Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Normal human IgG contains naturally occurring anti-C3 antibodies (anti-C3 NAbs) that have been proposed to regulate complement amplification. Here, we report a novel procedure for anti-C3 NAb purification. Pooled human IgG was fractionated on a DEAE column prior to affinity chromatography on IgG and then on C3. Anti-C3 NAbs co-purified with anti-F(ab')2 NAbs. In a refined protocol, IgG fractions were absorbed on Fc, F(ab')2, and C3, which allowed to isolate the directly accessible NAbs and to remove IgG hinge-region-specific NAbs. Since a substantial fraction of total anti-C3 NAbs in whole IgG pre-existed as complexes, IgG that did not bind to the three affinity columns was treated with urea and the affinity chromatography repeated to collect the dissociated NAbs. The urea-accessible anti-F(ab')2 NAbs were rather pure but anti-C3 NAbs yet contained substantial amounts of anti-F(ab')2 NAbs. Anti-C3 NAbs showed up to 400-fold and anti-F(ab')2 NAbs, up to 30-fold enrichment as compared to pooled normal human IgG. Anti-C3 NAb preparations exhibited nephritic factor activity that was up to 60 times stronger than that of total IgG from a patient with membranoproliferative glomerulonephritis type 2. In addition, anti-C3 NAbs promoted C3 convertase generation, when added to the convertase precursor or during convertase assembly, suggesting a non-nephritic-factor mechanism. Factors H and I reduced the overall level of activity but had no influence on the NAb dose-response curve meaning that NAbs did not interfere with factor H binding. Convertase promoting activity during assembly correlated with the content of anti-C3 NAbs in NAb complexes. In conclusion, anti-C3 NAbs associated with framework-specific anti-idiotypic NAbs stabilize C3 convertase and promote its generation but their activity is compensated for in whole IgG.
Mol Immunol 2005 Jul
PMID:IgG naturally occurring antibodies stabilize and promote the generation of the alternative complement pathway C3 convertase. 1595 Jul 35

The balance between proliferation and apoptosis of mesangial cells is a critical component of proliferative glomerulonephritis. The regulation of cell proliferation and apoptosis is linked at the level of the cell cycle (Shankland SJ. Kidney Int 52: 294-308, 199). cPLA2-interacting protein (PLIP), the Tip60 splice variant, interacts with cPLA2 and enhances the susceptibility of renal mesangial cells to serum deprivation-induced apoptosis (Sheridan AM, Force T, Yoon HJ, O'Leary E, Choukroun G, Taheri MR, and Bonventre JV. Mol Cell Biol 21: 4470-4481, 2001). We report that adenoviral-driven PLIP expression results in enhanced apoptosis of non-serum-deprived mesangial cells associated with a marked decrease in G0/G1 phase cells. The effect of PLIP on the cell cycle may be independent of its interaction with cPLA2 because a mutation of PLIP that does not interact with cPLA2 also causes a decrease in G0/G1 cells. Endogenous PLIP and Tip60 protein levels are increased in cells exposed to injurious stimuli including X-irradiation and H2O2, but the intracellular localization of the splice variants may differ. Whereas PLIP localizes in the nucleus of all mesangial cells, Tip60 localizes in the cytosol of untreated mesangial cells and of cells exposed to low concentrations (50-200 microM) of H2O2. Tip60 is targeted to the nucleus of cells exposed to high concentrations (1-2 mM) of H2O2. We conclude that PLIP may cause cells to exit from the cell cycle after the S phase and may function as part of a G2/M checkpoint mechanism. Tip60 splice variants may function in both cytosolic and nuclear signaling pathways in mesangial cells.
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PMID:cPLA2-interacting protein, PLIP, causes apoptosis and decreases G1 phase in mesangial cells. 1598 50

