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)

Plasmacytoid dendritic cells (pDC), the major interferon-producing cell type found in human blood, have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies in SLE have shown substantial deviations from normal in this minor but immunologically important leukocyte population. Many of the lupus patients studied were receiving corticosteroids. To determine the effects of steroid administration on pDC in healthy adults, four volunteers were given prednisone, 15-30 mg daily, for 4 days. Both counts of pDC, and their ability to produce IFN-alpha were significantly reduced (P = 0.02 and 0.004, respectively) during steroid administration, and rapidly recovered after discontinuation of the hormones. The overall reduction in pDC-derived IFN appeared to be attributable to falls of both number of circulating cells and of IFN produced per pDC. The effects observed with pDC were comparable in magnitude but opposite in direction to that observed for granulocytes. In contrast other blood leukocytes were little affected during steroid therapy.
Lupus 2003
PMID:Circulating human plasmacytoid dendritic cells are highly sensitive to corticosteroid administration. 1270 87

Systemic lupus erythematosus (SLE), a complex multigenic disease, is characterized by hypergammaglobulinemia, autoantibody production and immune complex-type lupus nephritis. In addition to these signs and symptoms in SLE, there can be symptoms of neurological disorders, including anxiety. To clarify mechanisms governing the anxiety seen in lupus, we carried out genome-wide scans, and found that the region including interferon-alpha (IFN-alpha) on NZB chromosome 4 is significantly linked to the anxiety-like behavior seen in SLE-prone New Zealand Black (NZB) x New Zealand White (NZW) F(1) (B/W F(1)) mice. This finding was confirmed by anxiety-like performances of mice with heterozygous NZB/NZW alleles in the susceptibility region onto the NZW background. In B/W F(1) mice, neuronal IFN-alpha levels were elevated, and blockade of the micro (1) opioid receptor or corticotropin-releasing hormone receptor 1, possible downstream effectors for IFN-alpha in the brain partially overcame the anxiety-like behavior seen in the B/W F(1) mice. Consistently, neuronal corticotropin-releasing hormone levels were higher in B/W F(1) than NZW mice. Furthermore, pretreatment of micro (1) opioid receptor antagonist abolished anxiety-like behaviour seen in IFN-alpha-treated NZW mice. Anxiety is shown to be mediated by multiple mediators. Our data suggest that a genetically determined endogenous excess amount of IFN-alpha in the brain may form one aspect of anxiety-like behavior seen in SLE-prone mice.
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PMID:Genetic dissection of anxiety in autoimmune disease. 1271 72

Leukopenia and anaemia are observed in about a fifth of all patients with systemic lupus erythematosus (SLE) and may be due either to the destruction of blood cells or their decreased production. The former may be humoral or cell-mediated or result from apoptosis of peripheral blood cells. Several observations suggest the occurrence of the latter reduced in vitro proliferation of pluripotent bone marrow progenitors from the bone marrow aspirates of SLE patients,reduced counts of CD34+ cells in bone marrow aspirates in SLE patients, apoptosis of lymphopoietic progenitors and apoptosis of bone marrow cells. The aim of our study was to investigate whether humoral factors may induce suppression of haematopoiesis by increased apoptosis of CD34+ cells. For this purpose, we incubated allogeneic CD34+-enriched cells with sera of 18 leukopenic SLE patients. Apoptosis was induced by four of 18 sera. This effect was independent of complement-inhibition and FAS-blockade. Although reduced proliferation of autologous pluripotent bone marrow progenitors has been attributed to an IgG serum inhibitor, removal of IgG from these four proapoptotic sera had no effect on apoptosis of allogeneic CD34+ cells. The proapoptotic effect was associated with high titres of anti-dsDNA antibodies and low haemoglobin concentrations, but not with high titres of antinuclear antibodies, TNF-alpha and IFN-alpha of the sera tested.
Lupus 2003
PMID:Apoptosis of CD34+ cells after incubation with sera of leukopenic patients with systemic lupus erythematosus. 1287 50

