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)

Hydroxychloroquine has several less well-known actions that may have clinical relevance in treating systemic lupus erythematosus (SLE). (1) Hydroxychloroquine has a possible anti-thrombotic action. It is a platelet inhibitor and appears to decrease the risk of thromboembolism in patients with anticardiolipin antibodies. (2) Hydroxychloroquine is associated with lower serum cholesterol and low-density lipoprotein levels compared to those present in patients who are taking corticosteroids but not antimalarials for SLE. (3) It may also decrease abnormal levels of cytokines. Interleukin-6 (IL-6), soluble CD8 and soluble IL-2 receptors (sIL-2R) are lower in patients taking antimalarials compared to those on corticosteroids alone or on neither medication. Serum levels of CD8 and sIL-2R decrease after 6 weeks of hydroxychloroquine treatment. These findings may help explain the favorable response of SLE patients treated with antimalarials.
Lupus 1993 Feb
PMID:The relevance of antimalarial therapy with regard to thrombosis, hypercholesterolemia and cytokines in SLE. 848 65

In serum and plasma from SLE patients, we have detected elevated levels of factors which regulate proliferative responses of CTLL cells to IL-2. Serum samples containing these factors have dose-dependent dual inhibitory and stimulatory activities on the proliferation of this IL-2-dependent T lymphocyte cell line. At high concentrations, the serum factors inhibit the proliferative responses of CTLL cells to IL-2. At low concentrations, they synergise with IL-2 stimulating the growth of cells. Similar inhibitory activity, but with lower titre, was also found to be elevated in sera of some MRL/lpr mice, an animal model of SLE. Functional characterisation of the serum factors shows that: (1) the inhibitory activity cannot be neutralised by exogenous IL-2; (2) the stimulatory activity is not due to the presence of serum IL-2 but synergy of the factor with IL-2; (3) the factors bind directly to CTLL cells but they do not bind to protein A; and (4) the serum factors are not dialysable but heat labile. The possible pathological implications of the serum factors, particularly for the defective T cell functions in lupus disease, are discussed.
Lupus 1995 Aug
PMID:Dual inhibitory and stimulatory activities in serum from SLE patients and lupus mice that regulate the proliferation of an IL-2-dependent T cell line. 852 27

In the BXSB autoimmune disease-prone mouse strain, male mice develop severe lupus-like symptoms and die early in life (4-6 mo), whereas females do not. We have previously demonstrated that profound phenotypic and functional changes occur with age in CD4+ cells from BXSB males. CD4+ cells from males (4 mo old) were predominantly CD44high, CD45RBlow, and MEL-14low (activated/memory phenotypes), while the reciprocal phenotypes characteristic of naive cells were prevalent in age-matched females and young adult males (2 mo old). CD4+ cells from older males proliferated less and produced less IL-2 and IFN-gamma than cells from either females or young males in response to immobilized anti-CD3 mAb. We tested the effect of CTLA4Ig treatment on the progression of disease in BXSB males. CD4+ cells from CTLA4Ig-treated mice at 4 mo of age were predominantly CD44low, CD45RBhigh, and MEL-14high phenotypes that were identical with those observed in CD4+ cells from young (3-mo-old) females. In contrast, control male mice treated with IgG2a accumulated the CD4+ memory phenotype. CD4+ cells from 4-mo-old male CTLA4Ig-treated mice proliferated and produced IL-2 at levels similar to those of cells from females in response to immobilized anti-CD3 mAb. Furthermore, in contrast to IgG2a-treated mice, female and CTLA4Ig-treated male mice at 4 mo of age produced no anti-chromatin Abs. Three of four male mice injected with CTLA4Ig until 6 mo of age appeared healthy at 8 mo of age, whereas all five of IgG2a-treated control males died by 6 mo of age. These 8-mo-old CTLA4Ig-treated males showed variable resistance to autoimmunity as well as function and phenotype marker expression, and a less striking glomerulonephritis than 4-mo-old untreated males. The results of this study demonstrate that the rampant T cell activation and T cell dysfunction that occur in male BXSB mice by 4 mo of age are abrogated by blocking the CTLA4-dependent costimulatory signal(s). They also show that treatment with CTLA4Ig can suppress the pathogenesis of disease and increase longevity.
 ...
PMID:Intervention of CD4+ cell subset shifts and autoimmunity in the BXSB mouse by murine CTLA4Ig. 855 6

