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PubMed1999

Transport of the ADP/ATP carrier of mitochondria from the TOM complex to the TIM22.54 complex.

Members of the mitochondrial carrier family such as the ADP/ATP carrier (AAC) are composed of three structurally related modules. Here we show that each of the modules contains a mitochondrial import signal recognized by Tim10 and Tim12 in the intermembrane space. The first and the second module are translocated across the outer membrane independently of the membrane potential, DeltaDeltapsipsi, but they are not inserted into the inner membrane. The third module interacts tightly with the TOM complex and thereby prevents complete translocation of the precursor across the outer membrane. At this stage, binding of a TIM9.10 complex confers a topology to the translocation intermediate which reflects the modular structure of the AAC. The precursor is then transferred to the TIM9.10.12 complex, still interacting with the TOM complex. Release of the precursor from the TOM complex and insertion into the inner membrane by the TIM22.54 complex requires a DeltaDeltapsipsi-responsive signal in the third module.

Binding Sites↗

PubMed2001

A nonsense mutation in the NDUFS4 gene encoding the 18 kDa (AQDQ) subunit of complex I abolishes assembly and activity of the complex in a patient with Leigh-like syndrome.

Sequence analysis of mitochondrial and nuclear candidate genes of complex I in children with deficiency of this complex and exhibiting Leigh-like syndrome has revealed, in one of them, a novel mutation in the NDUFS4 gene encoding the 18 kDa subunit. Phosphorylation of this subunit by cAMP-dependent protein kinase has previously been found to activate the complex. The present mutation consists of a homozygous G-->A transition at nucleotide position +44 of the coding sequence of the gene, resulting in the change of a tryptophan codon to a stop codon. Such mutation causes premature termination of the protein after only 14 amino acids of the putative mitochondrial targeting peptide. Fibroblast cultures from the patient exhibited severe reduction of the rotenone-sensitive NADH-->UQ oxidoreductase activity of complex I, which was insensitive to cAMP stimulation. Two-dimensional electrophoresis showed the absence of detectable normally assembled complex I in the inner mitochondrial membrane. These findings show that the expression of the NDUFS4 gene is essential for the assembly of a functional complex I.

Amino Acid Sequence↗

PubMed1985

Hybrid pyruvate dehydrogenase complexes reconstituted from components of the complexes from Escherichia coli and Azotobacter vinelandii.

The pyruvate dehydrogenase complex of Escherichia coli was isolated in a simple three-step procedure. Its chain stoichiometry, determined by trinitrobenzoate modification was found to be 1.4 E1:1 E2:0.6 E3. It was reproducible within 10% from preparation to preparation. The E. coli complex was resolved by chromatography on activated thiol Sepharose. Reconstitution of activity yielded a stoichiometry of 1.0 E1:1 E2:0.5 E3. The optimum binding stoichiometry of E1E2 and E2E3 subcomplexes was determined by sedimentation experiments and found to be 2.0 E1:1 E2 and 2.5 E3:1 E2, respectively. Competition between E1 and E3 was observed in the binding experiments, but not in the kinetic experiments. Hybrid active complexes could be reconstituted from either an E1E2 subcomplex from Azotobacter vinelandii and the E3 component from E. coli or from E2E3 subcomplex from E. coli and the E1 component from A. vinelandii. Low activity and weak binding was observed when E1 from E. coli was recombined with an E2E3 subcomplex from A. vinelandii or when E3 from A. vinelandii was recombined with an E1E2 subcomplex from E. coli. The association behaviour and stoichiometry of the reconstituted complexes is determined by the nature of the E2 component. The formation of hybrid complexes indicates a considerable structural similarity between the complexes from both sources, despite the differences in size and stoichiometry.

Azotobacter↗

PubMed1983

Circulating immune complexes in experimental syphilis: identification of treponemal antigens and specific antibodies to treponemal antigens in isolated complexes.

As a prelude to characterization of the host and treponemal antigens present in purified immune complexes from the sera of rabbits with disseminated syphilis, autoradiographic and immunoenzymatic analyses of solubilized extracts of Treponema pallidum, Treponema phagedenis biotype Reiter, and Treponema refringens were performed on electroblots of polypeptides first separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Electroblots of purified immune complexes were developed with the same panel of antisera so that protein profiles could be compared. Eight treponemal antigens were consistently present in isolated complexes; four of these cross-reacted with antisera prepared against avirulent treponemes. The average molecular weights of these antigens were 87,000, 76,000, 66,000, and 45,000. Antibodies dissociated from isolated immune complexes, when used for the development of T. pallidum electroblots, reacted with four antigens of comparable molecular weight. Antibodies to those polypeptides were also present in the sera of animals immunized with immune complexes. The demonstration of treponemal antigens in purified immune complexes convincingly argues that their occurrence in experimental syphilis is not merely due to tissue destruction and responses to endogenous host antigens.

