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PubMed1991

Menière's disease: an immune complex-mediated illness?

The cause of Menière's disease is unknown. Recent clinical research suggests that one etiology is immune-mediated damage to the inner ear. The diagnosis of autoimmune Menière's syndrome is largely based on history, response to steroids, or results of nonspecific laboratory tests such as serological studies. Polyethylene glycol (PEG) assay was used to determine levels of circulating immune complexes (CIC) in 30 patients with Menière's disease and 20 control subjects. Patients with Menière's disease had a statistically significant elevation of serum circulating immune complexes when compared to the control group. This suggests that CICs may be involved in the pathogenesis of Menière's disease, either as a direct cause of damage, or as a by-product of an underlying autoimmune abnormality. Therapeutic implications include use of plasmapheresis to remove the complexes or CIC monitoring to serve as a marker for treatment efficacy.

Adult↗
PubMed1991

Specificity for molecules of the major histocompatibility complex mediated by a hybrid immunoglobulin-T cell receptor.

A chimeric T-cell receptor (TCR) alpha-chain gene was produced by shuffling the immunoglobulin VDJH from a 40-140 digoxin-specific hybridoma onto alpha-chain constant region (C alpha) exons. This hybrid immunoglobulin-TCR gene was used to produce transgenic mice. Previous results indicated that this chimeric gene encoded a polypeptide that associated with endogenously encoded beta chains to form a hybrid TCR. T cells expressing this receptor could be stimulated with antibodies specific for CD3 or the 40-140 idiotype (Id40-140), and also with digoxin coupled to bovine serum albumin (digoxin-BSA). We were interested in determining whether a hybrid receptor such as this could also recognize the natural ligand of T cells, namely allelic variants of major histocompatibility complex (MHC) molecules. A T-cell hybridoma was produced that expressed a hybrid receptor with specificity for an IAk-encoded determinant, digoxin-BSA, or staphyloccocal enterotoxin B. Transfection experiments showed that the specificity for MHC determinants was dependent on both the hybrid alpha chain and a particular beta chain. These results indicate that a V beta domain combined with a VH domain can produce a receptor capable of reacting with MHC molecules, and at the same time retain specificities mediated by the beta chain and alpha chain alone. A conclusion is that the pervasive MHC specificity of the TCR is not unique to the family of TCR heterodimers, but is selected, and can be mediated by immunoglobulin domains.

Animals↗
PubMed1978

Evidence of both anti-GBM and immune complex mediated pathogenesis in the initial phase of Goodpasture's syndrome.

A 19 year old women presented with pulmonary hemorrhage, rapidly progressive glomerulonephritis and antiglomerular basement membrane antibody in her serum. In the initial phase of the disease a double layered linear deposit of IgG was seen on the glomerular capillary basement membrane together with a finely granular or focal and lumpy single layer deposit of C3 and numerous small subepithelial electron dense deposits. These findings are suggestive of the simultaneous occurrence of anti-GBM and immune complex glomerulonephritis.

Adult↗
PubMed1991

Azathioprine reduces extravasation and neutrophil trafficking in immune complex-mediated inflammation in the rat colon.

Azathioprine (AZ) has been used in the treatment of refractory inflammatory bowel disease. The mechanism by which AZ decrease colonic inflammation is not known. It is alluded that AZ may be effective in the maintenance of remission. We examined whether AZ in non-immunosuppressive doses reduces extravasation and neutrophil trafficking in a rat model of colonic inflammation. Rats were treated with I.P. injection of AZ (1 mg/kg) for 6 weeks. At the end of 2 and 6 weeks rats were injected I.V. immune complex and on the following day the proximal colon was perfused with 2.5% formaldehyde (local irritant 3 ml/hour for 5 mins). Extravasation was measured by Evans' blue technique and neutrophil concentration in the tissue was determined by measuring myeloperoxidase (MPO). AZ did not inhibit extravasation and MPO after 2 weeks of therapy. However, after 6 weeks, AZ reduced extravasation to 20 +/- 2 micrograms/gm compared to untreated animals (51 +/- 6 micrograms/gm tissue) and MPO levels to 0.3 +/- 13 compared to untreated rats (0.8 +/- 0.32 mU/gm). There was a good correlation between extravasation and MPO levels. These results suggest that long-term treatment with AZ may prevent extravasation and cause reduction in neutrophil trafficking. Such an effect may be beneficial for maintaining remission in IBD.

