Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0033687 (proteinuria)
24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-12 and IL-18 are mediators involved in the onset and progression of the autoimmune disease developing in MRL/Mp-Tnfrsf6(lpr) (lpr) mice, which display symptoms similar to the human systemic lupus erythematosus (SLE). The pathology is characterized by progressive lymphadenopathy and auto-antibody-mediated multiple organ failure, e.g. glomerulonephritis, or pneumonitis and a concomitant increase in serum levels for IFNgamma and tumor necrosis factor-alpha (TNFalpha). In this study, we intramuscularly injected lpr mice with plasmids encoding IL-12 and IL-18, either alone or in combination, in order to affect the development of the autoimmune disease. Five biweekly injections of the combined plasmids starting at 4-5 weeks of age diminished serum levels of TNFalpha and reduced the ability of lymphocytes from treated mice to produce IFNgamma in vitro. Injection of both plasmids synergistically attenuated the development of autoimmune syndromes, lymphoproliferation in secondary lymphoid organs, proteinuria and kidney damage, and pneumonitis. We conclude that IL-12 and IL-18 synergistically affect the pathogenesis of the T(h)1-dependent autoimmune syndrome of lpr mice and that approaches that target both IL-12 and IL-18 may be a therapeutic option in the treatment of autoimmune SLE.
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PMID:Injection of IL-12- and IL-18-encoding plasmids ameliorates the autoimmune pathology of MRL/Mp-Tnfrsf6lpr mice: synergistic effect on autoimmune symptoms. 1707 76

We report a 35-year-old Japanese woman with intravascular large B-cell lymphoma diagnosed by percutaneous renal biopsy. The patient was referred to our institution for further examination of fever of unknown origin. She had renal dysfunction with a creatinine clearance of 44.1 mL/min, and daily urinary excretion of 0.22 g of protein and 21.5 mg of beta 2 microglobulin. Computed tomography showed markedly enlarged kidneys bilaterally. Percutaneous renal biopsy showed that an island-like atypical lymphoid cell accumulation was encircled with the peritubular capillary walls in many areas of the tubulo-interstitium, resulting in marked destruction of tubular structure. However, almost all the glomeruli were intact. Immunohistochemical analysis confirmed the diagnosis of intravascular large B-cell lymphoma. Shortly after diagnosis, she was treated with rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, and prednisolone, and her renal function and size improved. Renal involvement by lymphoma has been classified into two categories: intraglomerular intravascular lymphoma and tubulointerstitial diffuse invasion type that is distinct from intravascular lymphoma. For the latter cases with renal dysfunction and marked bilateral nephromegaly but without proteinuria, intravascular lymphoma within intra-peritublar capillaries should be considered as a possible diagnosis.
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PMID:Renal intravascular large B-cell lymphoma localized only within peritubular capillaries. Report of a case. 1752 39

IgA nephropathy is the commonest form of glomerulonephritis worldwide, and is one of the major causes of terminal renal failure in most industrialised countries. It is defined by the dominance of IgA mesangial deposits in immunofluorescence studies. Corticosteroid-sensitive nephrosis lipoides (minimal change disease) with IgA deposits and superimposed crescentic glomerulonephritis are to be differentiated from primary IgA nephropathy (Berger's disease). In the latter, clinical manifestations are dominated by synpharyngitic macroscopic haematuria and permanent proteinuria. Terminal renal failure occurs in about 25% of patients after 10 years or more. Heavy proteinuria, hypertension, altered renal function and severe histological lesions at diagnosis are markers of poor prognosis. Primary IgA nephropathy is thought to be related to mesangial deposition of polymeric IgA1-containing immune complexes, owing to altered B cell responses to exogenous and endogenous antigens, together with hyperactivity of T helper type 1 and type 2 cells, both favoured by a genetic background. The 2 compartments of the IgA system (medullary and mucosal) may participate in the pathogenesis of the disease. Modulation of gut-associated lymphoid tissue and immune tonsillectomy are current lines of research. Although impressive results were obtained with an oligoantigenic diet, it is somewhat impractical. Pharmacological modulation of the mucosal immune response seems more promising. There is no proof that phenytoin, a drug which reduces bone marrow IgA synthesis, is beneficial. Emerging data suggest the potential of immune intervention in severely proteinuric patients before sclerotic lesions have occurred, using azathioprine and intravenous immunoglobulins. The benefit of early corticosteroid therapy is still unknown in both adults and children, and the efficiency of alkylating agents is unproven. The search for bacterial foci in primary IgA nephropathy is mandatory, as appropriate treatment may have a protective effect on renal function and help to improve or stabilise some patients. Slowing the progression of renal failure by a combination of ACE inhibitors, fish oil and, possibly, antiplatelet drugs is a promising therapeutic approach.
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PMID:Therapy of IgA nephropathy. 1802 May 66

