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)

Adhesion molecules are critical in the cellular interactions involved in specific immune responses. They are used for homing, cell migration, cell-cell contact and, in some cases, for the delivery of costimulatory signals. Since the host-versus-graft (HVG) reaction represents a particular form of T-B-cell interaction, we have explored whether the inhibition of lymphocyte function-associated antigen-1/intracellular adhesion molecule-1 (LFA-1/ICAM-1) interactions and the signalling through very late activation antigen-4 (VLA-4) have any effect on the development of a lupus-like disease in BALB/c mice injected at birth with (BALB/cxC57BL/6)F1 spleen cells. In close association with the development of tolerance to donor allografts, these mice show a polyclonal activation of F1 donor B cells by alloreactive host CD4+ T cells, manifested by the production of autoantibodies (autoAbs) and the development of a mild glomerulonephritis. The dose of the monoclonal antibody (mAb) employed has been adjusted to block completely the molecule on the surface of peripheral lymphocytes without interfering with the induction of neonatal tolerance. Injection of saturating doses (100 microg/2 days) of either anti-LFA-1alpha or anti-ICAM-1 mAbs, but not anti-VLA-4alpha or anti-LFA-1beta mAbs, blocks the production of anti-ssDNA autoAbs and the thrombocytopenia characteristic of this HVG disease (HVGD). However, anti-VLA-4alpha treatment is only able to delay the production of autoAbs and the anti-LFA-1beta treatment, not to modify the evolution of the HVGD. These results point to the relevance of LFA-1/ICAM-1 interactions, but not of the VLA-4-mediated signal, in the polyclonal B-cell activation occurring during the allogeneic interactions between host T helper type 2 cells and donor B cells in HVGD.
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PMID:Different roles for LFA-1 and VLA-4 integrins in T-B-cell interactions in vivo. 1044 65

Since the mechanism mediating the beneficial effect of intravenous cyclophosphamide (IVCY) in systemic lupus erythematosus (SLE) is unknown, we investigated lymphocyte subsets and markers of activated lymphocytes in patients received IVCY, and compared the results with the effect of steroid pulse. In 55 patients with SLE, 34 patients receiving IVCY [21 cases (61.8%) were responsive] and 25 patients received steroid pulse [21 cases (84.0%) were responsive] (four patients who were resistant to steroid pulse therapy were transferred to IVCY). When the lymphocyte subsets and markers of activated lymphocytes were compared in the responsive and unresponsive group of IVCY, soluble CD4 levels and the ratio of HLA-DP-positive T cells were significantly higher in the unresponsive group. Further, the changes of these markers and costimulatory molecules [LFA-1 (CD11a), ICAM-1 (CD54), CD40 and CD40-ligand (CD154)] were also examined in the responsive patients. The ratio of HLA-DP-positive T cells did not change in the IVCY-responsive group, while it decreased in the steroid pulse therapy-responsive group. The ratio of CD11a on T cells increased and CD54 on B cells decreased in the IVCY-responsive group. The ratio of CD154 on T cells increased in the steroid pulse-responsive group, while it decreased in the IVCY-responsive group. These results suggest that the effect of IVCY is different to that of steroid pulse therapy and mainly related to B cell activation, and that these markers may contribute to predict the responsiveness of IVCY.
Lupus 2000
PMID:Effect of intravenous cyclophosphamide in systemic lupus erythematosus: relation to lymphocyte subsets and activation markers. 1098 57