Aminosalicylic Acids↗
PubMed1992

Glomerulonephritis with organized deposits: a mesangiopathic, not immune complex-mediated disease? A pathologic study of two cases in the same family.

Similar glomerular changes (marked widening of the mesangial stalk, irregular basement membrane thickening, and presence of mesangial and subendothelial deposits) were observed by light microscopy in renal biopsy specimens from two patients (mother and daughter) affected by nephrotic syndrome. Electron microscopy disclosed huge glomerular electron-dense deposits containing 12-nm fibrils in both patients. Immunohistochemical investigations performed with antisera anti-immunoglobulin (Ig) and anti-complement fractions, anti-laminin, anti-collagen IV, and anti-fibronectin (FN) showed scant and focal Ig and complement deposits and strong deposits of FN in the mesangium and along glomerular basement membranes. Most glomerular FN was plasma-derived, as shown by immunohistochemical tests with monoclonal antibodies specific for both plasma and cell-derived FN (IST-4) and for cell-derived FN (IST-9). Electron-dense deposits with fibrillar component could hardly correspond to the Ig and complement deposits, whereas they could be related to FN deposits. Since it is known that in glomeruli FN binds to Ig and immune complexes, and the latter seem to be too scant to justify light and electron microscopic lesions and clinical findings, the hypothesis of a primary mesangiopathic glomerulonephritis in some way connected with abnormal plasma FN deposition within the glomeruli and subsequent non-specific immune reactant entrapment could be considered. We could be dealing with a peculiar form of fibrillary glomerulonephritis with rather indolent evolution, as shown by a slow decrease of glomerular function and the scarcely modified glomerular changes found in the second biopsy performed in the mother 8 years after the first investigation.

Adolescent↗
PubMed1991

RNA-protein complexes mediate in vitro capping of the spliced-leader primary transcript and U-RNAs in Trypanosoma cruzi.

A 39-nucleotide spliced leader (SL) is joined to the 5' ends of trypanosome mRNAs in a bimolecular or trans-splicing process. The SL in Trypanosoma cruzi is transcribed as an approximately 110-nucleotide RNA (SL-RNA or SL primary transcript) bearing the 39-nucleotide SL at the 5' end. The SL-RNA is 5' capped by a guanylyltransferase activity prior to trans-splicing and trypanosome mRNAs thus obtain their mature caps from the SL by trans-splicing. We have previously characterized a guanylyltransferase activity from T. cruzi nuclear extracts and shown that this capping activity has an unusual ATP dependence and an apparent specificity for the SL-RNA and U-RNAs. Herein, we show that the capping activity sediments as a 12-15S particle during velocity sedimentation in glycerol gradients and fractionates as a greater than 150-kDa particle during large-pore gel filtration chromatography. Moreover, the endogenous substrate RNAs--the SL-RNA and U-RNAs--consistently copurify with the capping activity, suggesting that the activity and the substrates form a ribonucleoprotein particle. The capping activity and substrate RNAs are not dissociated in isopycnic Cs2SO4 gradients and band at a density expected for an RNA-protein complex, confirming the existence of ribonucleoprotein particles bearing both the activity and its substrate RNAs. Finally, we partially purified these ribonucleoprotein particles and showed that the capping activity remains ATP dependent and highly specific for the SL-RNA and the U-RNAs. These observations are consistent with the hypothesis that one of the functions of trans-splicing is for mRNA capping.

Animals↗
PubMed1992

Immune complex-mediated glomerulonephritis associated with bacterial kidney disease in the rainbow trout (Oncorhynchus mykiss).

