Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several recent studies have demonstrated the central role of Fc receptors (FcR) rather than the complement system in triggering hypersensitivity reactions. We investigated the role of FcR for IgG (FcgammaR) using a murine model of accelerated anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis as a representative of type II hypersensitivity diseases. Intravenous injection of rabbit anti-GBM antibody after preimmunization with normal rabbit IgG induced proteinuria and azotemia in wild-type C57BL/6 and CD40(+/-) mice but not in FcR gamma chain (FcRgamma)(-/-) mice or CD40(-/-) mice. Light microscopic findings revealed marked tissue damage in the glomeruli of wild-type C57BL/6 and CD40(+/-) mice. However, no tissue damage except polymorphonuclear cell infiltration was observed in the glomeruli of FcRgamma(-/-) mice. The glomeruli of CD40(-/-) mice were almost normal. Immunohistochemistry revealed the binding of rabbit IgG to the GBM in all mice injected with anti-GBM antibody. However, depositions of mouse IgG and complement to the glomeruli were not observed in CD40(-/-) mice, and deposition of fibrin was not observed in FcRgamma(-/-) or CD40(-/-) mice. These findings suggest that FcgammaR may initiate anti-GBM antibody-mediated renal disease. We conclude that FcgammaR rather than the complement system is critically involved in the development of type II hypersensitivity diseases.
 ...
PMID:Abolition of anti-glomerular basement membrane antibody-mediated glomerulonephritis in FcRgamma-deficient mice. 1076 Aug 8

The CD154/CD40 pathway is required for the development and progression of disease in a variety of autoimmune model systems. We have demonstrated previously that long-term anti-CD154 treatment of nephritic (SWRxNZB)F1 mice prolonged survival and preserved kidney function. Herein we ask if long-term treatment is required and further characterize the protective effect on renal pathology by examining alpha-smooth muscle actin, collagen and TGF-beta1 expression in renal tissue. The effects of anti-CD154 on brain and heart inflammation are also examined. Three dosing strategies of anti-CD154 mAb were compared in SNF1 mice that exhibited moderate or severe nephritis: (1) weekly for 6 weeks; (2) monthly; (3) weekly for 6-12 weeks followed by monthly dosing. Proteinuria, serum anti-DNA, anti-CD154 pharmacokinetics and serum soluble CD154 analyses were performed. Anti-CD154 treatment of moderate disease increased survival across all regimens, although weekly followed by monthly maintenance dosing proved most efficacious. This regime also inhibited renal alpha-smooth muscle actin and collagen deposition. Only the most aggressive anti-CD154 treatment protocol increased survival in severely nephritic mice. Long-term anti-CD154 treatment significantly inhibits key mediators of kidney fibrosis and is required to maximize survival and renal function. Potential reasons for differential therapeutic efficacy in moderately vs severely nephritic mice are discussed.
 ...
PMID:Long-term anti-CD154 dosing in nephritic mice is required to maintain survival and inhibit mediators of renal fibrosis. 1124 13

CD40-CD40 ligand (L) interactions play a pivotal role in immune-mediated inflammatory responses via the activation of antigen-presenting cells (APCs). To investigate the effects of continuous activation of resident tissue APCs, in this case the Langerhans cells (LCs) of the skin, CD40L expression was targeted to the basal keratinocytes of the epidermis of mice using the keratin-14 promoter. Approximately 80% of the transgenic (Tg) mice spontaneously developed dermatitis on the ears, face, tail, and/or paws. Compared with littermates, Tgs had a >90% decrease in epidermal LCs yet increased numbers within the dermis suggestive of enhanced emigration of CD40-activated LCs. Tgs also displayed massive regional lymphadenopathy with increased numbers of dendritic cells and B cells. Moreover, a decrease in IgM and an increase in IgG1/IgG2a/IgG2b/IgE serum concentrations was detectable. Screening for autoantibodies revealed the presence of antinuclear antibodies and anti-dsDNA antibodies implicative of systemic autoimmunity. Accordingly, renal Ig deposits, proteinuria, and lung fibrosis were observed. Adoptive transfer of T cells from Tgs to nonTg recipients evoked the development of skin lesions similar to those found in the Tgs. Dermatitis also developed in B cell-deficient CD40L Tg mice. These findings suggest that in situ activation of LCs by CD40L in the skin not only leads to chronic inflammatory dermatitis but also to systemic mixed-connective-tissue-like autoimmune disorders, possibly by breaking immune tolerance against the skin.
 ...
PMID:Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity. 1153 30