Factor H (FH) is a central complement regulator both in plasma and on certain cellular and acellular surfaces that are in contact with plasma. Although FH deficiency has been shown to lead to similar diseases in man and mice (membranoproliferative glomerulonephritis or dense deposit disease) little is known about the similarity between the human and murine FH functions. We here characterize the interactions of murine FH (mFH) with C3b, glycosaminoglycans, and endothelial cells and compare these interactions with those of human FH (hFH). To achieve this we purified mFH and murine C3 from plasma, prepared murine C3b, and expressed recombinant mFH constructs containing domains 1-5 and 18-20 (mFH1-5 and mFH18-20). For comparisons, hFH, human C3b, and recombinant hFH1-5 and hFH18-20 were used. We demonstrate that mFH and mFH1-5 do act as cofactors for factor I-mediated cleavage of human C3b. Surface plasmon resonance analysis showed binding of mFH18-20 to murine C3b and weak binding to human C3b. The mFH18-20 construct bound to heparin in a manner comparable to hFH18-20. It was demonstrated by flow cytometry that mFH and mFH18-20 bind to human endothelial cells in a similar manner to hFH and hFH18-20. Taken together, locations of the key functions of mFH, i.e. complement regulation and surface recognition, are comparable to hFH. Recently, mutations in the carboxy-terminal end of hFH have been found to be associated with atypical hemolytic uremic syndrome (aHUS). Based on the results in this report it is conceptually attractive to establish a murine model for aHUS.
Mol Immunol 2006 Mar
PMID:Comparison of surface recognition and C3b binding properties of mouse and human complement factor H. 1602 8

The complement system is a central part of innate immunity and in its normal setting aimed to recognize and eliminate microbes. For elimination toxic activation products are generated locally and are reported directly of the surface of the invading microbe. A deregulation of the alternative pathway results in defective recognition and toxic activation products can be formed on the surface of host tissues and structures. Recent studies have shown that mutated or defective regulators of the alternative pathway of complement are associated with auto immune diseases of the kidney, including the atypical form of hemolytic uremic syndrome (HUS), membranoproliferative glomerulonephritis (MPGN) and also of the eye, such as age-related macular degeneration (ARMD). Current research provides clues how mutations occurring in genes coding for single complement components or the inactivation of single regulators lead to defective alternative pathway amplification, via the convertase C3bBb. These scenarios explain how defects of a single regulator lead to local, organ specific damage.
Mol Immunol 2006 Jan
PMID:Complement and diseases: defective alternative pathway control results in kidney and eye diseases. 1602 39

Environmental crystalline silica exposure has been associated with formation of autoantibodies and development of systemic autoimmune disease, but the mechanisms leading to these events are unknown. Silica exposure in autoimmune-prone New Zealand mixed (NZM) mice results in a significant exacerbation of systemic autoimmunity as measured by increases in autoantibodies and glomerulonephritis. Previous studies have suggested that silica-induced apoptosis of alveolar macrophages (AM) contributes to the generation of the autoantibodies and disease. Rottlerin has been reported to inhibit apoptosis in many cell types, possibly through direct or indirect effects on PKCdelta. In this study, rottlerin reduced silica-induced apoptosis in bone marrow-derived macrophages as measured by DNA fragmentation. In NZM mice, RNA and protein levels of PKCdelta were significantly elevated in AM 14 wk after silica exposure. Therefore, rottlerin was used to reduce apoptosis of AM and evaluate the progress of silica-exacerbated systemic autoimmune disease. Fourteen weeks after silica exposure, NZM mice had increased levels of anti-histone autoantibodies, high proteinuria, and glomerulonephritis. However, silica-instilled mice that also received weekly instillations of rottlerin had significantly lower levels of proteinuria, anti-histone autoantibodies, complement C3, and IgG deposition within the kidney. Weekly instillations of rottlerin in silica-instilled NZM mice also inhibited the upregulation of PKCdelta in AM. Together, these data demonstrate that in vivo treatment with rottlerin significantly decreased the exacerbation of autoimmunity by silica exposure.
Am J Physiol Lung Cell Mol Physiol 2005 Dec
PMID:Effects of rottlerin on silica-exacerbated systemic autoimmune disease in New Zealand mixed mice. 1604 Jun 31

The authors describe four patients with symptomatic lung disease morphologically representing a septal capillary injury syndrome temporally associated with serologic and culture evidence of active cytomegalovirus (CMV) infection but without classic cytopathic changes. The authors conducted a thorough review of clinical data, microscopic examination, and in situ hybridization to detect CMV mRNA encoding immediate early protein. The assay detects transcripts that encode early and immediate early proteins. In two cases additional tissue was available for direct immunofluorescent studies. The disease process in each of the patients was morphologically indistinguishable from the pattern of organ injury associated with autoimmune diseases including a small vessel microvascular injury syndrome involving skin and lung and immune complex- mediated glomerulonephritis. Cytopenias were seen in all cases, most commonly thrombocytopenia. All treated patients demonstrated improvement on combined ganciclovir and low-dose steroid therapy. CMV infection may be of pathogenetic importance in some cases of alveolar hemorrhage, especially when accompanied by peripheral blood cytopenia in otherwise healthy patients and if clinical worsening occurs in the setting of a traditional immunosuppressive regimen typically used to treat vasculitis.
Appl Immunohistochem Mol Morphol 2005 Sep
PMID:Cytomegalovirus-associated pulmonary septal capillary injury sine inclusion body change: a distinctive cause of occult or macroscopic pulmonary hemorrhage in the immunocompetent host. 1608 54