Systemic lupus erythematosus (SLE) manifested with multiple autoantibodies production and glomerulonephritis, is the best example of systemic autoimmune diseases. To further elucidate the role of cytokines and the potential involvement of natural killer cells (NK cells) in the pathogenesis of lupus, phenotypic analysis of peripheral blood mononuclear cells (PBMC), NK cells cytotoxicity and cytokines production pattern of SLE patients and normal controls were examined. In addition, the effect of a variety of cytokines on anti-dsDNA antibodies production was also investigated. Our results showed that: (a) there was an increased percentage of memory T cells and decreased percentage of NK cells in SLE patients when compared to normal controls (p < 0.05); (b) a decreased production of cytokines like gamma-IFN in mitogen-stimulated PBMCs was also noted in SLE patients; (c) cytolytic activity of NK cells was markedly reduced in SLE patients (p < 0.05); (d) spontaneous secretion of IgG anti-dsDNA antibodies by B cells isolated from SLE patients could be inhibited by gamma-IFN, but not by IL-2, IL-4 and IL-5. These data suggested that decreased functions of NK cells and related type 1 T helper cells be closely related to the immune dysregulation and autoantibodies production in SLE.
 ...
PMID:Phenotypic and functional analysis of natural killer cells in systemic lupus erythematosus patients. 860 62

Studies from our laboratory indicate that n-3 (fish oil, FO) lipids at 10% (w/w) in a nutritionally adequate, semipurified diet, and supplemented with equal levels of antioxidants, extended the life span of lupus-prone (NZB/NZW)F1 (B/W) female mice as compared to n-6 (corn oil, CO) lipids. The early rise of autoimmune disease in CO-fed mice was closely linked to the loss of T-cell function. Both IL-2 production and IL-2 receptor expression were reduced due to the loss of naive T-cells and a rise in memory T-cells. Proliferative response to both mitogens and superantigens (staphylococcal enterotoxins A and B) was higher in FO-fed 6.5-mon-old mice. These changes paralleled decreased PGE2 production by splenic cells from FO-fed mice. Analysis of mRNA expression in different organs revealed differential effects of dietary lipids. In FO-fed mice, transforming growth factor beta 1 (TGF beta 1) expression was decreased in kidneys, but splenic tissues had higher expression of TGF beta mRNA. As TGF beta promotes programmed cell death (PCD), we studied the effects of CO and FO on PCD rates in lymphocytes. Both propidium iodide staining and DNA fragmentation were elevated in lymphocytes of FO-fed mice when compared to CO-fed mice of similar age. Also, increased PCD correlated closely with increased Fas gene expression. Thus, in addition to various other antiinflammatory effects, dietary FO appears to increase PCD and prevent accumulation of self-reactive immune cells in lymphoid organs. Further studies are required to dissect the pro- and antiinflammatory mechanisms associated with dietary n-3 and n-6 lipids in modulating autoimmune disorders or malignancy during aging.
 ...
PMID:Modulation of antioxidant enzymes and programmed cell death by n-3 fatty acids. 872 1

The murine MRL/lpr model of lupus nephritis is characterized by a systemic autoimmune syndrome closely resembling the human disease. The lpr mutation represents a defect in the expression of the apoptosis-signaling Fas antigen gene which causes accelerated autoimmune disease in MRL/ lpr mice and a milder, non-lethal autoimmune syndrome in C57BL6-lpr/lpr mice. The role of cytokines in autoimmune pathogenesis and its relationship with the lpr mutation remains poorly understood. In this study we utilized a RNase protection assay to quantitatively and simultaneously examine the expression of 10 different cytokine genes, namely IL-1 alpha, II-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, and TNF-beta in kidney, spleen, liver, and lymph nodes obtained from pre-diseased and diseased lupus-prone MRL/lpr, pre-diseased MRL/+2 and C57BL/6-lpr mice, as well as healthy non-autoimmune C57BL/6 and Balb/c mice. Diseased MRL/lpr mice demonstrated marked and predominant IL-1 beta gene upregulation in kidneys, liver, lymph nodes and spleen. Increased message for both TNF-alpha and IFN-gamma genes was also observed in lymph nodes, and less consistently, in the spleen, and kidneys derived from diseased MRL/lpr mice as compared to pre-diseased MRL/+2 or normal nonautoimmune control mice. Furthermore, a modest increase in the expression of both IL-1 beta and IFN-gamma message was observed in lymphoid organs of pre-diseased MRL/lpr and C57BL/6-lpr mice compared with MRL/+2 and C57BL/6 controls, respectively. Increased IL-1 beta gene expression was associated with the presence of the lpr mutation, was observed during the prediseased stage, and increased during active disease in both male and female mice. In summary, these results demonstrate that generalized up-regulation of IL-1 beta gene expression, in concert with a more limited up-regulation of both TNF-alpha and IFN-gamma expression, are prominent features of the autoimmune syndrome in the MRL/lpr model of SLE and may contribute to the disease-accelerating effect of the lpr mutation.
 ...
PMID:Cytokine gene expression in the MRL/lpr model of lupus nephritis. 880 76

