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PubMed2004

Drosophila nipped-B protein supports sister chromatid cohesion and opposes the stromalin/Scc3 cohesion factor to facilitate long-range activation of the cut gene.

The Drosophila melanogaster Nipped-B protein facilitates transcriptional activation of the cut and Ultrabithorax genes by remote enhancers. Sequence homologues of Nipped-B, Scc2 of Saccharomyces cerevisiae, and Mis4 of Schizosaccharomyces pombe are required for sister chromatid cohesion during mitosis. The evolutionarily conserved Cohesin protein complex mediates sister chromatid cohesion, and Scc2 and Mis4 are needed for Cohesin to associate with chromosomes. Here, we show that Nipped-B is also required for sister chromatid cohesion but that, opposite to the effect of Nipped-B, the stromalin/Scc3 component of Cohesin inhibits long-range activation of cut. To explain these findings, we propose a model based on the chromatin domain boundary activities of Cohesin in which Nipped-B facilitates cut activation by alleviating Cohesin-mediated blocking of enhancer-promoter communication.

Animals↗
PubMed1980

Survey of synovial fluid cryoprecipitates.

Synovial fluid cryoproteins from various inflammatory and noninflammatory arthritides were examined for the presence of immunoglobulin, fibrinogen, antiglobulin activity, and third component of complement and correlated with the synovial fluid leucocyte count. The majority of rheumatoid synovial fluid cryoproteins contained either IgG-IgM complexes or IgG alone. Contrary to previous reports, many synovial fluid cryoproteins from psoriasis, Reiter's syndrome, nonspecific acute polyarthritis, gout, and gonococcal arthritis also contained IgG and occasionally IgG-IgM complexes. Noninflammatory synovial fluids were less likely to contain any immunoglobulin. The highest concentration of cryoprotein was found in Reiter's syndrome. There was a significant (P < 0.05) correlation between the presence of immunoglobulin and the concentration of the synovial fluid cryoprotein with the synovial fluid leucocyte count. Since synovial fluid cryoproteins containing immunoglobulin are present in the synovial fluids of many diverse rheumatic diseases not postulated to be immune complex mediated, they may be a nonspecific phenomenon related to the degree of inflammation.

Arthritis↗
PubMed1989

Urticaria/arthritis syndrome: report of four B51 positive patients.

The development of articular manifestations in the course of chronic urticaria or in urticarial vasculitis has been widely reported. It is not completely clear, however, whether common pathogenetic mechanisms are involved in all patients with these clinical features. Four consecutive patients with simultaneous urticarial and articular manifestations, but without any evidence of an immune complex mediated disease, are described. The HLA-B51 antigen was positive in all these patients, suggesting that a common genetic background may be present in some cases of urticaria with articular complaints.

Adult↗
PubMed1991

Influence of C4 null alleles on C4 activation in systemic lupus erythematosus.

Deficiencies of early components of the classical complement pathway are known to be associated with systemic lupus erythematosus (SLE). C4 null alleles, C4A Q0 and C4B Q0, are prime candidates for the major histocompatibility complex associated factor which determines susceptibility to SLE. There is poor correlation, however, between the presence of low concentrations of C4 and possession of C4 null alleles, and thus the basis of the association between C4A Q0, C4B Q0 and SLE remains obscure. The possibility that activation of C4 may be related to the possession of C4 null alleles was examined. C4 phenotypes were investigated, and C4 concentration and activation were estimated in patients with SLE. C4 activation was determined by measuring the concentration of C4d--a split product of C4. Twenty five of 35 patients had C4 phenotypes which include null alleles. No association between low C4 concentrations and C4 null alleles was found, but a significant association between low C4d concentrations and C4 phenotypes including null alleles, particularly those with C4A Q0, was noted. No correlation between concentrations of C4 and C4d was found. These results show an influence of C4 null alleles on the activation of the C4 molecule, which is independent of the concentration of C4. The possession of silent genes coding for C4 null alleles might predispose to SLE by conditioning poor C4 activation, a critical event for the clearance of immune complexes mediated by the classical complement pathway.