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and remains an important cause of end-stage renal failure. However, the basic molecular mechanism(s) underlying abnormal IgA synthesis, selective mesangial deposition with ensuing mesangial cell proliferation and extracellular matrix expansion remains poorly understood. Notably, the severity of tubulointerstitial lesions better predicts the renal progression than the degree of glomerular lesions. The task of elucidating the molecular basis of IgAN is made especially challenging by the fact that both environmental and genetic components likely contribute to the development and progression of IgAN. This review will summarize the earlier works on the structure of the IgA molecule, mechanisms of mesangial IgA deposition and pathophysiologic effects of IgA on mesangial cells following mesangial deposition. Recently, a series of important advances in the area of communication between the glomerular mesangium and renal tubular cells have emerged. These novel findings regarding the molecular pathogenesis of IgAN will be helpful in designing future directions for therapy.
Curr Mol Med 2005 Aug
PMID:Molecular basis of IgA nephropathy. 1610 76

Most of the present knowledge on pathomechanism of renal fibrosis is based on experimental studies with laboratory animals. Today, a variety of genetic and inducible animal models that mimic primary causes of human disease such as diabetes mellitus, glomerulonephritis, or lupus erythematodes are available. However, only few of these models progress consistently to interstitial fibrosis in the kidney involving interestitial fibrosis, tubular atrophy, and glomerulosclerosis, which are common features of renal fibrogenesis. In this chapter, the mouse models of nephrotoxic serum nephritis, COL4A3-deficiency, and unilateral urethral obstruction, which all result reliably into renal fibrosis, are described.
Methods Mol Med 2005
PMID:Animal models of renal fibrosis. 1611 58

Mutations of MYH9, the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA), cause a complex clinical phenotype characterized by macrothrombocytopenia and granulocyte inclusion bodies, often associated with deafness, cataracts and/or glomerulonephritis. The pathogenetic mechanisms of these defects are either completely unknown or controversial. In particular, it is a matter of debate whether haploinsufficiency or a dominant-negative effect of mutant allele is responsible for hematological abnormalities. We investigated 11 patients from six pedigrees with different MYH9 mutations. We evaluated NMMHC-IIA levels in platelets and granulocytes isolated from peripheral blood and in megakaryocytes (Mks) cultured from circulating progenitors. NMMHC-IIA distribution in Mks and granulocytes was also assessed. We demonstrated that all the investigated patients had a 50% reduction of NMMHC-IIA expression in platelets and that a similar defect was present also in Mks. In subjects with R1933X and E1945X mutations, the whole NMMHC-IIA of platelets and Mks was wild-type. No NMMHC-IIA inclusions were observed at any time of Mk maturation. In granulocytes, the extent of NMMHC-IIA reduction in patients with respect to control cells was significantly greater than that measured in platelets and Mks, and we found that wild-type protein was sequestered within most of the NMMHC-IIA inclusions. Altogether these results indicate that haploinsufficiency of NMMHC-IIA in megakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations, whereas in granulocytes a dominant-negative effect of mutant allele is involved in the formation of inclusion bodies. The finding that the same mutations act through different mechanisms in different cells is surprising and requires further investigation.
Hum Mol Genet 2005 Nov 01
PMID:Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. 1616 39

Immunological imbalances have been hypothesized as a cause for the onset of preeclampsia, which is a very severe, pregnancy-related disease. We recently described a novel preeclampsia mouse model by adoptively transferring activated BALB/c Th1-like splenocytes into allogeneically pregnant BALB/c female mice during late gestation. This cell transfer provoked preeclampsia symptoms (increased blood pressure and glomerulonephritis accompanied by proteinuria). Interestingly, preeclampsia-like symptoms could not be detected in nonpregnant animals receiving activated Th1-like cells. Adoptive cell transfer further affected pregnancy outcome by increasing fetal rejection through an inflammatory profile of uterine immune cells. This chapter describes the methods employed to develop the model as well as additional experiments developed to analyze cellular and molecular mechanisms involved.
Methods Mol Med 2006
PMID:A novel mouse model for preeclampsia by transferring activated th1 cells into normal pregnant mice. 1651 97


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