Animals↗

PubMed1984

IgE class immune complexes in Felty's syndrome: characterisation of antibody activities in isolated complexes.

By means of a double polyethylene glycol (PEG) precipitation and PRIST technique IgE was detected in 3% PEG precipitates and in the immune complex enriched fractions purified by solid-phase Clq adsorption from sera of 11 of 20 patients with Felty's syndrome. No correlation was found between the occurrence of complexed IgE and total protein content of the immune complex enriched material. IgE rheumatoid factor and anti-IgE antibody activity were detected in some of the immune complex fractions. Serum levels of complement C3, C4, and factor B were low in IgE immune complex positive cases. Only 4 of 20 patients with articular rheumatoid arthritis had IgE-containing immune complexes.

Aged↗

PubMed1977

Clinical relevance of circulating immune complexes in human leukemia. Association in acute leukemia of the presence of immune complexes with unfavorable prognosis.

The occurrence of circulating immune complexes was investigated in 467 serum samples from 230 leukemia patients using the [(125)I]Clq-binding test. There was an increased serum [(125)I]Clq-binding activity in 40% of patients with acute myeloid leukemia, 23% with acute lymphatic leukemia, 46% in blastic crisis of chronic myeloid leukemia, 12% with chronic lymphatic leukemia, and 13% with chronic myeloid leukemia. In 48 patients, serum was also tested for soluble immune complexes by the Raji cell radioassay; the correlation between results of the two tests was significant. The Clq-binding material had properties identical with those of immune complexes. It sedimented as 14-28s material on sucrose density gradient. It contained IgG which could be dissociated at acid pH. Its Clq-binding properties could be removed after passage through anti-IgG immuno-absorbant or after a mild reduction-alkylation treatment, but were not sensitive to deoxyribonuclease treatment. Circulating immune complexes were found most commonly during the blastic stage of leukemia.Remission took place in 75.4% of patients with no detectable circulating immune complexes at the onset of acute leukemia, but in only 32.7% of those with detected complexes during this period. Median survival times of the former group of patients were more than 18 mo in acute myeloid leukemia and acute lymphatic leukemia and more than 8(1/2) mo in blastic crisis of chronic myeloid leukemia. The corresponding median survival times in the latter patient group were 64, 135, and 90 days. These findings were unrelated to prognostic features already known.

Adolescent↗

PubMed1996

Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts but with combined complex I and IV deficiencies in muscle.

A 2-month-old boy died of a lethal infantile mitochondrial disease with severe lactic acidosis and involvement of the CNS. Histochemical analysis of skeletal muscle showed that cytochrome c oxidase staining was lacking in all muscle fibers but was present in arterioles. Ragged red fibers were not seen, but some fibers showed excessive staining for succinate dehydrogenase. Biochemical analysis revealed a combined complex I and IV deficiency in skeletal muscle but only a complex I deficiency in his fibroblasts. Two-dimensional native SDS electrophoresis confirmed these enzymatic findings at the protein level. Analysis of mitochondrial translation products in fibroblasts revealed no abnormalities, and analysis of mitochondrial DNA in muscle showed no depletion, large-scale deletions, or frequently occurring point mutations. We conclude that this disease must have been the result of either a nuclear DNA mutation in a gene controlling the expression or assembly of both complex I and the muscle-specific isoform of complex IV or, alternatively, a heteroplasmic point mutation in a mitochondrial tRNA, which codon is used more often by mtDNA encoded subunits of complex I than by mtDNA encoded subunits of complex IV. A different degree of heteroplasmy in skeletal muscle and fibroblasts would then explain the curious heterogeneous tissue expression of defects in this patient.

Acidosis, Lactic↗

PubMed2001

Thermal stability of MHC class I-beta 2-microglobulin peptide complexes in the endoplasmic reticulum is determined by the peptide occupancy of the transporter associated with antigen processing complex.

Once MHC class I heavy chain binds beta(2)-microglobulin (beta(2)m) within the endoplasmic reticulum, an assembly complex comprising the class I heterodimer, TAP, TAPasin, calreticulin, and possibly Erp57 is formed before the binding of high affinity peptide. TAP-dependent delivery of high affinity peptide to in vitro translated K(b)beta(2)m complexes within microsomes (TAP(+)/TAPasin(+)) was studied to determine at which point peptide binding becomes resistant to thermal denaturation. It was determined that the thermal stability of K(b)-beta(2)m-peptide complexes depends on the timing of peptide binding to K(b)beta(2)m relative to TAP binding high affinity peptide. Premature exposure of the TAP complex to high affinity peptide before its association with class I heavy chain results in K(b)beta(2)m-peptide-TAP complexes that lose peptide upon exposure to elevated temperature after solubilization away from microsome-associated proteins. These findings suggest that the order in which class I heavy chain associates with endoplasmic reticulum-resident chaperones and peptide determines the stability of K(b)beta(2)m-peptide complexes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

Precipitated immune complexes of IgM as well as of IgG can bind to rabbit polymorphonuclear leucocytes but only the immune complexes of IgG are readily phagocytosed.

