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

Osteopontin (OPN) has an adhesive recognition sequence such as Arg-Gly-Asp (RGD) tripeptide and is known to be secreted by activated T cells. The concentration of serum OPN protein is elevated in autoimmune-prone MRL-lpr mice as well as SLE patients. Previously it was shown that CD4-CD8- double-negative (DN) T lymphocytes, a major T cell population in MRL-lpr mice, expressed OPN mRNA. Moreover, OPN induced the polyclonal activation of B cells, resulting in the augmented production of immunoglobulin. To analyze the role of OPN in immune system and in autoimmune diseases specifically, we have generated transgenic mice which express OPN. In the transgenic mice, B1 cell population in peritoneal cavity was markedly increased and titer of IgM and IgG3 antibodies in the serum was considerably higher than that in wild type. Most importantly, the titer of IgM anti-double-stranded and single-stranded DNA was significantly elevated in the transgenic mice. These results strongly suggest that OPN may have an important role in propagation and differentiation of B1 cells and production of autoantibodies.
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PMID:[Relationship between osteopontin expression and autoimmune disease--analysis of osteopontin expressed in transgenic mice]. 984 78

MRL-Fas(lpr) mice spontaneously develop a chronic lupus-like renal disease, characterized by immune complex-mediated glomerulonephritis and abundant mononuclear cell infiltration in the interstitium. In the present study we have examined whether the macrophage chemoattractant osteopontin (Opn) could be important in the recruitment of macrophages in this murine model of autoimmune renal injury. We have examined the expression of Opn in the kidney of MRL-Fas(lpr) mice and have correlated Opn synthesis with the degree of macrophage infiltration. Immunofluorescence staining revealed prominent expression of Opn by proximal tubules in MRL-Fas(lpr) mice but not in MRL-++ control mice. Northern blot analysis demonstrated that steady-state transcript levels for Opn mRNA were also significantly increased in MRL-Fas(lpr) kidneys compared with control kidneys. Furthermore, in situ hybridization showed massive Opn mRNA transcripts in proximal tubules in MRL-Fas(lpr) mice but not in controls. The diffuse macrophage infiltration in the kidney of MRL-Fas(lpr) correlated with the enhanced Opn expression. Opn secretion in vitro by cultured renal tubular epithelial cells was upregulated by TNF-alpha and 1,25(OH)2-vitamin D3, whereas no regulation was observed in a control macrophage cell line. We conclude that the enhanced expression of the chemotactic molecule Opn by tubular cells is a prominent feature of murine lupus nephritis and might be promoted by the proinflammatory cytokine environment in MRL-Fas(lpr). The chronic upregulation of Opn could participate in the recruitment of monocytes in the kidney of MRL-Fas(lpr) mice, thereby contributing to the pathogenesis of autoimmune renal disease.
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PMID:Enhanced osteopontin expression and macrophage infiltration in MRL-Fas(lpr) mice with lupus nephritis. 986 26

Osteopontin (OPN) is an Arg-Gly-Asp-containing phosphoprotein that is secreted by activated T cells. The concentration of serum OPN protein is elevated in autoimmune-prone MRL-lpr mice as well as in patients with systemic lupus erythematosus. Previously, it was shown that OPN induces the polyclonal activation of B cells, resulting in the augmented production of immunoglobulin, indicating that OPN plays some role in the development of autoimmune disease. However, the link between OPN and development of autoimmune disease remains unclear. To analyze the role of OPN in immune system and autoimmune diseases, we have generated two kinds of transgenic mice: one carries the immunoglobulin (Ig) enhancer/SV40 promoter and the other carries the cytomegalovirus enhancer/chicken beta-actin (CAG) promoter. In both groups of transgenic mice, the B1 cell population in peritoneal cavity was markedly increased and titer of IgM and IgG3 antibodies in the serum was considerably higher than that in wild-type mice. Most important, the titer of the IgM class of anti-double-stranded DNA antibody was significantly elevated in transgenic mice. These results strongly suggest that OPN may have an important role in the propagation and differentiation of B1 cells and production of autoantibodies.
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PMID:Introduction of an osteopontin gene confers the increase in B1 cell population and the production of anti-DNA autoantibodies. 988 52

Osteopontin (SPP1) is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of Th1 responses, and activation of B1 B cells. It has been implicated in the development of murine lupus and is overexpressed in humans with systemic lupus erythematosus (SLE). We examined a polymorphism of osteopontin for an association with lupus in humans in an effort to determine whether there is any evidence that a genetic predisposition to altered osteopontin expression might explain the overexpression seen in human SLE patients. A silent polymorphism (707C>T, rs1126616) of osteopontin was significantly associated with SLE. Additional associations with renal disease and opportunisitic infections were suggested. This is the first phenotypic association with a polymorphic variant of osteopontin.
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PMID:An osteopontin (SPP1) polymorphism is associated with systemic lupus erythematosus. 1193 3