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease, in which sunlight (especially its ultraviolet radiation (UVR)) is known to induce exacerbation of cutaneous lesions as well as systemic manifestations of the disease. The aim of this in vitro study was to investigate whether UVR (UVA, UVB) amplifies pro-inflammatory factors in cultured dermal fibroblasts (DF) or lymph node cells derived from premorbid or morbid mice from the murine SLE strains (MRL-1pr/1pr, (NZB/NZW)F1), in comparison to cells derived from normal mice from the non-SLE strains (C57BL/6, BALB/c). Our results demonstrate the following. Dermal fibroblast of premorbid SLE mice showed increased susceptibility to UVA and UVB irradiation, determined by viability assay, in comparison to those of normal mice. UVB irradiation induced an enhanced expression of ICAM-1 in such SLE derived cells, in comparison to cells of normal mice. UVA and UVB increased functional activity of LFA-1 in lymph node cells of premorbid SLE mice and not in normal controls. UVB irradiation induced increased production and secretion of pro-inflammatory cytokines (IL-1, IL-6, TNF-alpha) in DF of premorbid SLE mice, in comparison to normal controls. The enhanced pro-inflammatory responses to UVR were also observed in experiments conducted with cells derived from morbid SLE mice. In conclusion, the pro-inflammatory proneness detected in the premorbid stage of murine SLE could be of major importance in SLE pathogenesis. Furthermore, it suggests that the autoimmune inflammatory process in vivo, triggered initially by immune complex deposition, could be further amplified by UVR.
Lupus 2001
PMID:In vitro ultraviolet irradiation induces pro-inflammatory responses in cells from premorbid SLE mice. 1134 Nov 4

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex-mediated tissue injury. Many different adhesion molecules are thought to participate in the development of SLE; however, few studies have directly examined the contributions of these proteins. Here we demonstrate that LFA-1 plays an essential role in the development of lupus in MRL/MpJ-Fas(lpr) mice. Mice deficient in LFA-1, but not Mac-1, showed significantly increased survival, decreased anti-DNA autoantibody formation, and reduced glomerulonephritis. The phenotype of the LFA-1-deficient mice was similar to that observed in beta(2) integrin-deficient (CD18-null) MRL/MpJ-Fas(lpr) mice, suggesting a lack of redundancy among the beta(2) integrin family members and other adhesion molecules. These studies identify LFA-1 as a key contributor in the pathogenesis of autoimmune disease in this model, and further suggest that therapeutic strategies targeting this adhesion molecule may be beneficial for the treatment of SLE.
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PMID:Loss of LFA-1, but not Mac-1, protects MRL/MpJ-Fas(lpr) mice from autoimmune disease. 1527 34

Costimulatory and adhesion molecules are known to play a major role in the pathogenesis of systemic lupus erythematosus. Since fish oil and calorie restriction have been reported to attenuate the development of disease in lupus prone (NZBxNZW)F1 mice, the objective of this study was to assess the expression of these key inflammatory molecules in these mice fed diets differing in n-6 and n-3 fatty acid content and fed either food restricted or ad libitum. Age-associated increases in the expression of CD28, ICAM-1, and PGP-1 molecules that are involved in the recruitment of inflamed lymphocytes into the kidney were attenuated in mice restricted in food intake. The increase in costimulatory (CD80 and CD86) and adhesion (ICAM-1, PGP-1, LFA-1, and Mac-1) in peripheral blood mononuclear cells was also attenuated by food restriction and to a lesser extent by fish oil alone. Interestingly, amelioration of lupus (laminin expression and proteinuria) correlated with the above beneficial effects and could be seen even in 24-month-old mice. In summary, food restriction and fish oil delay the onset of lupus disease and increase life span in B/W mice by prolonging the maintenance of a youthful immune phenotype.
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PMID:Age associated alterations in costimulatory and adhesion molecule expression in lupus-prone mice are attenuated by food restriction with n-6 and n-3 fatty acids. 1535 6

Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligand (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L-/- mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.
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PMID:Costimulation requirements of induced murine systemic autoimmune disease. 1549 42

Mycophenolate mofetil (MMF) has been reproducibly shown to inhibit lymphocyte adhesion and penetration of endothelial cell surfaces. The mechanism is not yet elucidated. In vitro studies on the effects of MMF on cell adhesion molecules (CAM) using human umbilical vein endothelial cells (HUVEC) have shown conflicting results. Different studies have independently shown that MMF increased, decreased or had no effect on intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). Several studies suggest MMF may reduce the endothelial expression of E-selectin. Recent studies have been unable to replicate initial work, which suggested that MMF impaired glycosylation of lymphocyte CAM. The same studies concluded that MMF had no effect on the surface expression of lymphocyte CAM, but altered the binding ability of these molecules. ICAM-1/LFA-1 (lymphocyte function-associated antigen-1), VCAM-1/VLA-4 (very late antigen-4) and P-selectin/PSGL-1 (P-selectin glycoprotein ligand-1) ligand pairs are most likely to be involved. Few in vivo and no conclusive human studies have been carried out. The literature relevant to cell adhesion molecules in systemic lupus erythematosus (SLE) is reviewed in detail.
Lupus 2005
PMID:Adhesion molecules, mycophenolate mofetil and systemic lupus erythematosus. 1580 27

