocytes are associated with autoimmunity. We investigated the immunopathological mechanisms for activation of Th17 cells of patients with systemic lupus erythematosus (SLE). Concentration of cytokines/chemokine in plasma and culture supernatant from SLE patients and healthy controls were measured by ELISA or flow cytometry. Plasma IL-12, IL-17, IL-23 and CXCL10 concentrations and the number of Th17 cells were significantly elevated in SLE patients than control subjects (both p<0.05). Elevated IL-12, IL-17 and CXCL10 concentrations correlated positively and significantly with SLEDAI (all p<0.05). Plasma IL-12 and IL-17 showed significant and positive correlation with plasma Th1 chemokine CXCL10 concentration in SLE patients (all p<0.05). Ex vivo inductions of IL-17 by IL-23 or IL-18 from co-stimulated lymphocytes were significantly higher in SLE patients than controls (all p<0.05). The activated IL-23/IL-17 axis is important for the inflammatory immunity in SLE.
 ...
PMID:Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. 1837 53

Nuclear factor-kappaB (NF-kappaB) is an inducible transcription factor controlled by two principal signaling cascades, each activated by a set of signal ligands: the classical/canonical NF-kappaB activation pathway and the alternative/noncanonical pathway. The former pathway proceeds via phosphorylation and degradation of inhibitor of NF-kappaB (IkappaB) and leads most commonly to activation of the heterodimer RelA/NF-kappaB1(p50). The latter pathway proceeds via phosphorylation and proteolytic processing of NF-kappaB2 (p100) and leads to activation, most commonly, of the heterodimer RelB/NF-kappaB2 (p52). Both pathways play critical roles at multiple levels of the immune system in both health and disease, including the autoimmune inflammatory response. These roles include cell cycle progression, cell survival, adhesion, and inhibition of apoptosis. NF-kappaB is constitutively activated in many autoimmune diseases, including diabetes type 1, systemic lupus erythematosus, and rheumatoid arthritis (RA). In this review we survey recent developments in the involvement of the classical and alternative pathways of NF-kappaB activation in autoimmunity, focusing particularly on RA. We discuss the involvement of NF-kappaB in self-reactive T and B lymphocyte development, survival and proliferation, and the maintenance of chronic inflammation due to cytokines such as tumor necrosis factor-alpha, IL-1, IL-6, and IL-8. We discuss the roles played by IL-17 and T-helper-17 cells in the inflammatory process; in the activation, maturation, and proliferation of RA fibroblast-like synovial cells; and differentiation and activation of osteoclast bone-resorbing activity. The prospects of therapeutic intervention to block activation of the NF-kappaB signaling pathways in RA are also discussed.
 ...
PMID:The roles of the classical and alternative nuclear factor-kappaB pathways: potential implications for autoimmunity and rheumatoid arthritis. 1877 89

Lupus is an Ab-mediated autoimmune disease. One of the potential contributors to the development of systemic lupus erythematosus is a defect in naturally occurring CD4(+)CD25(+) regulatory T cells. Thus, the generation of inducible regulatory T cells that can control autoantibody responses is a potential avenue for the treatment of systemic lupus erythematosus. We have found that nasal administration of anti-CD3 mAb attenuated lupus development as well as arrested ongoing lupus in two strains of lupus-prone mice. Nasal anti-CD3 induced a CD4(+)CD25(-)latency-associated peptide (LAP)(+) regulatory T cell that secreted high levels of IL-10 and suppressed disease in vivo via IL-10- and TFG-beta-dependent mechanisms. Disease suppression also occurred following adoptive transfer of CD4(+)CD25(-)LAP(+) regulatory T cells from nasal anti-CD3-treated animals to lupus-prone mice. Animals treated with nasal anti-CD3 had less glomerulonephritis and diminished levels of autoantibodies as measured by both ELISA and autoantigen microarrays. Nasal anti-CD3 affected the function of CD4(+)ICOS(+)CXCR5(+) follicular helper T cells that are required for autoantibody production. CD4(+)ICOS(+)CXCR5(+) follicular helper T cells express high levels of IL-17 and IL-21 and these cytokines were down-regulated by nasal anti-CD3. Our results demonstrate that nasal anti-CD3 induces CD4(+)CD25(-)LAP(+) regulatory T cells that suppress lupus in mice and that it is associated with down-regulation of T cell help for autoantibody production.
 ...
PMID:Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+ CD25- LAP+ regulatory T cell and is associated with down-regulation of IL-17+ CD4+ ICOS+ CXCR5+ follicular helper T cells. 1894 Nov 93

