Persistent Mitochondrial Hyperpolarization, Increased Reactive Oxygen Intermediate Production, and Cytoplasmic Alkalinization Characterize Altered IL-10 Signaling in Patients with Systemic Lupus Erythematosus

Gergely, P; Niland, Brian; Gonchoroff, Nick J.; Pullmann, R; Phillips, Paul E. M.; Perl, András

doi:10.4049/jimmunol.169.2.1092

Cited by 173 publications

(125 citation statements)

References 59 publications

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“…Dramatically increased ⌬⌿ m is only observed in effector cells in the presence of virus. A recent pair of studies by Gergely et al (24,25) also observed mitochondrial hyperpolarization in lymphocytes isolated from systemic lupus erythematosus patients. Increased mitochondrial potential may be due to TCR stimulation in vivo, which may be due to an increased need for oxidative metabolism to make cytokines and perforin granules, and to sustain the rapid replication that these cells undergo.…”

Section: Discussionmentioning

confidence: 98%

Mitochondrial Potential and Reactive Oxygen Intermediates in Antigen-Specific CD8+ T Cells During Viral Infection

Grayson

Laniewski

Lanier

et al. 2003

The Journal of Immunology

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Following many viral infections, there are large expansions of Ag-specific CD8+ T cells. After viral clearance, mechanisms exist to ensure that the vast majority of effector cells undergo apoptosis. In studies of thymocyte apoptosis, loss of mitochondrial potential (ΔΨm) and excess production of reactive oxygen intermediates have been implicated as key events in cellular apoptosis. The purpose of the experiments presented in this work was to determine these parameters in Ag-specific CD8+ T cells during a physiological response such as viral infection. Using lymphocytic choriomeningitis virus infection of mice, we found that Ag-specific CD8+ effector T cells that had undergone recent TCR stimulation had an increased ΔΨm. These cells also had increased levels of superoxide. As these cells progressed through the contraction of the immune response, their potential decreased, but superoxide levels remained similar to naive cells. One of the consequences of reduced mitochondrial potential is membrane permeability and subsequent caspase activation. We examined both the enzymatic activity and levels of cleaved caspase 3, an effector caspase, and could only detect increased levels in Ag-specific CD8+ T cells on day 5 postinfection, a time point in which virus was still present. This contrasts with Ag-specific effector cells examined during the contraction phase that had no detectable caspase activity directly ex vivo. These data suggest that the apoptotic program begins earlier than previously expected on day 5, during the expansion phase.

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Section: Discussionmentioning

confidence: 98%

Mitochondrial Potential and Reactive Oxygen Intermediates in Antigen-Specific CD8+ T Cells During Viral Infection

Grayson

Laniewski

Lanier

et al. 2003

The Journal of Immunology

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“…Mitochondrial transmembrane potential (ΔΨ m ) may be elevated for several hours during T cell activation or cell death. Interleukin-3 (IL-3), interleukin-10 (IL-10), transforming growth factor-β 1 (TGF-β 1 ), and interferon-gamma (IFN-γ) were also found to elicit transient ΔΨ elevation [31][32][33][34].…”

Section: Persistent Mitochondrial Hyperpolarization and Atp Depletionmentioning

confidence: 99%

The role of nitric oxide in abnormal T cell signal transduction in systemic lupus erythematosus

Nagy

Perl

2006

Clinical Immunology

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by production of antinuclear autoantibodies and diverse array of clinical manifestations. T cells from patients with SLE have been shown to be activated in vivo and provide help to autoreactive B cells. Lupus T cells exhibit enhanced spontaneous and diminished activation-induced apoptosis and predisposition to necrosis. Persistent mitochondrial hyperpolarization and ATP depletionassociated with significantly increased mitochondrial mass -characterize T lymphocyte dysfunction in SLE. In addition to cell death abnormalities, mitochondrial dysfunction is associated with altered signal transduction through the T cell receptor and Ca 2+ fluxing. Exposure of normal T cell to nitric oxide induces mitochondrial hyperpolarization and biogenesis and regenerates the Ca 2+ signaling profile of lupus T cells. This article reviews a novel understanding of the role of nitric oxide in signal transduction and cell death abnormalities in SLE.

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“…Mitochondrial hyperpolarization appears to be the earliest change associated with Fas (24), H 2 O 2 (46), HIV-1 (44), p53 (47), TNFa (48), and staurosporin-induced apoptosis (49). Elevation of Dc m is also triggered by activation of the CD3/CD28 complex (50,51) or stimulation with Con A (24). Therefore, elevation of Dc m or mitochondrial hyperpolarization represents an early but reversible switch not exclusively associated with apoptosis.…”

Section: Mitochondrial Checkpoints Of Apoptosis: Mitochondrial Transmmentioning

confidence: 99%

The pathogenesis of transaldolase deficiency

Perl¹

2007

IUBMB Life

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SummaryThe signaling networks that mediate cell growth, differentiation, and survival are dependent on complex metabolic and redox pathways. Metabolism of glucose through the pentose phosphate pathway (PPP) fulfills two unique functions: formation of ribose 5-phosphate for the synthesis of nucleotides, RNA, and DNA in support cell growth and formation of NADPH for biosynthetic reactions and neutralization of reactive oxygen intermediates (ROI). Balancing of NADPH and ROI levels by the PPP enzyme transaldolase (TAL) regulates the mitochondrial trans-membrane potential (Dw m ), a critical checkpoint of ATP synthesis and cell survival. While complete deficiency of glucose 6-phosphate dehydrogenase (G6PD) or transketolase (TK) is lethal, TAL-deficient mice developed normally with the exception of male sterility due to structural and functional damage of sperm cell mitochondria. Recently, two cases of complete TAL deficiency have been reported in patients with liver cirrhosis which results from increased cell death of hepatocytes. Delineation of the cell type-specific role that TAL plays in the PPP and cell death signal processing will be critical for understanding the pathogenesis of TAL deficiency.

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Persistent Mitochondrial Hyperpolarization, Increased Reactive Oxygen Intermediate Production, and Cytoplasmic Alkalinization Characterize Altered IL-10 Signaling in Patients with Systemic Lupus Erythematosus

Cited by 173 publications

References 59 publications

Mitochondrial Potential and Reactive Oxygen Intermediates in Antigen-Specific CD8+ T Cells During Viral Infection

Mitochondrial Potential and Reactive Oxygen Intermediates in Antigen-Specific CD8+ T Cells During Viral Infection

The role of nitric oxide in abnormal T cell signal transduction in systemic lupus erythematosus

The pathogenesis of transaldolase deficiency

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