Costimulatory blockade with CTLA4Ig and anti-CD40L along with a single dose of cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F(1) mice. To understand the mechanisms for remission and for impending relapse, we examined the expression profiles of 61 inflammatory molecules in the perfused kidneys of treated mice and untreated mice at different stages of disease. Further studies using flow cytometry and immunohistochemistry allowed us to determine the cellular origins of several key markers. We show that only a limited set of inflammatory mediators is expressed in the kidney following glomerular immune complex deposition but before the onset of proteinuria. Formation of a lymphoid aggregate in the renal pelvis precedes the invasion of the kidney by inflammatory cells. Regulatory molecules are expressed early in the disease process and during remission but do not prevent the inevitable progression of active inflammation. Onset of proliferative glomerulonephritis and proteinuria is associated with activation of the renal endothelium, expression of chemokines that mediate glomerular cell infiltration, and infiltration by activated dendritic cells and macrophages that migrate to different topographical areas of the kidney but express a similar profile of inflammatory cytokines. Increasing interstitial infiltration by macrophages and progressive tubular damage, manifested by production of lipocalin-2, occur later in the disease process. Studies of treated mice identify a type II (M2b)-activated macrophage as a marker of remission induction and impending relapse and suggest that therapy for systemic lupus erythematosus nephritis should include strategies that prevent both activation of monocytes and their migration to the kidney.
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PMID:Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. 1820 92

In glomerulonephritis we find various anatomical and pathological aspects of the kidneys, despite the clinical manifestations are almost identical (haematuria, proteinuria, nephrotic or nephritic syndrome). The anatomical damage and the clinical manifestations is produced by a known or unknown antigenic insult, in relation to the predisposing genetic factors and to the defences predisposed by the immunological system. From the '80, some publications showed an immunological pathogenesis of the glomerulonephritis, with the participation of haematological elements such as lymphoid cells. Therefore, the pathogenesis of the primitive glomerulonephritis are in great part unknown, although we know that the increased permeability of the glomerular capillary is correlated to the production of proinflammatory lymphokines from T cells, which are overexpressed (RANTES). Not to succeed to adequately eliminate these cells can be, thus, a cause of relapse with the final result of renal infiltration and amplification of the immune response.
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PMID:[Glomerulonephritis]. 1826 13

A 63-year-old man with systemic lupus erythematosus developed tubular proteinuria. All subclasses of serum IgG increased, and the largest IgG subclass increase was IgG4. A renal biopsy showed lupus nephritis (Class II) with severe tubulointerstitial nephritis (so-called predominant tubulointerstitial lupus nephritis, an unusual form of lupus nephritis). Immunofluorescence microscopy revealed positive granular staining for IgG, C3 and C1q in the mesangium and peritubular interstitium, and along the tubular basement membranes (TBM). Electron microscopy also showed electron-dense deposits in the mesangium and TBM. Immunophenotyping of interstitial infiltrating cells disclosed a predominance of T cells. CD8-positive cytotoxic T cells infiltrated the peritubular interstitium, and some of these cells infiltrated the tubules. B cell-rich lymphoid follicles were also observed. IgG subclass analyses showed glomerular IgG1, IgG2 and IgG4 deposition, positive staining of IgG4 in the peritubular interstitium and along the TBM, and abundant IgG1-, IgG3- and IgG4-positive plasma cells in the interstitium. The patient responded well to moderate-dose steroid therapy. This is the first report of immunophenotyping of interstitial infiltrates in predominant tubulointerstitial lupus nephritis. The results suggest CD8-positive cytotoxic T cell-mediated tubular injury. Furthermore, immune complexes containing IgG4 might be one of etiologic factors.
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PMID:Predominant tubulointerstitial nephritis in a patient with systemic lupus erythematosus: phenotype of infiltrating cells. 1853 20

