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Peter Gergely

Publications and source records attributed to Peter Gergely.

13 recordsLinked to original sources
PubMed2006

Regulation of CD4 expression via recycling by HRES-1/RAB4 controls susceptibility to HIV infection.

A novel 2986-base transcript encoded by the antisense strand of the HRES-1 human endogenous retrovirus was isolated from peripheral blood lymphocytes. This transcript codes for a 218-amino acid protein, termed HRES-1/Rab4, based on homology to the Rab4 family of small GTPases. Antibody 13407 raised against recombinant HRES-1/Rab4 detected a native protein of identical molecular weight in human T cells. HRES-1 nucleotides 2151-1606, located upstream of HRES-1/Rab4 exon 1, have promoter activity when oriented in the direction of HRES-1/Rab4 transcription. The human immunodeficiency virus, type 1 (HIV-1), tat gene stimulates transcriptional activity of the HRES-1/Rab4 promoter via trans-activation of the HRES-1 long terminal repeat. Transfection of HIV-1 tat into HeLa cells or infection of H9 and Jurkat cells by HIV-1 increased HRES-1/Rab4 protein levels. Overexpression of HRES-1/Rab4 in Jurkat cells abrogated HIV infection, gag p24 production, and apoptosis, whereas dominant-negative HRES-1/Rab4(S27N) had the opposite effects. HRES-1/Rab4 inhibited surface expression of CD4 and targeted it for lysosomal degradation. HRES-1/Rab4(S27N) enhanced surface expression, recycling, and total cellular CD4 content. Infection by HIV elicited a coordinate down-regulation of CD4 and up-regulation of HRES-1/Rab4 in PBL. Moreover, overexpression of HRES-1/Rab4 reduced CD4 expression on peripheral blood CD4+ T cells. Stimulation by HIV-1 of HRES-1/Rab4 expression and its regulation of CD4 recycling reveal novel coordinate interactions between an infectious retrovirus and the human genome.

Antigens, CD↗
PubMed2006

Coexistent Marfan's syndrome and ankylosing spondylitis.

We describe a 22-year-old woman with coexisting Marfan's syndrome (MFS) and ankylosing spondylitis (AS). A change of fibrillin-1 due to mutation of the FBN1 gene (MFS) or a cell-mediated autoimmune response in AS could account for a common pathology.

Adult↗
PubMed2005

Increased prevalence of transfusion-transmitted virus and cross-reactivity with immunodominant epitopes of the HRES-1/p28 endogenous retroviral autoantigen in patients with systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) patients produce autoantibodies to HRES-1/p28, a human endogenous retrovirus-encoded nuclear protein. To identify cross-reactive viral antigens capable of triggering autoreactivity, HRES-1/p28 epitopes were mapped by SLE antibodies. METHODS: Forty-four peptides overlapping HRES-1/p28 and 13 viral peptides were synthesized on cellulose membrane and tested for recognition by antibodies from 16 HRES-1 Western blot seropositive SLE patients. Transfusion-transmitted virus (TTV) was detected by gene amplification in sera of 211 SLE patients, 78 healthy SLE family members, 199 unrelated healthy donors, and 91 rheumatoid arthritis (RA) patients. RESULTS: HRES-1/p28 residues 41-55, 121-135, and 156-170 were recognized by 12/16 (75.0%), 11/16 (68.8%), and 9/16 lupus sera (56.25%) and considered immunodominant. HRES-1/p28 residues 121-135 harbor cross-reactive epitope with retroviral peptides and the 70 K U1snRNP lupus autoantigen. HRES-1/p28 residues 41-55 and 156-170 exhibited the highest prevalence of cross-reactivity with TTV peptide ORF2a (14/16, 87%). Prevalence of TTV DNA was increased in lupus patients (120/211) with respect to healthy (66/199; P < 0.0001) or RA controls (23/91; P < 0.0001). TTV prevalence in healthy lupus relatives (40/78) was decreased with respect to lupus patients (80/121; P = 0.0184) and increased with respect to unrelated healthy donors (66/199; P = 0.0026). HRES-1/p28 Western blot reactivity was observed in 12/23 TTV PCR-negative donors and 43/58 TTV PCR-positive donors (P < 0.0281). CONCLUSIONS: Increased prevalence of TTV and molecular mimicry with HRES-1/p28 may contribute to generation of antinuclear antibodies and pathogenesis of SLE.