Infections are common in systemic lupus erythematosus (SLE), and remain a source of mortality. The types of infections (such as pneumonia, urinary tract infection, cellulitis, and sepsis) in SLE patients are similar to the general population and include the same pathogens (Gram-positive and Gram-negative). SLE patients may also develop opportunistic infections, especially when treated with immunosuppressive agents. As a high-risk population, identification and treatment of chronic infections such as tuberculosis, hepatitis B, or human immunodeficiency virus (HIV), are important prior to the institution of immunosuppression to prevent reactivation or exacerbation of the infection. A common caveat is to distinguish between a lupus flare and an acute infection; judicious use of corticosteroids and cytotoxic drugs is critical in limiting infectious complications. The risk factors associated with susceptibility to disease include severe flares, active renal disease, treatment with moderate or high doses of corticosteroids and/or immunosuppressive agents, and others. Genetic factors (complement deficiencies, mannose-binding lectin, Fcgamma III, granulocyte macrophage colony-stimulating factor [GM-CSF], osteopontin) may predispose certain SLE patients to develop infections. Parameters including C-reactive protein (CRP) and adhesion molecules may help to differentiate an infectious disease from an exacerbation of the disease. Finally, the mechanism of molecular mimicry by specific microbial agents may play a role in the induction of SLE.
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PMID:SLE and infections. 1279 59

Early T-lymphocyte activation 1 (Eta-1)/osteopontin is a soluble ligand with pleomorphic immunologic activities including activation of macrophage chemotaxis, promotion of Th1 responses, and activation of B1 B-cells. A recent study suggested that a single-nucleotide polymorphism (SNP) at position nt 9250 (C to T) in exon 7 was highly associated with systemic lupus erythematosus (SLE). Eta-1/osteopontin was reported to be highly expressed in the MRL/lpr mouse, which is recognized as one of the spontaneous autoimmune models of SLE. In the present study, we first investigated the association with this SNP and susceptibility to primary biliary cirrhosis (PBC). The allele frequencies of C/C, C/T, and T/T at position nt 9250 on the Eta-1/osteopontin gene in 50 PBC patients were 20, 32, and 48%, respectively, compared with 9, 47, and 44% in 34 healthy controls (P<0.16-0.72). The gene frequencies of C and T at this position in such PBC patients were 0.36 and 0.64, whereas those in the healthy controls were 0.32 and 0.68 (P<0.91), respectively. Moreover, clinical findings and pathologic stages were not correlated with the variation of SNP. Those findings suggest no associations with Eta-1/osteopontin genetic polymorphism and susceptibility to PBC.
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PMID:Eta-1/osteopontin genetic polymorphism and primary biliary cirrhosis. 1280 34

Mycophenolate mofetil (MMF) is a potential new treatment for diffuse proliferative lupus nephritis. This study examines the clinical and histopathological effects, and potential mechanisms, of combination MMF/prednisone therapy in diffuse proliferative lupus nephritis. Nine patients with diffuse proliferative lupus nephritis confirmed by renal biopsy received MMF/prednisone for six months when repeat biopsies were performed. Clinical and histopathological parameters of activity and chronicity were studied. Collagens were detected by Sirus red staining; leucocyte phenotype, osteopontin (OPN), fibrinectin (FN), alpha-smooth muscle actin (alpha-SMA) and TGF-beta1 were detected by immunohistochemistry. The changes of clinical and histopathologic parameters were assessed and compared to histopathologic indicators. Eight of the nine patients achieved clinical remission; renal function deteriorated in one. Histopathological activity indices reduced significantly (9.56 +/- 2.83 versus 5.22 +/- 1.86, P < 0.01); however, the chronicity indices did not change (3.56 +/- 1.42 versus 3.22 +/- 1.20). T-cell and monocyte/macrophage infiltration. OPN expression and the percentage of proliferative cells in both glomerulus and tubulo-interstitium decreased significantly. Other features of chronic lesions, except for glomerular collagen deposition, did not change. In conclusion, MMF/prednisone therapy was effective for our patients with proliferative lupus nephritis. The active inflammatory lesions could be ameliorated through reduction of lymphocyte and monocyte/macrophage infiltration, inhibition of cell proliferation and downregulation of adhesive molecules. However, the chronic fibrotic lesions could not be significantly reduced.
Lupus 2004
PMID:Mycophenolate mofetil combined with prednisone for diffuse proliferative lupus nephritis: a histopathological study. 1499 4