Agonists of the type 1 sphingosine-1-phosphate (S1P) receptor inhibit lymphocyte migration, causing their sequestration in lymphoid tissue. The S1P agonist FTY720 prolongs the survival of organ allografts and blocks T-cell mediated autoimmune diseases in experimental models; however, it is a non-selective agonist of four of the five S1P receptors. In this study female MRL/lpr mice, which develop an aggressive form of spontaneous autoimmune kidney disease, were treated with a more selective agonist of the type 1 receptor (KRP-203) or vehicle at 12 or 16 weeks of age. Eighty percent of the mice treated at 12 weeks, before the onset of visible disease, survived to the 24 weeks end point with decreased tubulointerstitial disease and significantly fewer infiltrating CD4(+) and CD8(+) T-cells. Only half of the control vehicle-treated mice survived. All of the mice treated at 16 weeks survived with reduced proteinuria. Mice in both groups had significant reductions in circulating lymphocytes. Mice receiving KRP-203 for 8-12 weeks had significant reductions in T-cells and consequently less adenopathy. Ex vivo treatment of lymphocytes from MRL/lpr mice with KRP-203 enhanced their apoptosis. Our study indicates that KRP-203 attenuates kidney injury in MRL/lpr mice, in part, by reducing T-cell infiltrates.
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PMID:Increased survival and reduced renal injury in MRL/lpr mice treated with a novel sphingosine-1-phosphate receptor agonist. 1876 69

Adult onset Still's Disease (ASD) is a systemic inflammatory disorder of unknown etiology characterized by chronic and fluctuant fever with accompanying rash, polyarthritis and involvement of multiple organs, especially lymphoid tissues. Although kidney involvement may appear in some cases of adult Still's disease, membranous glomerulonephyritis has not been described before. We herein report a 38-year-old man diagnosed with Still's disease with longstanding polyarthritis unresponsive to high-dose steroids and various immunosuppressive drugs for 5 years. He was referred to our clinic with bilateral pretibial edema on his legs. Urine examination revealed 10.5 g/day proteinuria with membranous glomerulonephritis and his renal biopsy came up with it. Infliximab was initiated, and his complaints were totally resolved also with a normal urine test in the following 3 months. To the best of our knowledge, this is the first report that clearly shows the efficacy of infliximab in a patient with refractory ASD with membranous glomerulonephyritis.
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PMID:Successful treatment of refractory adult Still's disease and membranous glomerulonephritis with infliximab. 2010 29

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE(0)DQ2). These AE(0)DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE(0)DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE(0)DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE(0)DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE(0)DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a 'fingerprint' substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE(0)DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE(0)DQ2 mice compared with AE(0)DQ6 mice (p < 0.001). In conclusion, AE(0)DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice. Lupus (2010) 19, 815-829.
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PMID:Spontaneous lupus-like syndrome in HLA-DQ2 transgenic mice with a mixed genetic background. 2014 96

FTY720 is a novel investigational agent targeting the sphingosine 1-phosphate (S1P) receptors with an ability to cause immunosuppression by inducing lymphocyte sequestration in lymphoid organs. Systemic lupus erythematosus (SLE) is refractory autoimmune disease characterized by the production of a wide variety of autoantibodies and immune complex (IC)-mediated lupus nephritis. Among several SLE-prone strains of mice, BXSB is unique in terms of the disease-associated monocytosis in periphery and the reduced frequency of marginal zone B (MZ B) cells in spleen. In the present study, we examined the effect of FTY720 on lupus nephritis of BXSB mice. FTY720 treatment resulted in a marked decrease in lymphocytes, but not monocytes, in peripheral blood, and caused relocalization of marginal zone B (MZ B) cells into the follicle in the spleen. These changes did not affect the production of autoantibodies, thus IgG and C3 were deposited in glomeruli in FTY720-treated mice. Despite these IC depositions, FTY720-treated mice showed survival advantage with the improved proteinuria. Histological analysis revealed that FTY720 suppressed mesangial cell proliferation and inflammatory cell infiltration. These results suggest that FTY720 ameliorates lupus nephritis by inhibiting the end-stage inflammatory process following IC deposition in glomeruli.
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PMID:FTY720 exerts a survival advantage through the prevention of end-stage glomerular inflammation in lupus-prone BXSB mice. 2023 77


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