B cell deficient animals obtained by various strategies of gene targeting were used to study the B cell development and examine the role of different immune compartments in the immune response to microbes. Study of muMT, JHD, lambda 5T and JHT models of B cell deficiency, was essential in order to understand the role of pre-B cell receptor in B cell development, allelic exclusion and variable gene rearrangement regulation. In the immune response to influenza virus, a protective role of T cells in a total absence of B cell compartment, was revealed by studying the JHD -/- model. Further, it was established that a T cell compartment is sufficient to mediate the recovery from influenza infection. Examination of immune response in muMT and JHD models of definitive B cell deficiency to various blood stage Plasmodia species, showed that whereas B cells are not required for recovery from infection with P. chabaudi adami, P. vinckei petteri and P. chabaudi chabaudi (CB), B cell compartment is important in the later stages of infection with P. chabaudi chabaudi (AS). Studies carried out in muMT model suggested a possible role for T gamma delta subpopulation in the immune response to blood stage malaria parasite. B cell deficiency models are valuable for understanding the normal and pathological immune response. Studies carried out in muMT model indicated that T cell responses are not significantly affected in the absence of B cells. These data can neither rule out a role for B cells in T cell priming, nor in triggering an effective T cell help for humoral response. Study of double homozygous mice deficient for B cells and FAS or IL-2 gene, pinpointed the role of B cells in pathogenesis of lupus-like nephritis and vasculitis from lpr mouse and in hemolytic anemia from IL-2 -/- mouse model, respectively.
 ...
PMID:Immunoglobulin deficient mice generated by gene targeting as models for studying the immune response. 888 29

Preliminary evidence suggests there is a toxin in the sera of systemic lupus erythematosus patients which reacts with a commercial enzyme-linked immunosorbent assay kit for the detection of the marine toxin, okadaic acid. Data is presented which supports the hypothesis that an okadaic acid-like toxin may be the principle agent of lymphocyte dysregulation in systemic lupus erythematosus and other immune-dysregulated states. The okadaic acid-like toxin can produce the specific abnormalities in T-lymphocyte phenotype and function typical of systemic lupus erythematosus, principally through its ability to inhibit serine/threonine phosphatases necessary for secondary signalling processes and through its ability to inhibit calcium which is crucial to protein kinase C-mediated signalling of T-lymphocytes. The disruption probably occurs through the protein tyrosine kinase p56lck pathway crucial for IL-2. Additionally, the toxin's ability to disrupt voltage-sensitive ion channels in cell membranes may be responsible for the multi-organ pathology observed in systemic lupus erythematosus patients, particularly neurological, cardiac and nephritic. Data from a different study conducted by the author suggests that latent and persistent viruses are reactivated in active lupus. This activation could be the result of the toxin's ability to act as an immune modulator, or its ability to act as a transactivating factor.
 ...
PMID:Okadaic acid-like toxin in systemic lupus erythematosus patients: hypothesis for toxin-induced pathology, immune dysregulation, and transactivation of herpesviruses. 889 23

There is strong evidence to implicate the involvement of sex steroid hormones in the pathogenesis of systemic lupus erythematosus (SLE). However, the precise role of an imbalance of circulating sex hormones in the pathogenesis of the disease remains to be fully elucidated. Recent studies of our own as well as others have shown that dehydroepiandrosterone (DHEA), an intermediate compound in testosterone synthesis, significantly up-regulates IL-2 production of normal T cells and that administration of exogenous DHEA or IL-2 via a vaccinia construct to mice with murine lupus dramatically reverses their clinical autoimmune diseases. Thus, it is possible that in patients with SLE, the reported deficiency of IL-2 production is associated with defective DHEA activity. Indeed, we found that nearly all of the patients examined have very low levels of serum DHEA. The decreased DHEA levels are not simply a reflection of long term corticosteroid treatment, since serum samples drawn at the onset of disease, prior to any corticosteroid treatment also contained low levels of DHEA. In addition, supplementation with DHEA of the in vitro cultures of T cells restored impaired IL-2 production in patients with SLE. Thus, it would be suggested that defects of IL-2 synthesis in patients with SLE are at least in part due to the low DHEA activity in the serum, and that supplementation of DHEA could improve clinical manifestations in patients with SLE.
 ...
PMID:Hormones and lupus: defective dehydroepiandrosterone activity induces impaired interleukin-2 activity of T lymphocytes in patients with systemic lupus erythematosus. 895 43

In systemic lupus erythematosus (SLE) is a disease characterized by B cell hyperactivity, autoantibody production and immune complex deposition in vital organs. To explain the mechanisms responsible for immune dysregulation in SLE cytokines have received increasing attention. This review has discussed a number of cytokines which appear to be involved in lupus pathogenesis. Recent studies have shown that disease activity and the main symptoms of SLE are associated with increasing serum levels of cytokines such as interleukin-(IL)-1, IL-2, IL-6, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (THF-alpha). Constitutive expression and in vitro induction of specific cytokines are also aberrant in SLE. The presence of IL-1, IL-6 and IFN-gamma in involved kidneys suggests that they have local pathogenic effects. Moreover IFN-gamma, IL-6 and IL-1 modulate spontaneous IgG production by SLE mononuclear cells. During the next several years, the exact role of these cytokine in the pathogenesis of lupus become more fully elucidated.
 ...
PMID:[Cytokines in systemic lupus erythematosus]. 899 65


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