Drug-induced lupus (DIL) is a lupus-like syndrome. Its clinical and laboratory features are very similar to idiopathic lupus. First description of DIL is from 1945. Since that time over 80 medications are known to be responsible for development of the disease. Nevertheless mechanisms responsible for this process are not known enough. Nowadays direct and indirect mechanisms in DIL are known. The slow acetylator status has an important position. Moreover the role of estrogens and anti-TNF-alpha therapy are taken into consideration. The T cells' participation and the methylation of DNA and their role in graft-vs.-host disease, which is the murine model for DIL, are considered among others. Researches point also to the LFA-1 and the IL-6 as factors responsible for DIL's development. Another element which could be significant in this process is the presence of antimielo-peroxydase antibodies. Also the role of disruption of T-cell maturation in the thymus induced by the drugs' metabolites may have an important position. Nevertheless it is still very hard to say which of those mechanisms is the main one. In spite of everything it's not clear enough if the observed clinical manifestations are caused by drugs/their metabolites,- DIL or that they are consequences of a induction of silent process leading to SLE development.
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PMID:[Drug-induced lupus erythematosus and systemic lupus erythematosus--differences and similarities]. 1840 55

Drug-induced autoimmunity is an idiosyncratic, non-IgE immune related drug reaction. Interestingly, although many drugs have been reported to induce autoantibodies, only a few have a definitive association with drug-induced autoimmune disease. The prototype disease is drug-induced lupus and the typical drug for drug-induced lupus is minocycline. The production of autoantibodies and the induction of symptoms in drug-induced lupus results from a variety of mechanisms, which can include suppression of central or peripheral tolerance, alteration of gene transcription in T and B cells, abnormal cytokine and/or cytokine receptor balance and function, chromatin structure modification and antigen modification. Multiple mechanisms may apply for different drugs, and understanding the pharmacological actions of these agents helps us decipher the etiology. For example, DNA hypomethylation may occur with hydralazine, which leads to increased transcription, increased LFA-1, the generation of autoreactive T cells and a breakdown in peripheral tolerance. Frequently, more than one pathway may be involved. Interestingly, most patients with newly formed autoantibodies resulting from drugs do not develop clinical disease. Nonetheless, the explosion in the use of biological modifiers has been associated with production of autoantibodies, an observation that illustrates the complex nature of these interactions, in that these agents are frequently used to treat autoimmunity, yet may produce autoimmune diseases themselves.
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PMID:Drugs and autoimmunity--a contemporary review and mechanistic approach. 2001 13

Systemic lupus erythematosus is a complex autoimmune disease caused by genetic and epigenetic alterations. DNA methylation abnormalities play an important role in systemic lupus erythematosus disease processes. MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states, including human lupus. Whereas previous studies have shown miRNAs can regulate DNA methylation by targeting the DNA methylation machinery, the role of miRNAs in aberrant CD4+ T cell DNA hypomethylation of lupus is unclear. In this study, by using high-throughput microRNA profiling, we identified that two miRNAs (miR-21 and miR-148a) overexpressed in CD4+ T cells from both patients with lupus and lupus-prone MRL/lpr mice, which promote cell hypomethylation by repressing DNA methyltransferase 1 (DNMT1) expression. This in turn leads to the overexpression of autoimmune-associated methylation-sensitive genes, such as CD70 and LFA-1, via promoter demethylation. Further experiments revealed that miR-21 indirectly downregulated DNMT1 expression by targeting an important autoimmune gene, RASGRP1, which mediated the Ras-MAPK pathway upstream of DNMT1; miR-148a directly downregulated DNMT1 expression by targeting the protein coding region of its transcript. Additionally, inhibition of miR-21 and miR-148a expression in CD4+ T cells from patients with lupus could increase DNMT1 expression and attenuate DNA hypomethylation. Together, our data demonstrated a critical functional link between miRNAs and the aberrant DNA hypomethylation in lupus CD4+ T cells and could help to develop new therapeutic approaches.
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PMID:MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. 2048 47


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