Adult↗
PubMed2005

Antinucleosome antibodies and decreased deoxyribonuclease activity in sera of patients with systemic lupus erythematosus.

Nucleosomes are the dominant autoantigens in patients with systemic lupus erythematosus (SLE), and immune complexes involving nucleosomes are the major cause of tissue damage. The activity of DNase I, the enzyme responsible for nucleosome degradation, has been found to be decreased in patients with SLE. However, it is not known whether DNase activity is a clinically useful parameter. The aim of our study was to assess DNase activity in a prospective study of 113 patients with SLE in relation to disease activity and organ involvement. We included two control groups: 9 patients with undifferentiated connective tissue disease (UCTD) and 14 healthy individuals. DNase activity was found to be lower in patients with SLE (63.75%+/-12.1%) than in the controls (81.3%+/-9.25%) (P<0.001). DNase activity in patients with UCTD (64.9%+/-18.2%; P=0.854) did not differ from that in patients with SLE. Patients with SLE had higher antinucleosome antibody titers (356.3+/-851) than the controls (1.44+/-2.77; P<0.01) or UCTD patients (39.9+/-57.7; P<0.01). In addition, samples positive for antinucleosome antibodies displayed low levels of DNase activity. Within the SLE group, the presence of renal disease had no impact on DNase activity or antinucleosome antibody titers. Also, the SLE disease activity index showed no correlation with DNase activity. In a longitudinal study of six SLE patients, DNase activity did not follow disease activity or autoantibody titers. Our results confirm that serum DNase activity is decreased in patients with SLE, but we conclude that it is not a clinically useful parameter for the prediction of flare-ups of disease or renal involvement.

Autoantibodies↗
PubMed2005

Detection of TT virus in patients with idiopathic inflammatory myopathies.

The TT virus, a recently identified single-stranded DNA virus with unknown pathogenicity, has been shown to commonly infect humans. Viruses have been considered to contribute to disease pathogenesis in autoimmune disorders including idiopathic inflammatory myopathies (IIMs) and rheumatoid arthritis (RA). We assessed the prevalence of TTV infection in IIM compared with that in patients with RA and healthy blood donors. Detection of TTV was conducted by nested PCR and real-time PCR in the sera of 94 patients with IIM, 95 RA patients. and 95 age- and sex-matched healthy blood donors. Identity of the PCR products was confirmed by sequencing. TTV DNA was detected in 61 of 94 (64.9%) patients with IIM, in 64 of 95 (67.4%) patients with RA, and in 62 of 95 (65.3%; P > 0.05) healthy individuals. Age, sex, activity, or duration of disease had no influence on TTV positivity in either group. However, patients with severe IIM (n = 36) had a significantly higher rate of TTV infection (31/36, 86.1%) than patients with mild disease (30/58, 51.7%, P < 0.05, chi(2) = 10.0). Disease was considered severe in IIM when immunosuppressive treatment was necessary because of continuous high activity and/or serious inner-organ involvement despite corticosteroid treatment. In conclusion, although we found the detection rate of TTV similar in patients with idiopathic inflammatory myopathies and rheumatoid arthritis and comparable to that in healthy controls, our data suggest that infection with TT virus may result in a more severe disease in patients with idiopathic inflammatory myopathies.

Adult↗
PubMed2004

Relapsing polychondritis.

Relapsing polychondritis (RP) is a rare multisystem autoimmune disease of unknown origin characterized by recurrent episodes of inflammation and progressive destruction of cartilaginous tissues. Elastic cartilage of the ears and nose, hyaline cartilage of peripheral joints, vertebral fibrocartilage and tracheobronchial cartilage, as well as proteoglycan-rich structures of the eye, heart, blood vessels or inner ear may all be affected. In most patients RP manifests in a fluctuating but progressive course which eventually results in a significant shortening of life expectancy. The relatively uncommon occurrence, the unknown etiopathogenesis, the ambiguous clinical pattern, as well as the variety in its course and response to therapy may all contribute to the difficulties the physician must overcome when managing RP. Beside describing the main features of RP and seven clinical cases of our own, in the present review we focus on recent findings in the etiopathogenesis and novel treatment options.