Rainbow trout (Oncorhynchus mykiss) developed a post-infectious chronic membranous glomerulonephritis 15 months after they had been experimentally infected with Renibacterium salmoninarum. Histologically, peritubular and periglomerular fibrosis, hypercellular glomeruli with occluded Bowman's space, and partial or complete adhesion to Bowman's capsule were constant features. Electron microscopy revealed thickened glomerular basement membranes with spikes accompanied by finely granular electron-dense deposits at the epithelial side and dense material in the mesangial matrix. Indirect immunofluorescence indicated linear immunoglobulin deposits along the glomerular basement membrane. The presence of R. salmoninarum was demonstrated by culture and by indirect immunofluorescence. Low serum hemagglutination-inhibiting antibody titers were demonstrated.

Animals↗
PubMed1992

Does co-aggregation of the CD45 and CD3 antigens inhibit T cell antigen receptor complex-mediated activation of phospholipase C and protein kinase C?

The binding of agonistic monoclonal antibodies (mAb) to the CD3 antigen in T cells induces a rapid increase in tyrosine phosphorylation, inositive phosphate (IP) production, a rise in intracellular calcium and protein kinase C (PKC) activation. These intracellular signals have been implicated in the control of interleukin-2 and interleukin-2R receptor gene expression, thereby regulating T cell proliferation. Previous studies have shown that co-ligation of the CD45 and CD3 antigens inhibits CD3-induced tyrosine phosphorylation, IP production, calcium signals and T cell proliferation. It has therefore been suggested that the CD45 antigen uncouples the T cell receptor (TcR) from mitogenic signal pathways. In this study co-ligation of the CD3 and CD45 antigens with precisely constructed bispecific mAb did not inhibit CD3-induced T cell proliferation, IP production, calcium signals, diacylglycerol production or PKC activation. Furthermore, co-ligation of CD3 and CD45 antigens already cross-linked with IgM mAb did not lead to inhibition of CD3-induced calcium signals. Inhibitions of CD3-induced intracellular signals were observed following co-ligation of IgG CD45 and CD3 mAb with anti-IgG (F(ab')2 fragments. However, comparable inhibitions were also noted following co-ligation of CD3 with other abundant cell-surface antigens such as CD5 and LFA-1, and inhibitions were only observed when the CD3 mAb used required cross-linking to induce signals. These results suggested that the inhibitory effects of CD45 IgG mAb were not specific and were caused by the prevention of CD3-CD3 cross-linking following CD3 antigen co-ligation with other cell surface molecules. These findings are inconsistent with a specific inhibitory role for the CD45 phosphotyrosine phosphatase in uncoupling the TcR from mitogenic signal pathways.

Antibodies, Monoclonal↗
PubMed1991

Effects of sigma ligands on mouse cerebellar cyclic guanosine monophosphate (cGMP) levels in vivo: further evidence for a functional modulation of N-methyl-D-aspartate (NMDA) receptor complex-mediated events by sigma ligands.