Double negative (DN) T cells are expanded in patients with systemic lupus erythematosus (SLE) and stimulate autoantibody production as efficiently as CD4(+) T cells. In this study, we demonstrate that DN T cells from patients with SLE produce significant amounts of IL-17 and IFN-gamma, and expand when stimulated in vitro with an anti-CD3 Ab in the presence of accessory cells. Furthermore, IL-17(+) and DN T cells are found in kidney biopsies of patients with lupus nephritis. Our findings establish that DN T cells produce the inflammatory cytokines IL-17 and IFN-gamma, and suggest that they contribute to the pathogenesis of kidney damage in patients with SLE.
 ...
PMID:Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. 1905 Feb 97

Interleukin 21 (IL-21) is a pleiotropic cytokine produced by CD4 T cells that affects the differentiation and function of T, B, and NK cells by binding to a receptor consisting of the common cytokine receptor gamma chain and the IL-21 receptor (IL-21R). IL-21, a product associated with IL-17-producing CD4 T cells (T(H)17) and follicular CD4 T helper cells (T(FH)), has been implicated in autoimmune disorders including the severe systemic lupus erythematosus (SLE)-like disease characteristic of BXSB-Yaa mice. To determine whether IL-21 plays a significant role in this disease, we compared IL-21R-deficient and -competent BXSB-Yaa mice for multiple parameters of SLE. The deficient mice showed none of the abnormalities characteristic of SLE in IL-21R-competent Yaa mice, including hypergammaglobulinemia, autoantibody production, reduced frequencies of marginal zone B cells and monocytosis, renal disease, and premature morbidity. IL-21 production associated with this autoimmune disease was not a product of T(H)17 cells and was not limited to conventional CXCR5(+) T(FH) but instead was produced broadly by ICOS(+) CD4(+) splenic T cells. IL-21 arising from an abnormal population of CD4 T cells is thus central to the development of this lethal disease, and, more generally, could play an important role in human SLE and related autoimmune disorders.
 ...
PMID:A critical role for IL-21 receptor signaling in the pathogenesis of systemic lupus erythematosus in BXSB-Yaa mice. 1916 19

TNF-alpha has both proinflammatory and immunoregulatory functions. Whereas a protective role for TNF administration in systemic lupus erythematosus (SLE)-prone (New Zealand Black x New Zealand White)F(1) mice has been established, it remains uncertain whether this effect segregates at the individual TNFR. We generated SLE-prone New Zealand Mixed 2328 mice genetically deficient in TNFR1, in TNFR2, or in both receptors. Doubly-deficient mice developed accelerated pathological and clinical nephritis with elevated levels of circulating IgG anti-dsDNA autoantibodies and increased numbers of CD4(+) T lymphocytes, especially activated memory (CD44(high)CD62L(low)) CD4(+) T cells. We show that these cells expressed a Th17 gene profile, were positive for IL-17 intracellular staining by FACS, and produced exogenous IL-17 in culture. In contrast, immunological, pathological, and clinical profiles of mice deficient in either TNFR alone did not differ from those in each other or from those in wild-type controls. Thus, total ablation of TNF-alpha-mediated signaling was highly deleterious to the host in the New Zealand Mixed 2328 SLE model. These observations may have profound ramifications for the use of TNF and TNFR antagonists in human SLE and related autoimmune disorders, as well as demonstrate, for the first time, the association of the Th17 pathway with an animal model of SLE.
 ...
PMID:Accelerated pathological and clinical nephritis in systemic lupus erythematosus-prone New Zealand Mixed 2328 mice doubly deficient in TNF receptor 1 and TNF receptor 2 via a Th17-associated pathway. 1920 10

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.
 ...
PMID:CD45RC isoform expression identifies functionally distinct T cell subsets differentially distributed between healthy individuals and AAV patients. 1938 Dec 93

Recent work has implicated a novel Th effector cell subset, the Th17 cell subset, in the development of both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) because of the ability of Th17 cells to produce cytokines like IL-17 and IL-21 that can drive both inflammatory and humoral responses. In this review, we will discuss recent studies that have begun elucidating the factors that regulate the development of Th17 cells and provide a brief overview of the role of Th17 cells in RA and SLE.
 ...
PMID:Th17 cells in rheumatoid arthritis and systemic lupus erythematosus. 2043 87


1 2 3 4 5 6 7 8 9 10 Next >>