Animals↗
PubMed2004

Apoptosis and mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by abnormal activation and cell death signaling within the immune system. Activation, proliferation, or death of cells of the immune system are dependent on controlled reactive oxygen intermediate (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (Delta(Psi)m) reflects the energy stored in the electrochemical gradient across the inner mitochondrial membrane, which in turn is used by F0F1-ATPase to convert adenosine 5'-diphosphate to ATP during oxidative phosphorylation. Mitochondrial hyperpolarization and transient ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T lymphocytes of patients with SLE exhibit elevated Delta(Psi)m, that is, persistent mitochondrial hyperpolarization, cytoplasmic alkalinization, increased ROI production, as well as diminished levels of intracellular glutathione and ATP. Oxidative stress affects signaling through the T-cell receptor as well as the activity of redox-sensitive caspases. ATP depletion may be responsible for diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Mitochondrial dysfunction is identified as a key mechanism in the pathogenesis of SLE.

Adenosine Triphosphate↗
PubMed2002

Persistent mitochondrial hyperpolarization, increased reactive oxygen intermediate production, and cytoplasmic alkalinization characterize altered IL-10 signaling in patients with systemic lupus erythematosus.

Abnormal death signaling in lymphocytes of systemic lupus erythematosus (SLE) patients has been associated with elevation of the mitochondrial transmembrane potential (Delta psi(m)) and increased production of reactive oxygen intermediates (ROI). The resultant ATP depletion sensitizes T cells for necrosis that may significantly contribute to inflammation in patients with SLE. In the present study, the role of mitochondrial signal processing in T cell activation was investigated. CD3/CD28 costimulation of PBL elicited transient mitochondrial hyperpolarization and intracellular pH (pH(i)) elevation, followed by increased ROI production. Baseline Delta psi(m), ROI production, and pH(i) were elevated, while T cell activation-induced changes were blunted in 15 patients with SLE in comparison with 10 healthy donors and 10 rheumatoid arthritis patients. Similar to CD3/CD28 costimulation, treatment of control PBL with IL-3, IL-10, TGF-beta(1), and IFN-gamma led to transient Delta psi(m) elevation. IL-10 had diametrically opposing effects on mitochondrial signaling in lupus and control donors. Unlike healthy or rheumatoid arthritis PBL, cells of lupus patients were resistant to IL-10-induced mitochondrial hyperpolarization. By contrast, IL-10 enhanced ROI production and cell death in lupus PBL without affecting ROI levels and survival of control PBL. Ab-mediated IL-10 blockade or stimulation with antagonistic lymphokine IL-12 normalized baseline and CD3/CD28-induced changes in ROI production and pH(i) with no impact on Delta psi(m) of lupus PBL. The results suggest that mitochondrial hyperpolarization, increased ROI production, and cytoplasmic alkalinization play crucial roles in altered IL-10 responsiveness in SLE.

Adolescent↗
PubMed2002

Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus.