In the present investigation, the effects of sigma ligands [WY-47384 [8-fluoro-2,3,4,5-tetrahydro-2[3-(3-pyridinyl)propyl)1H- pyrido(4,3b)indole], (+)-pentazocine, (+)-SFK 10,047 (N-allylnormetazocine), mafoprazine, opipramol, dextromethorphan, dextrorphan, (+)-3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine], (-)-butaclamol, DTG [1,3-di(2-tolyl)guanidine], rimcazole, ifenprodil and BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoropyrimidinyl)-1-piperazine butanol]] on harmaline-, pentylenetetrazol (PTZ)-, methamphetamine (MA)- and D-serine-induced increases in mouse cerebellar levels of cGMP were determined. Ifenprodil, BMY-14802, dextromethorphan, dextrorphan, (+)-SKF 10,047, opipramol and mafoprazine reversed harmaline-, PTZ-, MA- and D-serine-induced increases in levels of cGMP. Rimcazole reversed only the harmaline-induced response. WY-47384 reversed harmaline-, MA-, D-serine-, but not PTZ- or quisqualate-induced increases in levels of cGMP. (+)-Pentazocine attenuated harmaline- and D-serine-, but not PTZ- and MA-induced cGMP responses. Haloperidol did not affect harmaline- and D-serine-induced cGMP responses. (+)-3-PPP and (-)-butaclamol did not affect any of the responses studied. Furthermore, (+)-3-PPP-induced increases in levels of cGMP were reversed by the competitive N-methyl-D-aspartate (NMDA) antagonist, CPP]3-(2-carboxypiperazin-4-yl)propyl- 1-phosphonic acid, the non-competitive NMDA antagonist, (+)-MK-801 (dizocilipine maleate), the NMDA-associated glycine receptor antagonist, HA-966 (3-amino-1-hydroxypyrrolidin-2-one), the partial glycine agonist, DCS (D-cycloserine) as well as by the sigma ligands, ifenprodil, WY-47384, (+)-pentazocine, (+)-SKF 10,047, dextromethorphan and dextrorphan but not by rimcazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

In vivo responses to inhaled proteins. II. Induction of interstitial pneumonitis and enhancement of immune complex-mediated alveolitis by inhaled concanavalin A.

An animal model of environmental lung disease is described in which phytomitogen, antigen, or both, are administered in aerosol form to previously immunized or immunologically naive rabbits. Inhalation of concanavalin A alone induced an interstitial pneumonitis in nonimmunized rabbits. Inhalation of concanavalin A alone induced an interstitial pneumonitis in nonimmunized rabbits. Inhalation of bovine serum albumin (BSA) alone typically produced only focal eosinophilic granulomas in BSA-immunized animals, and no injury whatever in nonimmune animals. However, simultaneous administration of BSA-concanavalin A aerosol mixtures to BSA-immunized rabbits induced a severe interstitial pneumonitis and granulomatous vasculitis, together with areas of frank parenchymal necrosis. When repeated on a chronic basis over a 4- or 8-week interval, challenge with BSA-concanavalin A aerosols resulted in both acute necrotic lesions as well as areas of frank interstitial fibrosis. Necrotic foci in acutely injured lungs were associated with interstitial deposits of BSA, rabbit anti-BSA antibody, and complement. Electron microscopy revealed numerous neutrophils within the pulmonary interstitial spaces of these animals, often in association with collagen and elastin fibers. The pattern of injury in immune rabbits induced by antigen-concanavalin A aerosols, in its nonnecrotizing form, is consistent with that of an extrinsic allergic alveolitis. However, the severe, necrotizing form of acute injury closely resembles changes seen in Wegener's granulomatosis. Possible mechanisms of injury produced by antigen and phytomitogen inhalation are discussed.

Aerosols↗
PubMed1978

Stacking interactions between aromatic amino acids and adenine ring of ATP in zinc mediated ternary complexes.

Spectrophotometric studies have provided evidence for zinc-mediated ternary complexes between ATP and aromatic amino acids. The hypochromicity observed in the 260 nm band of ATP increased in the order phenylalanine less than tyrosine less than tryptophan. Adding alanine did not produce any change of the ATP spectrum. The association constant was four fold higher for the ATP-Zinc-Tryptophan complex than for that of the ATP-Zinc-Alanine. The increased stability of the former complex was ascribed to the stacking interaction between indole and adenine rings. The maximum concentration of the ATP-Zinc-Tryptophan complex occurred at about pH 8.0. For these ternary complexes several possible stacked structures involving or not involving N(7) of adenine are discussed.

Adenine↗
PubMed1978

Immune complex glomerulonephritis mediated by thyroid antigens.