Augmentation of osteopontin (OPN) expression in renal tubuli is often observed in lupus nephritis. To investigate whether this might depend on histopathological type of glomerular lesions, comparative studies of the distribution and levels of OPN expression in kidneys were performed by in situ hybridization and real-time polymerase chain reaction in mouse lupus nephritis manifesting inflammatory (endocapillary proliferative) and deposit (wire loop) types of glomerular lesions. These glomerular lesions were developed in C.B-17/Inc-scid/scid mice by injection of IgG3 antibody producing hybridoma clones, 2B11.3 and 7B6.8, respectively, which are derived from an MRL/Mp-lpr/lpr (MRL/lpr) lupus mouse. Both clones significantly augmented OPN expression in renal tubuli, but a non-nephritogenic IgG3 clone, 1G3, derived from the same MRL/lpr mouse, did not. The OPN augmentation was prominent in the renal cortex and the inner stripe of the outer medulla. These results indicate that OPN augmentation in renal tubuli is not associated with a histopathological type of glomerular lesion in lupus nephritis, at least not with an inflammatory or a deposit type.
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PMID:Augmentation of osteopontin expression in renal tubuli is independent of a histopathological type of glomerular lesions in mouse lupus nephritis. 1649 46

Infectious antigens may be triggers for the exacerbation of systemic lupus erythematosus. The underlying mechanism causing acceleration and exacerbation of lupus nephritis (LN) is largely unknown. Bacterial lipopolysaccharide (LPS) is capable of inducing an accelerated model of LN in NZB/W mice, featuring diffuse proliferation of glomerular resident cells. We hypothesized that mesangial cells (MCs) from LN subjects are more responsive to LPS than normal subjects. Cultured primary NZB/W and DBA/W (nonautoimmune disease-prone strain with MHC class II molecules identical to those of NZB/W) MCs were used. Monocyte chemoattractant protein-1 (MCP-1) and osteopontin (OPN) expressions either in the baseline (normal culture) condition or in the presence of LPS were evaluated by real-time PCR, ELISA, or western blot analysis. NF-kappaB was detected by ELISA, electrophoresis mobility-shift assay, and immunofluorescence. First, either in the baseline condition or in the presence of LPS, NZB/W MCs produced significantly higher levels of MCP-1 and OPN than the DBA/W MC controls. Second, NZB/W MCs expressed significantly higher levels of Toll-like receptor 4, myeloid differentiation factor 88, and NF-kappaB than the DBA/W MC controls, both receiving exactly the same LPS treatment. In conclusion, NZB/W MCs are significantly more sensitive than their normal control DBA/W MCs in producing both MCP-1 and OPN. With LPS treatment, the significantly elevated levels of both chemokines produced by NZB/W MCs are more likely due to a significantly greater activation of the Toll-like receptor 4-myeloid differentiation factor 88-associated NF-kappaB pathway. The observed abnormal molecular events provide an intrarenal pathogenic pathway involved in an accelerated type of LN, which is potentially infection triggered.
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PMID:Mesangial cells of lupus-prone mice are sensitive to chemokine production. 1761 18

Osteopontin (SPP1) is an important bone matrix mediator found to have key roles in inflammation and immunity. SPP1 genetic polymorphisms and increased osteopontin protein levels have been reported to be associated with SLE in small patient collections. The present study evaluates association between SPP1 polymorphisms and SLE in a large cohort of 1141 unrelated SLE patients [707 European-American (EA) and 434 African-American (AA)], and 2009 unrelated controls (1309 EA and 700 AA). Population-based case-control association analyses were performed. To control for potential population stratification, admixture adjusted logistic regression, genomic control (GC), structured association (STRAT), and principal components analysis (PCA) were applied. Combined analysis of 2 ethnic groups, showed the minor allele of 2 SNPs (rs1126616T and rs9138C) significantly associated with higher risk of SLE in males (P = 0.0005, OR = 1.73, 95% CI = 1.28-2.33), but not in females. Indeed, significant gene-gender interactions in the 2 SNPs, rs1126772 and rs9138, were detected (P = 0.001 and P = 0.0006, respectively). Further, haplotype analysis identified rs1126616T-rs1126772A-rs9138C which demonstrated significant association with SLE in general (P = 0.02, OR = 1.30, 95%CI 1.08-1.57), especially in males (P = 0.0003, OR = 2.42, 95%CI 1.51-3.89). Subgroup analysis with single SNPs and haplotypes also identified a similar pattern of gender-specific association in AA and EA. GC, STRAT, and PCA results within each group showed consistent associations. Our data suggest SPP1 is associated with SLE, and this association is especially stronger in males. To our knowledge, this report serves as the first association of a specific autosomal gene with human male lupus.
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PMID:Osteopontin and systemic lupus erythematosus association: a probable gene-gender interaction. 1833 26


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