Alleles↗
PubMed1981

Localisation of immunoglobulin on the liver cell surface in primary biliary cirrhosis.

Direct immunofluorescence studies were performed on isolated liver cells in order to detect surface localisation of IgG in acute and chronic hepatitis and primary biliary cirrhosis. Membrane-bound IgG was demonstrated in nine patients. Six of eight patients with primary biliary cirrhosis showed granular fluorescence on their liver cell surfaces suggesting that an antibody or immune complex-mediated cytotoxicity might be involved in the pathogenesis of this disease.

Cell Membrane↗
PubMed1994

AIDS presenting as focal segmental membranous glomerulopathy.

The case of a young, heterosexual man who was investigated for proteinuria is reported. A renal biopsy specimen showed a focal and segmental membranous glomerulopathy. He was later found to be HIV positive and died from cerebral infarction associated with HIV vasculitis 16 months after his initial presentation. Unusual forms of immune complex mediated glomerulopathies should alert the pathologist to the possibility of HIV associated disease.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Structural characterization of a new lipid/DNA complex showing a selective transfection efficiency in ovarian cancer cells.

We investigated, for the first time, by using Energy Dispersive X-ray Diffraction, the structure of a new ternary cationic liposome formulated with dioleoyl trimethylammonium propane (DOTAP), 1,2-dioleoyl-3-phosphatidylethanolamine (DOPE) and cholesterol (Chol) (DDC) which has been recently found to have a selective high gene transfer ability in ovarian cancer cells. Our structural results provide a further experimental support to the widely accepted statement that there is not a simple and direct correlation between structure and transfection efficiency and that the factors controlling cationic lipid/DNA (CL-DNA) complexes-mediated gene transfer depend not only on the formulations of the cationic liposomes and their thermodynamic phase, but also significantly on the cell properties.

Animals↗
PubMed1991

Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster.

Membrane cofactor protein (MCP; CD46) is a widely distributed C3b/C4b-binding cell surface glycoprotein which serves as an inhibitor of complement activation on host cells. The protein has been purified, multiple cDNAs cloned and sequenced, and the genomic organization determined. MCP belongs to a family known as the regulators of complement activation (RCA) gene cluster. The RCA members are related structurally [possess approximately 60 amino acid repeating motifs termed short consensus repeats (SCR)], functionally (bind C3b/C4b), and genetically (genes are tightly clustered on chromosome 1 at q3.2). Beginning at its amino-terminus, MCP is composed of four SCRs, a ser/thr/pro-enriched region, an area of undefined function, a transmembrane hydrophobic domain, a cytoplasmic anchor and cytoplasmic tail. On SDS-PAGE, MCP migrates as two broad forms with Mrs of 59,000-68,000 and 51,000-58,000. The quantity of each form expressed is inherited in an autosomal codominant fashion. This structural heterogeneity is partly explained by the expression of multiple cDNA/protein isoforms that arise by alternative splicing of ser/thr/pro-rich exons (sites of heavy O-glycosylation) and of cytoplasmic tails. This protein is of interest to immunologists and clinicians because of its role in regulation of the complement pathways and, therefore, inflammation in immune complex-mediated syndromes; to reproductive immunologists on account of its expression on sperm and at the maternal-fetal interface; and to tumor immunologists because of its high expression on malignant cells. The availability of monoclonal and polyclonal antibodies and molecular probes will be helpful in addressing questions about the biology of MCP in these and other areas.

Amino Acid Sequence↗
PubMed2004

Cytokine function of heat shock proteins.

Extensive work in the last 10 years has suggested that heat shock proteins (HSPs) may be potent activators of the innate immune system. It has been reported that Hsp60, Hsp70, Hsp90, and gp96 are capable of inducing the production of proinflammatory cytokines by the monocyte-macrophage system and the activation and maturation of dendritic cells (antigen-presenting cells) in a manner similar to the effects of lipopolysaccharide (LPS) and bacterial lipoprotein, e.g., via CD14/Toll-like receptor2 (TLR2) and CD14/TLR4 receptor complex-mediated signal transduction pathways. However, recent evidence suggests that the reported cytokine effects of HSPs may be due to the contaminating LPS and LPS-associated molecules. The reasons for previous failure to recognize the contaminant(s) as being responsible for the reported HSP cytokine effects include failure to use highly purified, low-LPS preparations of HSPs; failure to recognize the heat sensitivity of LPS; and failure to consider contaminant(s) other than LPS. Thus it is essential that efforts should be directed to conclusively determine whether the reported HSP cytokine effects are due to HSPs or to contaminant(s) present in the HSP preparations before further exploring the implication and therapeutic potential of the putative cytokine function of HSPs.