Hypothyroidism, microscopic hematuria, and proteinuria developed in an 11-year-old girl. A renal biopsy specimen showed increased mesangial cells and matrix with focal glomerular basement membrane thickening. Three years later, a pronounced increase in proteinuria was detected. Elevated levels of antibody to thyroid microsomal antigen and thyroglobulin were found in the serum. A renal biopsy specimen showed a pronounced increase in mesangial cells and matrix with generalized glomerular basement membrane thickening. Electron microscopic studies demonstrated granular deposits in the capillary walls and mesangium. Immunofluorescent studies revealed granular deposits of IgG, IgM, and C3, primarily on the glomerular basement membrane. By indirect immunofluorescence, granular glomerular basement membrane and mesangial staining were detected with antibody specific for thyroglobulin and thyroid microsomal antigen. These observations suggest development of immune complex glomerulonephritis mediated by thyroid antigens.

Antigen-Antibody Complex↗
PubMed2026

Mechanisms of Transcriptional Regulation by Salicylic Acid Receptors.

Salicylic acid (SA) is a key phytohormone that activates plant defense responses 1-3. In Arabidopsis, NPR1 (also known as NIM1) and NPR3/NPR4 have been identified as dual SA receptors responsible for perceiving SA 4-6. However, the mechanisms of how SA binding to the NPR proteins leads to induction of defense gene expression remain unclear. Here, we elucidate how SA triggers transcriptional activation via NPR1 and relieves transcriptional repression mediated by NPR3/NPR4. We identified Mediator Complex Subunit 15A (MED15A) as a bridge between NPR1 and the Mediator complex governing transcription. SA induces direct interaction of NPR1 with MED15A. Structural and functional analysis showed that the binding of NPR1 to MED15A is essential for NPR1-mediated transcriptional activation. Meanwhile, SA relieves transcriptional repression mediated by NPR3/NPR4. NIM1-interacting 1 (NIMIN1) interacts with NPR3/NPR4 and the Topless (TPL) co-repressor, connecting them to Polycomb Repressive Complex 2 (PRC2) to mediate H3K27 trimethylation of SA-responsive genes. SA inhibits the interactions between NPR3/NPR4 and NIMIN1, reduces H3K27 trimethylation levels and increases histone acetylation of the target genes to release NPR3/NPR4-mediated repression. Our study offers a comprehensive view of SA-mediated defense gene activation. These findings lay a foundation for designing more effective SA analogs as agrochemicals and for engineering crop resistance by manipulating SA perception and signaling.

Journal Article↗
PubMed1992

Internalization of the urokinase-plasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor.

The role of the urokinase receptor (uPAR) in the internalization of the urokinase-plasminogen activator inhibitor type-1 (uPA.PAI-1) complex has been investigated. First, exploiting the species specificity of uPA binding, we show that mouse LB6 cells (that express a mouse uPAR) were unable to bind or degrade the human uPA.PAI-1 complex. On the other hand, LB6 clone 19 cells, which express a transfected human uPAR, degraded uPA.PAI-1 complexes with kinetics identical to the human monocytic U937 cells. We also show by immunofluorescence experiments with anti-uPA antibodies that in LB6 clone 19 cells, the uPA.PAI-1 complex is indeed internalized. While at 4 degrees C uPA fluorescence was visible at the cell surface, shift of the temperature to 37 degrees C caused a displacement of the immunoreactivity to the cytoplasmic compartment, with a pattern indicating lysosomal localization. If uPA.PAI-1 internalization/degradation is mediated by uPAR, inhibition of uPA.PAI-1 binding to uPAR should block degradation. Three different treatments, competition with the agonist amino-terminal fragment of uPA, treatment with a monoclonal antibody directed toward the binding domain of uPAR or release of uPAR from the cell surface with phosphatidylinositol-specific phospholipase C completely prevented uPA.PAI-1 degradation. The possibility that a serpin-enzyme complex receptor might be primarily or secondarily involved in the internalization process was excluded since a serpin-enzyme complex peptide failed to inhibit uPA.PAI-1 binding and degradation. Similarly, complexes of PAI-1 with low molecular mass uPA (33 kDa uPA), which lacks the uPAR binding domain, were neither bound nor degraded. Finally we also show that treatment of cells with uPA.PAI-1 complex caused a specific but partial down-regulation of uPAR. A similar result was obtained when PAI-1 was allowed to complex to uPA that had been previously bound to the receptor. The possibility therefore exists that the entire complex uPA.PAI-1-uPAR is internalized. All these data allow us to conclude that internalization of the uPA.PAI-1 complex is mediated by uPAR.