The objective was to study the occurrence of autoantibodies and cytokines in serum and cerebrospinal fluid (CSF) in neuropsychiatric systemic lupus erythematosus (NPSLE). In total, 28 consecutive patients with NPSLE and 16 systemic lupus erythematosus (SLE) patients without neuropsychiatric involvement (non-NPSLE) were studied. IFN-alpha, IL-6, IL-10, soluble terminal complement complex (TCC), anti-ribosomal P protein antibodies (anti-P) and anti-cardiolipin antibodies (aCL) were measured in serum and CSF by immunoassays. Analyses of white blood cell differential count, CSF-albumin/serum-albumin ratio, IgG-index in CSF and isoelectric focusing in serum and CSF were also performed. CSF specimens from 23 healthy individuals were used as controls. IFN-alpha was elevated in the CSF of 5 of 28 NPSLE patients compared to three of 14 among the non-NPSLE patients. IL-6 was elevated in CSF in three of 26 NPSLE patients. Normal concentration of IL-10 was found in CSF in all 27 NPSLE-patients analysed. IFN-alpha in serum was elevated in 18 of 28 NPSLE patients. No distinct clinical phenotype was related to elevated cytokine concentration in serum or CSF. One patient with cerebral involvement complicated by progressive multifocal leukoencephalopathy displayed a very high IFN-alpha concentration in serum. High concentration of TCC was present in CSF from only one patient with systemic vasculitis and focal cerebral symptoms. In conclusion, the results of this study suggest that the diagnostic value of serum and CSF concentrations of IFN-alpha, IL-10, IL-6 and TCC is limited in unselected neuropsychiatric SLE, probably due to the heterogeneity of NPSLE pathogenesis.
Lupus 2003
PMID:The heterogeneity of neuropsychiatric systemic lupus erythematosus is reflected in lack of association with cerebrospinal fluid cytokine profiles. 1466 1

Altered regulation of interferon-alpha (IFNalpha) in systemic lupus erythematosus (SLE) was first demonstrated nearly 25 years ago. However, only recently has due attention been directed towards the central role of this cytokine family in SLE. Several laboratories have used large-scale microarray technology to study global gene expression patterns in heterogeneous populations of peripheral blood cells from lupus patients and control subjects. The results of these studies demonstrate that IFN-regulated genes are among the most significantly overexpressed in SLE mononuclear cells. In view of the protean effects of IFNs on immune system function, increased activity of IFNs may account for many of the immune system alterations that characterize SLE and contribute to autoimmunity. Definition of the nature of the major IFNs, or other factors, that drive the IFN-regulated gene expression signature noted in SLE is an important area for investigation that may lead to new approaches to targeted therapy of SLE.
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PMID:Microarray analysis of interferon-regulated genes in SLE. 1498 25

Systemic lupus erythematosus (SLE), like other autoimmune diseases, is a complex genetic trait with contributions from both major histocompatibility complex (MHC) genes and multiple non-MHC genes. Most of the contributing genes have yet to be identified. Studies of mouse models of lupus have provided important insight into the immunopathogenesis of lupus-like IgG autoantibody production and lupus nephritis, and genetic analyses of these mice are helping to unravel the complex and heterogeneous genetic basis of disease. Recent studies in both human SLE and mouse models of lupus have emphasized a potential role of type I interferons (IFN-alpha/beta) in the initiation and perpetuation of disease. There is now increasing interest in genes that affect IFN-alpha/beta expression-activity and IFN-regulated target genes that may be involved in the disease process. One example is interferon-inducible gene 202 (Ifi202), which has been identified as a major candidate susceptibility gene in the New Zealand hybrid model of lupus. Studies suggest that increased expression of this transcription factor leads to lupus through inhibition of lymphocyte apoptosis, although its effects on immune function are extremely complex and have yet to be fully defined. This review will focus on the genetic basis of disease in mouse lupus with a special emphasis on those genetic contributions that may affect IFN-alpha/beta activity and those that may be target genes of IFN-alpha/beta action.
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PMID:Links between type I interferons and the genetic basis of disease in mouse lupus. 1498 26

Type I interferons (IFN-alphabeta) are immunoregulatory cytokines that promote both innate and adaptive immune responses. Although they have been implicated in human SLE, recent studies in mice have helped solidify this connection. By using lupus-prone mice with knockout of the IFN-alphabeta receptor, we and others have documented that lack of IFN-alphabeta leads to a marked reduction in disease manifestations, including autoantibody production, target organ damage and mortality. Furthermore, IFN-alphabeta was found to potentially contribute to several levels of disease pathogenesis. These included the differentiation and activation of dendritic cells, the activation and proliferation of T cells, T cell survival and the activation and survival of autoantibody-producing B cells. These findings strongly support the targeting of IFN-alphabeta in SLE and suggest that definition of the specific pathways critical for disease induction will be important for optimal intervention.
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PMID:Inhibition of lupus by genetic alteration of the interferon-alpha/beta receptor. 1498 27