OBJECTIVE: Peripheral blood lymphocytes (PBLs) from systemic lupus erythematosus (SLE) patients exhibit increased spontaneous and diminished activation-induced apoptosis. We tested the hypothesis that key biochemical checkpoints, the mitochondrial transmembrane potential (deltapsim) and production of reactive oxygen intermediates (ROIs), mediate the imbalance of apoptosis in SLE. METHODS: We assessed the deltapsim with potentiometric dyes, measured ROI production with oxidation-sensitive fluorochromes, and monitored cell death by annexin V and propidium iodide staining of lymphocytes, using flow cytometry. Intracellular glutathione levels were measured by high-performance liquid chromatography, while ATP and ADP levels were assessed by the luciferin-luciferase assay. RESULTS: Both deltapsim and ROI production were elevated in the 25 SLE patients compared with the 25 healthy subjects and the 10 rheumatoid arthritis patients. Intracellular glutathione contents were diminished, suggesting increased utilization of reducing equivalents in SLE. H2O2, a precursor of ROIs, increased deltapsim and caused apoptosis in normal PBLs. In contrast, H2O2-induced apoptosis and deltapsim elevation were diminished, particularly in T cells, and the rate of necrotic cell death was increased in patients with SLE. The intracellular ATP content and the ATP:ADP ratio were reduced and correlated with the deltapsim elevation in lupus. CD3:CD28 costimulation led to transient elevation of the deltapsim, followed by ATP depletion, and sensitization of normal PBLs to H2O2-induced necrosis. Depletion of ATP by oligomycin, an inhibitor of F0F1-ATPase, had similar effects. CONCLUSION: T cell activation and apoptosis are mediated by deltapsim elevation and increased ROI production. Mitochondrial hyperpolarization and the resultant ATP depletion sensitize T cells for necrosis, which may significantly contribute to inflammation in patients with SLE.

Adenosine Triphosphate↗
PubMed2002

Differential regulation of hydrogen peroxide and Fas-dependent apoptosis pathways by dehydroascorbate, the oxidized form of vitamin C.

Dehydroascorbate (DHA), the oxidized form of vitamin C (ascorbate), enhanced antioxidant defenses of human T cells preferentially importing DHA over ascorbate. In itself, DHA did not affect cytosolic or mitochondrial reactive oxygen intermediate levels as monitored by flow cytometry using oxidation-sensitive fluorescent probes. DHA at 200-1,000 microM stimulated activity of pentose phosphate pathway enzymes glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and transaldolase, elevated intracellular glutathione levels, and inhibited H(2)O(2)-induced changes in mitochondrial transmembrane potential and cell death. With respect to the CD4 antigen, DHA selectively enhanced cell-surface expression of the Fas receptor and increased susceptibility of Jurkat and H9 human T cells to Fas-mediated cell death. The data identify DHA as a selective regulator of H(2)O(2)- and Fas-dependent apoptosis pathways.

Animals↗
PubMed2002

Metabolic switches of T-cell activation and apoptosis.

The signaling networks that mediate activation, proliferation, or programmed cell death of T lymphocytes are dependent on complex redox and metabolic pathways. T lymphocytes are primarily activated through the T-cell receptor and co-stimulatory molecules. Although activation results in lymphokine production, proliferation, and clonal expansion, it also increases susceptibility to apoptosis upon crosslinking of cell-surface death receptors or exposure to toxic metabolites. Activation signals are transmitted by receptor-associated protein tyrosine kinases and phosphatases through calcium mobilization to a secondary cascade of kinases, which in turn activate transcription factors initiating cell proliferation and cytokine production. Initiation and activity of cell death-mediating proteases are redox-sensitive and dependent on energy provided by ATP. Mitochondria play crucial roles in providing ATP for T-cell activation through the electron transport chain and oxidative phosphorylation. The mitochondrial transmembrane potential (DeltaPsi(m)) plays a decisive role not only by driving ATP synthesis, but also by controlling reactive oxygen species production and release of cell death-inducing factors. DeltaPsi(m) and reactive oxygen species levels are regulated by the supply of reducing equivalents, glutathione and thioredoxin, as well as NADPH generated in the pentose phosphate pathway. This article identifies redox and metabolic checkpoints controlling activation and survival of T lymphocytes.

Adenosine Triphosphate↗
PubMedDate not supplied

Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus.

Activation, proliferation, or programmed cell death of T lymphocytes are dependent on controlled reactive oxygen intermediates (ROI) production and ATP synthesis in mitochondria. The mitochondrial transmembrane potential (Delta Psi(m)) also plays a decisive role in cell survival by controlling activity of redox-sensitive caspases. T lymphocytes of patients with systemic lupus erythematosus (SLE) exhibit mitochondrial hyperpolarization, increased ROI production, diminished intracellular glutathione levels, cytoplasmic alkalinization, and ATP depletion that mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. These redox and metabolic checkpoints represent novel targets for pharmacological intervention in SLE.

Adenosine Triphosphate↗