Animals↗
PubMed2003

Effect of GLP-2 on mucosal morphology and SGLT1 expression in tissue-engineered neointestine.

Using tissue-engineering techniques, we have developed a neointestine that regenerates the structural and dynamic features of native small intestine. In this study, we tested neointestinal responsiveness to glucagon-like peptide 2 (GLP-2). Neointestinal cysts were engineered by seeding biodegradable polymers with neonatal rat intestinal organoid units. The cysts were matured and anastomosed to the native jejunum of syngeneic adult recipients. Animals were treated with GLP-2 [Gly2] (twice daily, 1 microg/g body wt) or vehicle alone (control) for 10 days. Rats were then killed, and tissues were harvested for analysis. Na+-glucose cotransporter (SGLT1) mRNA expression was assessed with Northern blotting and in situ hybridization. SGLT1 protein was localized by using immunofluorescence. GLP-2 administration resulted in 1.8- and 1.7-fold increases (P < 0.05) in neointestinal villus height and crypt depth, respectively. GLP-2 administration also resulted in a 2.4-fold increase (P < 0.01) in neomucosal SGLT1 mRNA expression. SGLT1 mRNA expression was localized to enterocytes throughout the villi, and SGLT1 protein was localized to the brush border of enterocytes along the entire length of villi from the neointestine of GLP-2-treated animals. The response of tissue-engineered neointestine to exogenous GLP-2 includes mucosal growth and enhanced SGLT1 expression. Therefore, tissue-engineering principles may help in dissecting the regulatory mechanisms mediating complex processes in the intestinal epithelium.

Animals↗
PubMed1985

Hypersensitive prostaglandin and thromboxane response to hormones in rabbit colitis.

Inflammation of the colon is associated with increased production of prostaglandins (PG) and thromboxanes (Tx), and these eicosanoids may contribute to the inflammatory, secretory, and motility dysfunctions in colitis. To evaluate the potential role of peptide hormones in the enhanced eicosanoid release, colitis was established in rabbits by a delayed-type hypersensitivity reaction to dinitrochlorobenzene and by an immune-complex-mediated reaction. PG and Tx were identified in the venous effluent of isolated perfused colons by radiochromatography after [14C]arachidonic acid prelabeling, as well as by bioassay, and then quantitated by immunoassay. The two colitis models were morphologically similar. Basal release of PGE2, PGI2, and TxA2 was two- to threefold greater from colitis tissue than from control tissue. Bradykinin (BK) and angiotensin II (ANG II) increased release of 14C-labeled eicosanoids, whereas several gastrointestinal hormones had no effect. In control colons, BK and ANG II increased PGE2 and PGI2 release (by about 2-fold) but did not alter TxA2. In contrast, BK and ANG II markedly exaggerated the release of eicosanoids in colitis. BK increased TxA2 release with 10-ng bolus injections in colitis, but there was no response with up to 10-micrograms bolus injections in control colons. The BK-induced Tx release in colitis was associated with an increase in vascular resistance (measured as perfusion pressure). Infusion of the selective Tx inhibitors dazoxiben and OKY-046 reduced TxB2 release by 96% and blunted the transient rise in perfusion pressure (from 17 +/- 5 to 5 +/- 2 mmHg). Since BK and possibly ANG II are increased at sites of inflammation, the hypersensitive eicosanoid response to these peptides may augment the eicosanoid-mediated manifestations of colitis.

Animals↗
PubMed2003

Response properties of whisker-associated trigeminothalamic neurons in rat nucleus principalis.