The molecular pathogenesis of focal/diffuse proliferative lupus glomerulonephritis was studied by cDNA microarray analysis of gene expression in glomeruli from clinical biopsies. Transcriptional phenotyping of glomeruli isolated by laser-capture microscopy revealed considerable kidney-to-kidney heterogeneity in increased transcript expression, resulting in four main gene clusters that identified the presence of B cells, several myelomonocytic lineages, fibroblast and epithelial cell proliferation, matrix alterations, and expression of type I IFN-inducible genes. Glomerulus-to-glomerulus variation within a kidney was less marked. The myeloid lineage transcripts, characteristic of those found in isolated activated macrophages and myeloid dendritic cells, were widely distributed in all biopsy samples. One major subgroup of the samples expressed fibrosis-related genes that correlated with pathological evidence of glomerulosclerosis; however, decreased expression of TGF-beta1 argued against its role in lupus renal fibrosis. Expression of type I IFN-inducible transcripts by a second subset of samples was associated with reduced expression of fibrosis-related genes and milder pathological features. This pattern of gene expression resembled that exhibited by activated NK cells. A large gene cluster with decreased expression found in all samples included ion channels and transcription factors, indicating a loss-of-function response to the glomerular injury.
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PMID:Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli. 1519 7

Both the type I (IFN-alpha beta) and type II (IFN-gamma) IFNs have been heavily implicated in the pathogenesis of systemic lupus erythematosus. To test the relative roles of these systems, congenic lupus-prone MRL/CD95(lpr/lpr) (MRL/lpr) mice lacking the type I IFN receptor (IFN-RI), type II IFN receptor (IFN-RII), or both, were derived. As expected, deficiency for IFN-RII protected MRL/lpr mice from the development of significant autoimmune-associated lymphadenopathy, autoantibodies, and renal disease. However, deficiency for the IFN-RI surprisingly worsened lymphoproliferation, autoantibody production, and end organ disease; animals doubly deficient for IFN-RI and IFN-RII developed an autoimmune phenotype intermediate between wild-type and IFN-RII-deficient animals, all correlating with an ability of type I IFN to suppress MRL B cell activation. Thus, type I IFNs protect against both the humoral and end organ autoimmune syndrome of MRL/lpr mice, independent of IFN-gamma. These findings warrant caution in the use of type I IFN antagonists in the treatment of autoimmune diseases and suggest further investigation into the interplay between the types I and II IFNs during the ontogeny of pathogenic autoantibodies.
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PMID:Type I IFN protects against murine lupus. 1526 50

One of the most interesting functions of the placenta is the regulation of the maternal immune response such that the fetal semi-allograft is tolerated during pregnancy. Trophoblasts are presumed to be essential to this phenomenon because they lie at the maternal-fetal interface, where they are in direct contact with cells of the maternal immune system. Trophoblasts do not express classic major histocompatibility complex (MHC) class II molecules. Surprisingly, cytotrophoblasts express more HLA-G, a MHC class Ib molecule, as they invade the uterus. Progesterone plays an important role in postovulatory regulation of the menstrual cycle. If fertilization occurs, progesterone supports implantation of the ovum and maintains the pregnancy. Progesterone has been named the 'hormone of pregnancy', because in preparing the endometrium for embryo implantation and facilitating endometrial development, it is critical to the very survival of a pregnancy. In addition, this key hormone inhibits the rejection of T cell-mediated tissue and also decreases myometrial activity and sensitivity throughout pregnancy. The cellular actions of progesterone are mediated through intracellular progesterone receptors (PRs), which are well studied gene regulators, not express classic major histocompatibility complex. The more used paradigm is relative to the alteration of relationship TH1/TH2, but the complexity of the respective distributions of cytokines at the materno-fetal interface, strongly suggest that, as useful as it certainly was for a while, the Th1/Th2 paradigm must now be considered as an oversimplification. Rather, the existing data point to sequential windows and are suggestive of a system where an extreme complexity is allied to very precise timing and tuning. They also suggest that the materno-fetal relationship is not simply maternal tolerance of a foreign tissue, but a series of intricate mutual cytokine interactions governing selective immune regulation and also control of the adhesion and vascularization processes during this dialogue. However, as shifting the immune response toward the Th2 pattern (IL-4, IL-5, IL-6) may benefit the fetus, whereas development of proinflammatory Th1 cells (secreting IL-2, IFN g, TNF a) may be harmful. Now we are working to open comprise the precise behaviour of NK populations, with the hope of obtaining a diagnostic test of the condition of abortion from 'immunological causes'.
Lupus 2004
PMID:Progesterone supplement in pregnancy: an immunologic therapy? 1548 93


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