We have shown by in vitro experiments, using immunofluorescence techniques, that precipitated immune complexes of IgM antibodies and ovalbumin (ICIgM) are able to bind to rabbit blood polymorphonuclear leucocytes (PMN), as well as immune complexes of IgG antibodies (ICIgG). This binding capacity for both classes of immune complexes is exhibited by more than 80% of the PMN cell population and is independent of Ca2+ in the medium. For ICIgG the binding to PMN can be completely inhibited by preincubation of the cells with soluble IgG used at physiological concentrations (competition for the Fc gamma receptors) while for ICIgM there is no such inhibition by fluid-phase IgM. After binding to the leucocytes there was a striking difference in the fate of ICIgM and ICIgG: whereas the ICIgG was readily phagocytosed (endocytosed), the ICIgM remained mostly on the cell surface, being only poorly endocytosed after 1 hr incubation at 37 degrees. This was demonstrated by a quantitative fluorimetric method developed to assay phagocytosis of immune complexes, and was confirmed by a qualitative fluorescence quenching technique. These results may have implications for understanding the fate of these classes of immune complexes formed in circulation or deposited in tissues, and the participation of PMN in inflammatory reactions and tissue injury in immune complex diseases.

Animals↗

PubMed1986

The relationship of soluble immune complexes, insulin antibodies and insulin-anti-insulin complexes to platelet and coagulation factors in type 1 diabetic patients with and without proliferative retinopathy.

The possible correlation between soluble immune factors and platelet and coagulation factors has been evaluated in Type 1 diabetic patients with and without proliferative retinopathy, and in non-diabetic controls. Soluble immune complexes, platelet factor IV (PF4), beta-thromboglobulin, fibrinogen, factor VIII related antigen and anti-thrombin III were significantly increased in Type 1 diabetic patients with retinopathy as compared to non-diabetic controls. Fibrinogen and anti-thrombin III were also higher in those patients with retinopathy compared to those without retinopathy. A significant correlation was found between positive values of soluble immune complexes and increased levels of PF4 and beta-thromboglobulin in diabetic patients with retinopathy. The presence of soluble immune complexes and insulin-anti-insulin complexes was associated with a significantly greater number of elevated haemostatic factors in retinopathic patients. Our findings suggest that the interaction of platelets and soluble immune complexes or insulin-anti-insulin complexes may be pathologically relevant to the development of diabetic retinopathy.

Adult↗

PubMed1981

Substrate hydrolysis by immune complex-activated neutrophils: effect of physical presentation of complexes and protease inhibitors.

The ability of rat leukocytes to hydrolyze a radiolabeled, surface-bound protein substrate in a solid phase assay was determined, and various factors that influence the process were measured. Unstimulated leukocytes hydrolyzed very little substrate. When the cell suspension was mixed with zymosan particles or incubated with preformed immune complexes, the amount of substrate hydrolysis increased dramatically. Not surprisingly, immune complexes at equivalence proved to be the most effective in eliciting the response. Immune complexes attached to the surface along with the protein substrate were able to effectively induce hydrolysis, though they were not as effective as immune complexes in suspension. Three protease inhibitors, alpha 1-antitrypsin, alpha 2-macroglobulin, and soybean trypsin inhibitor, which were able to neutralize nearly all of the protease activity in rat neutrophil lysates, were tested for their ability to inhibit immune complex-induced protein hydrolysis. It was found that when the inhibitors were surface bound along with the substrate protein, they were effective in preventing the neutrophils from hydrolyzing the protein. However, when the same inhibitors were present in the fluid phase, they were much less effective. The relative ineffectiveness of fluid phase protease inhibitors to block the protease activity of contact-activated leukocytes may explain how immune complex injury can take place in the presence of high concentrations of serum inhibitors.

Animals↗

PubMed1980

Carbohydrate-mediated clearance of immune complexes from the circulation. A role for galactose residues in the hepatic uptake of IgG-antigen complexes.