Nucleus principalis (PrV) of the brain stem trigeminal complex mediates the processing and transfer of low-threshold mechanoreceptor input en route to the ventroposterior medial nucleus of the thalamus (VPM). In rats, this includes tactile information relayed from the large facial whiskers via primary afferent fibers originating in the trigeminal ganglion (NV). Here we describe the responses of antidromically identified VPM-projecting PrV neurons (n = 72) to controlled ramp-and-hold deflections of whiskers. For comparison, we also recorded the responses of 64 NV neurons under identical experimental and stimulus conditions. Both PrV and NV neurons responded transiently to stimulus onset (ON) and offset (OFF), and the majority of both populations also displayed sustained, or tonic, responses throughout the plateau phase of the stimulus (75% of NV cells and 93% of PrV cells). Average ON and OFF response magnitudes were similar between the two populations. In both NV and PrV, cells were highly sensitive to the direction of whisker deflection. Directional tuning was slightly but significantly greater in NV, suggesting that PrV neurons integrate inputs from NV cells differing in their preferred directions. Receptive fields of PrV neurons were typically dominated by a "principal" whisker (PW), whose evoked responses were on average threefold larger than those elicited by any given adjacent whisker (AW; n = 197). However, of the 65 PrV cells for which data from at least two AWs were obtained, most (89%) displayed statistically significant ON responses to deflections of one or more AWs. AW response latencies were 2.7 +/- 3.8 (SD) ms longer than those of their corresponding PWs, with an inner quartile latency difference of 1-4 ms (+/-25% of median). The range in latency differences suggests that some adjacent whisker responses arise within PrV itself, whereas others have a longer, multi-synaptic origin, possibly via the spinal trigeminal nucleus. Overall, our findings reveal that the stimulus features encoded by primary afferent neurons are reflected in the responses of VPM-projecting PrV neurons, and that significant convergence of information from multiple whiskers occurs at the first synaptic station in the whisker-to-barrel pathway.

Adaptation, Physiological↗
PubMed2003

A learning and memory area in the octopus brain manifests a vertebrate-like long-term potentiation.

Cellular mechanisms underlying learning and memory were investigated in the octopus using a brain slice preparation of the vertical lobe, an area of the octopus brain involved in learning and memory. Field potential recordings revealed long-term potentiation (LTP) of glutamatergic synaptic field potentials similar to that in vertebrates. These findings suggest that convergent evolution has led to the selection of similar activity-dependent synaptic processes that mediate complex forms of learning and memory in vertebrates and invertebrates.

Animals↗
PubMed2006

Functional nonsynonymous single nucleotide polymorphisms from the TGF-beta protein interaction network.

Protein complexes mediated by protein-protein interactions are essential for many cellular functions. Transforming growth factor (TGF)-beta signaling involves a cascade of protein-protein interactions and malfunctioning of this pathway has been implicated in human diseases. Using an in silico approach, we analyzed the naturally occurring human genetic variations from the proteins involved in the TGF-beta signaling (10 TGF-beta proteins and 242 other proteins interacting with them) to identify the ones that have potential biological consequences. All proteins were searched in the dbSNP database for the presence of nonsynonymous single nucleotide polymorphisms (nsSNPs). A total of 118 validated nsSNPs from 63 proteins were retrieved and analyzed in terms of 1) evolutionary conservation status, 2) being located in a functional protein domain or motif, and 3) altering putative protein motif or phosphorylation sites. Our results indicated the presence of 31 nsSNPs that occurred at evolutionarily conserved residues, 37 nsSNPs were located in protein domains, motifs, or repeats, and 46 nsSNPs were predicted to either create or abolish putative protein motifs or phosphorylation sites. We undertook this study to analyze the human genetic variations that can affect the protein function and the TGF-beta signaling. The nsSNPs reported in here can be characterized by experimental approaches to elucidate their exact biological roles and whether they are related to human disease.

Computational Biology↗
PubMed2004

Renal vacuolar H+-ATPase.