To determine the role of CD154-CD40 interactions in the B cell overactivity exhibited by patients with active systemic lupus erythematosus (SLE), CD19+ peripheral B cells were examined before and after treatment with humanized anti-CD154 mAb (BG9588, 5c8). Before treatment, SLE patients manifested activated B cells that expressed CD154, CD69, CD38, CD5, and CD27. Cells expressing CD38, CD5, or CD27 disappeared from the periphery during treatment with anti-CD154 mAb, and cells expressing CD69 and CD154 disappeared from the periphery during the post-treatment period. Before treatment, active-SLE patients had circulating CD38 (bright) Ig-secreting cells that were not found in normal individuals. Disappearance of this plasma cell subset during treatment was associated with decreases in anti-double-stranded DNA (anti-dsDNA) Ab levels, proteinuria, and SLE disease activity index. Consistent with this finding, peripheral B cells cultured in vitro spontaneously proliferated and secreted Ig in a manner that was inhibited by anti-CD154 mAb. Finally, the CD38(+/++)IgD(+), CD38(+++), and CD38(+)IgD(-) B cell subsets present in the peripheral blood also disappeared following treatment with humanized anti-CD154. Together, these results indicate that patients with active lupus nephritis exhibit abnormalities in the peripheral B cell compartment that are consistent with intensive germinal center activity, are driven via CD154-CD40 interactions, and may reflect or contribute to the propensity of these patients to produce autoantibodies.
 ...
PMID:Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. 1461 48

Chronic low-dose-rate gamma irradiation at 0.35 or 1.2 mGy/h prolonged the life span of MRL-lpr/lpr mice carrying a deletion in the apoptosis-regulating Fas gene that markedly shortens life due to severe autoimmune disease. Immunological modifications as indicated by a significant increase of CD8(+) T cells and a significant decrease of CD3(+) CD45R/B220(+) as well as CD45R/B220(+) CD40(+) cells were found in parallel with amelioration of total-body lymphadenopathy, splenomegaly, proteinuria, and kidney and brain syndromes.
 ...
PMID:Prolongation of life span associated with immunological modification by chronic low-dose-rate irradiation in MRL-lpr/lpr mice. 1473 Oct 73

Vascular endothelial growth factor (VEGF) is produced by several cell types in the kidney, and its expression is tightly regulated for the maintenance of normal renal physiology. Increases or decreases in its expression are associated with proteinuria and renal disease. Recently, we found that the expression of VEGF is markedly induced following interactions between CD40 ligand (CD40L) and CD40. Here, endothelial cells (EC) or Jurkat T cell lines were transiently transfected with luciferase reporter constructs under the control of the human VEGF promoter and were treated with human soluble CD40L (sCD40L). We identified a CD40-responsive 68-bp region (bp -50 to +18) of the promoter and 43 bp within this region (bp -25 to +18) that have 97% homology to a sequence of CpG dinucleotides. A computerized search revealed that the CpG region has putative binding domains for the transcriptional repressor protein methyl CpG binding protein-2 (MeCP2). In EMSA, we found that the 43-bp methylated sequence formed four complex(es) with nuclear extracts from untreated EC and reduced binding of at least one complex when nuclear lysates from sCD40L-activated EC (30 min) were used. Supershift analysis using anti-MeCP2 demonstrated that most of the complex(es) in both untreated and sCD40L-activated EC involved interactions between the 43-bp DNA and MeCP2. In addition, we found that other CpG binding proteins may also interact with this region of the promoter. Taken together, this is the first demonstration that CpG binding transcriptional repressor proteins including MeCP2 may be of importance in VEGF biology.
 ...
PMID:CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island. 1514 Jul 61

Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8(+) T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses.
 ...
PMID:FK506 controls CD40L-induced systemic autoimmunity in mice. 1670 68

We have previously demonstrated that biomarkers of inflammation and immune activity detected within intraoperative renal transplant allograft biopsies are linked to adverse short-term post-transplantation clinical outcomes. Now we provide a post hoc analysis of our earlier data in the light of longer clinical follow-up. A total of 75 consecutively performed renal allografts were analyzed for gene expression of proinflammatory molecules, inflammation-induced adhesion molecules, and antiapoptotic genes expressed 15 minutes after vascular reperfusion to determine whether this analysis can aid in predicting long-term quality of renal function, proteinuria, graft loss, and death-censored graft. We have built predictive models for proteinuria (area under the curve = 0.859, p = 0.0001) and graft loss (area under the curve = 0.724, p = 0.027) 2 years post-transplantation using clinical variables in combination with intragraft gene expression data of tumor necrosis factor-alpha, interleukin-6, CD40, CD3, and tumor necrosis factor-alpha, Bcl-2, and interferon-gamma, respectively. This post hoc analysis demonstrates that hypothesis-driven, targeted polymerase chain reaction profiling of gene expression in the donor kidney at the time of engraftment can predict 2-year post-transplantation clinical outcomes.
 ...
PMID:Gene expression profiling of the donor kidney at the time of transplantation predicts clinical outcomes 2 years after transplantation. 2015 9

1. CD40 and CD40 ligand (CD40L) have a critical role in the pathophysiology and risk prediction of coronary artery syndrome, including atherothrombosis and atherosclerosis. However, the contribution of the CD40/CD40L dyad, especially the soluble form of CD40L (sCD40L), to the pathophysiology of hypertension and associated organ damage remains unknown. 2. In the present study, serum levels of CD40 and sCD40L were measured in 328 hypertensive patients with varying degrees of organ damage. The data revealed that serum levels of CD40 were significantly greater in patients with severe, but not mild, organ damage compared with patients without any organ damage. There were no significant differences in serum concentrations of sCD40L between patients with no, mild and severe organ damage. Concentrations of soluble CD40 were comparable in patients with mild organ damage that included left ventricular hypertrophy, retinal damage, renal dysfunction and proteinuria. In contrast, concentrations of soluble CD40 were increased significantly in patients with certain forms of severe organ damage, specifically stroke, but not coronary and peripheral artery disease. 3. Collectively, our data indicate that upregulation of the CD40 system in hypertensive patients with certain forms of severe end-organ damage may contribute to the pro-inflammatory, pro-atherogenic and prothrombotic milieu in hypertension.
 ...
PMID:Association between serum levels of soluble CD40/CD40 ligand and organ damage in hypertensive patients. 2045 28

The CD40-CD154 costimulatory pathway has been shown to be critical for both T- and B-cell activation in autoimmune disease. Here, we assessed the effects of blocking this pathway using CD40 DNA vaccine enhanced by dendritic cell targeting on the development of active Heymann nephritis, a rat model of human membranous nephropathy. DNA vaccination delivers plasmid DNA encoding the target antigen, either alone or in combination with enhancing elements, to induce both humoral and cellular immune responses. To determine whether CD40 DNA vaccine targeting the encoded CD40 directly to dendritic cells would improve the efficacy of the vaccination against self-protein CD40, we utilized a plasmid encoding a single-chain Fv antibody specific for the dendritic cell-restricted antigen-uptake receptor DEC205 (scDEC), the target gene CD40, and the adjuvant tetanus sequence p30. This vaccine plasmid was compared to a control plasmid without scDEC. Rats vaccinated with scDEC-CD40 had significantly less proteinuria and renal injury than did rats receiving scControl-CD40 and were protected from developing Heymann nephritis. Thus, CD40 DNA vaccination targeted to dendritic cells limits the development of Heymann nephritis.
 ...
PMID:DNA vaccine encoding CD40 targeted to dendritic cells in situ prevents the development of Heymann nephritis in rats. 2322 73


1 2 3 Next >>