The purpose of these experiments was to evaluate the hypothesis that galactose residues on IgG mediate the clearance of IgG.antigen complexes from the circulation. After 28 days of immunization of rats with bovine serum albumin (BSA), approximately 90% of anti-BSA antibody was IgG; the circulating half-life of trace amounts of BSA antigen in immunized rats was 6 min, compared to 24 h in nonimmunized rats. Similarly, soluble IgG.125I-BSA complexes formed in vitro, under conditions of antibody excess, had a circulating half-life of 4 min in normal rats. For both antigen in immunized rats, or IgG.125I-BSA complexes in normal animals, clearance was markedly inhibited by pre- or co-injection of asialofetuin, but was insensitive to large doses of fetuin, ovalbumin, or mannan. Liver parenchymal cells were the major site of uptake of complexes formed in vivo or in vitro. In vitro binding of IgG.125I-BSA complexes by isolated hepatocytes was effectively competed by asialofetuin, asialo-orosomucoid, galactose, and N-acetylgalactosamine, but was unaffected by fetuin, orosomucoid, ovalbumin, mannan, or mannose. These data suggest that antigen-induced conformational changes in IgG result in both recognition of galactose residues on IgG and clearance of IgG-immune complexes from the circulation by the galactose-specific receptor in hepatic parenchymal cells.

Animals↗

PubMed1994

[Utility of the direct culture examination (Ziehl-Neelsen) using the Bactec system for the presumptive identification of Mycobacterium tuberculosis complex, Mycobacterium avium complex, Mycobacterium xenopi, and Mycobacterium kansasii].

BACKGROUND: The usefulness of the microscopic examination of Bactec 12B and 13A growth medium as a method for the possible identification of M. tuberculosis complex, M. avium complex, M. xenopi, and M. kansasii was performed out to guide the selection of different genetic identification probes and, in the case of M. xenopi, the selection of the temperature of subcultures incubation. METHODS: Upon detection of an index of growth greater than 100 in Bactec tubes, staining was performed by the Ziehl-Neelsen technique. On the basis of the morphology observed, the possible identification was performed by genetic probes. Subcultures were used for definitive identification. RESULTS: Three hundred forty-four positive samples were studied by radiometric technique. A total of 190 strains were identified as M. tuberculosis, 88 strains as M. avium-intracellulare (MAI), 33 strains as M. xenopi, 14 strains as M. kansasii and 19 strains were identified as: M. gordonae (10), unpigmented rapid growth microbacteria (7), and M. simiae (2). Sensitivity, specificity, positive predictive value, and negative predictive value were 97.9%, 95.4%, 96.4%, and 97.3%, respectively for M. tuberculosis complex, 84.0%, 99.2%, 97.3% 94.7% for M. avium complex; 63.6%, 98.3%, 80.7%, 96.2% for M. xenopi; 35.7%, 98.1%, 45.5% 97.2% for M. kansasii. CONCLUSIONS: The morphology of M. tuberculosis complex examined in the radiometric system in useful to differentiate this species from other microbacteria (MOTT), allowing the selection of specific probe used. Within the MOTT, M. avium complex also has morphological characteristics which are useful for its differentiation, the morphology usually described for the remaining species was frequently not observed.

Bacteriological Techniques↗

PubMed1996

Immune response & modulation of immune response induced in the guinea-pigs by Mycobacterium avium complex (MAC) & M. fortuitum complex isolates from different sources in the south Indian BCG trial area.

A total of 139 guineapigs were used to study the immune response and its modulation induced by Mycobacterium avium complex (MAC) and M. fortuitum complex strains obtained from different sources in the south Indian BCG trial area. The guineapigs were divided into groups and some were directly sensitised/immunised with different MAC strains. M. fortuitum complex strain or BCG and others were sensitised with MAC or M. fortuitum complex and then immunised with BCG. The resulting delayed type hypersensitivity (DTH) response in the different groups of guineapigs was studied by skin tests using PPD-RT23 and PPD-B, and protective response was studied by challenging the guineapigs with a south Indian low virulent strain of M. tuberculosis and enumerating the bacilli in spleen at different points of time. The 3 strains of MAC induced similar low levels of DTH to PPD-RT23 but much higher and varying levels of DTH to PPD-B. MAC strains from soil and sputum induced different levels of immune modulation during subsequent immunisation with BCG on the DTH response to PPD-RT23 and PPD-B. At 2 wk after challenge, 23.8, 81 and 90.5 per cent protection was induced by the standard strain, soil isolate and sputum isolate of MAC, respectively, while 33.3 per cent protection was induced by the M. fortuitum complex strain compared to the protection induced by BCG alone. Prior exposure to MAC or M. fortuitum complex did not have any modulatory effect on the protective immunity due to BCG at this time point. However, at 6 wk after challenge, while the guineapigs immunised with BCG were protected, modulation of the protective response resulting from BCG was observed in the guineapigs sensitised with MAC and M. fortuitum from soil.

Animals↗

PubMed1988