Amino Acid Sequence↗
PubMed1992

The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells.

The resistance of mice to lethal infection by murine CMV (MCMV) is under complex host genetic control with contributions from both H-2 and non-H-2 genes. We have previously shown that an autosomal, non-MHC encoded gene, Cmv-1, controls MCMV replication in the spleen. We have investigated the mechanism by which the Cmv-1 resistance gene confers protection against MCMV infection. Using H-2 compatible irradiation bone marrow chimeras, the enhanced resistance to MCMV infection that is associated with the Cmv-1l allele in the C57BL background was shown to be mediated by an irradiation-sensitive bone marrow-derived cell population, or a factor produced by these cells. The lack of correlation between serum IFN titers and the strain distribution pattern of Cmv-1 in CXB recombinant inbred mouse strains suggests that IFN does not mediate resistance conferred by this gene. Similarly, the lack of effect of in vivo depletion of mature CD4+ and CD8+ T cells on virus replication in C57BL/6J mice indicates that T cells are unlikely to be involved. In contrast, in vivo depletion of NK cells by injection of the anti-NK1.1 mAb PK136 abrogated restricted splenic virus replication in C57BL/6J----BALB.B chimeric mice and in the Cmv-1l CXB strains. These data indicate that the effect of the Cmv-1 gene is mediated by NK cells. The significant augmentation in NK cell activity after MCMV infection of the susceptible Cmv-1h strains (BALB/cBy), CXBG/By, CXBH/By, CXBI/By, and CXBK/By) indicates the existence in these mice of NK cells that are functionally and phenotypically distinct from those in Cmv-1l strains. NK cells present in the Cmv-1h strains are unable to restrict efficiently splenic MCMV replication in vivo, possibly due to a lack of specificity for virus-infected target cells. Finally, flow cytometric analysis of NK1-1 expression in CXB and BXD RI mice together with MCMV replication studies in the BXD RI strains indicate that Cmv-1 is closely linked to NK1.1 and other loci that reside on a distal segment of murine chromosome 6 in a region that has recently been defined as the natural killer complex.

Animals↗
PubMed1992

Membrane attack complex (MAC)-mediated damage to spermatozoa: protection of the cells by the presence on their membranes of MAC inhibitory proteins.

Although antibody and complement are known to cause immobilization and killing of spermatozoa in vitro the components of the complement system mediating these effects remain undefined. Here we have examined the effects of the membrane attack complex (MAC) on spermatozoa and demonstrate that spermatotoxic effects are dependent on assembly of the complete MAC. We subsequently examined the presence and functional significance of the complement regulatory proteins decay accelerating factor (DAF), MAC-inhibiting protein (MIP) and CD59 antigen on spermatozoa. Both DAF and CD59 antigen were present on the membranes of these cells. Neutralization of CD59 antigen with specific antibodies increased the susceptibility of the cells to MAC-mediated damage, suggesting a role for this molecule in the protection of spermatozoa from complement-mediated damage in the female reproductive tract.

Antigens, CD↗
PubMed1975

[Pathophysiological implications of antigen-antibody complexes (author's transl)].

Seventy years after the description of the Arthus phenomenon, the concept of immune complex mediated pathology is widely recognized in clinical pathophysiology. The availability of methods for the detection of soluble immune complexes opens new paths for clinical investigation in this field. This is demonstrated for systemic lupus erythematosus, viral hepatitis B and herpes zoster disease. New experimental approaches deal with the question of tissue localization of immune complex mediated diseases, e.g. through affinity of antigens for certain tissue structures.

Animals↗