Vacuolar H(+)-ATPases are ubiquitous multisubunit complexes mediating the ATP-dependent transport of protons. In addition to their role in acidifying the lumen of various intracellular organelles, vacuolar H(+)-ATPases fulfill special tasks in the kidney. Vacuolar H(+)-ATPases are expressed in the plasma membrane in the kidney almost along the entire length of the nephron with apical and/or basolateral localization patterns. In the proximal tubule, a high number of vacuolar H(+)-ATPases are also found in endosomes, which are acidified by the pump. In addition, vacuolar H(+)-ATPases contribute to proximal tubular bicarbonate reabsorption. The importance in final urinary acidification along the collecting system is highlighted by monogenic defects in two subunits (ATP6V0A4, ATP6V1B1) of the vacuolar H(+)-ATPase in patients with distal renal tubular acidosis. The activity of vacuolar H(+)-ATPases is tightly regulated by a variety of factors such as the acid-base or electrolyte status. This regulation is at least in part mediated by various hormones and protein-protein interactions between regulatory proteins and multiple subunits of the pump.

Animals↗
PubMed2000

IgA nephropathy and Reiter's syndrome. Report of two cases and review of the literature.

Immunoglobulin A (IgA) nephropathy is the commonest type of primary glomerulonephritis worldwide. It has previously been reported in association with the seronegative spondyloarthropathies (ankylosing spondylitis, Behcet's syndrome, psoriatic arthritis, Reiter's syndrome and the postenteritic arthritides). Since this condition was first described in 1968, 5 previous case reports of biopsy-proven IgA nephropathy associated with Reiter's syndrome have been published in the English-language literature. Here we report 2 more such cases, along with a review of the literature describing the association of IgA nephropathy and a number of other immune-complex-mediated glomerulonephritides with the seronegative spondyloarthropathies.

Adult↗
PubMed2001

Renal involvement induced by human parvovirus B19 infection.

In an attempt to clarify the renal involvement induced by human parvovirus B19 (HPB19) infection, we investigated 6 adult patients with transient urinary abnormalities followed by erythema infectiosum. All patients had HPB19-specific IgM antibody and showed mild proteinuria of 0.2-1.2 g/day with or without microscopic hematuria. In 5 patients a decrease of complement was present, and in 2 the circulating immune complex levels were elevated. All patients showed mild or moderate endocapillary proliferation with leukocytic infiltrates in glomeruli and leukocytic infiltrates with edema around interlobular arteries and arterioles. Immunofluorescence microscopy revealed C3c deposits with immunoglobulins along the glomerular capillary walls and in the walls of small arteries and arterioles. Electron microscopic studies showed swelling of the endothelial cells and small electron-dense deposits in mesangium (in all 6 patients) and subendothelium (in 5 of 6 patients). However, HPB19 VP1 and VP2 capsid antigens were not demonstrated in the glomerulus or the vascular wall in any patient. These findings suggest that the renal lesions caused by an immune complex mediated phenomenon would be closely correlated with the HPB19 infection, although the precise mechanism is not entirely clear, and that in adults HPB19 should be thought of as a possible cause of acute postinfectious glomerulonephritis.

Adult↗
PubMedDate not supplied

Membranous glomerulopathy associated with graft-versus-host disease following allogeneic stem cell transplantation. Report of 2 cases and review of the literature.

We report two cases of nephrotic syndrome presenting 18 and 20 months after allogeneic stem cell transplantation (alloSCT) with chronic myelogenous leukemia. Both patients had acute and chronic graft-versus-host disease (GVHD) and renal biopsy findings of membranous glomerulopathy (MG). A review of the literature revealed 10 additional cases of immune-complex-mediated glomerular disease following alloSCT, 8 of which were diagnostic of MG. All patients showed evidence of acute or chronic GVHD. Patients typically presented with preserved renal function (mean creatinine 1.2 mg/dl) and full nephrotic syndrome including heavy proteinuria (mean 9.2 g/24 h), edema, hypoalbuminemia (mean 2.1 g/dl) and hypercholesterolemia (mean 472 mg/dl). Most patients showed stabilization of renal function and significant decreases in proteinuria when treated with steroids and/or cyclosporine. The close temporal association as well as evidence from murine models of GVHD support a pathogenetic association between GVHD and the development of MG.

Acute Disease↗