Defective CD3-Mediated Cell Death in Activated T Cells from Patients with Systemic Lupus Erythematosus: Role of Decreased Intracellular TNF-α

Kovacs, Birgit; Vassilopoulos, Dimitrios; Vogelgesang, Scott A.; Tsokos, George C.

doi:10.1006/clin.1996.0192

Cited by 104 publications

(72 citation statements)

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“…Regulatory T-cell function and numbers have been reported to be decreased in SLE patients, albeit the reports are not definitive (30). Activationinduced cell death is defective in SLE patients (31), and this may account for the failure to eliminate activated autoreactive T cells in a timely manner. Estrogeninitiated suppression of IL-2 production may not represent the only mechanism whereby estrogens contribute to the aberrant immunoregulation in SLE patients.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Moulton

Holcomb

Zajdel

et al. 2012

Mol Med

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Section: Discussionmentioning

confidence: 99%

Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Moulton

Holcomb

Zajdel

et al. 2012

Mol Med

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“…Whereas mutations of the Fas receptor (FasR) or Fas ligand (FasL) have been associated with a lupus-like autoimmune syndrome in mice with the lpr or gld genetic background [29], Fas-mediated signaling appears to be intact in human SLE [30]. Lupus T cells demonstrate defective activation-induced cell death (AICD) [31]. By contrast, increased spontaneous apoptosis of PBLs has also been observed in SLE [32].…”

Section: Mhp Increased Roi Production Cytoplasmic Alkalinization Anmentioning

confidence: 99%

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Perl

Gergely

Nagy

et al. 2004

Trends in Immunology

220

142

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T-cell activation, proliferation and selection of the cell death pathway depend on the production of reactive oxygen intermediates (ROIs) and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ). Mitochondrial hyperpolarization (MHP) and ATP depletion represent early and reversible steps in T-cell activation and apoptosis. By contrast, T cells of patients with systemic lupus erythematosus (SLE) exhibit persistent MHP, cytoplasmic alkalinization, increased ROI production and depleted ATP, which mediate enhanced spontaneous and diminished activation-induced apoptosis and sensitize lupus T cells to necrosis. Necrotic, but not apoptotic, cell lysates activate dendritic cells and might account for increased interferon a production and inflammation in lupus patients. MHP is proposed as a key mechanism of SLE pathogenesis and is therefore a target for pharmacological intervention.Innate and adaptive immune responses depend on controlled production of ATP and reactive oxygen intermediates (ROIs) in mitochondria. In response to antigenic stimulation, clonal expansion of T and B cells are continuously downsized and potentially autoreactive cells are eliminated by apoptosis. An array of signals through the T-cell receptor (TCR), costimulatory molecules, cell death receptors, lymphokines, and other circulating metabolites, such as ATP, NAD, cADPR, glucose, glutathione, nitric oxide (NO) and ROIs, determine the fate of T cells [1]. T-cell activation and death pathway selection depend on the production of ROIs and ATP synthesis, which are tightly regulated by the mitochondrial transmembrane potential (ΔΨ m ) (Box 1). Disruption of ΔΨ m has been proposed as the point of no return in apoptotic signaling [2] T-cell activation is regulated by mitochondrial ROI productionROIs modulate T-cell activation, cytokine production and proliferation at multiple levels [12]. The antigen-binding αβ or γδTCR is associated with a multimeric receptor module comprising the CD3γδε and TCRζ chains. The cytoplasmic domains of the CD3 and ζ chains contain a common motif, termed the immunoreceptor tyrosinebased activation motif (ITAM), which is crucial for the coupling of intracellular tyrosine kinases [13]. . Thus, expression of cytokines can be selectively regulated by oxidative stress depending on the relative expression level of transcription factors involved (e.g. IL-2 is expressed through a promoter that has AP-1 and NFAT motifs, and IL-4 is expressed through an AP-1-less NFAT enhancer; Figure 1). Redox control of apoptosis signal processingProgrammed cell death (PCD) or apoptosis is a physiological mechanism for elimination of autoreactive lymphocytes during development. Signaling through the Fas or structurally related TNF family of cell-surface death receptors has emerged as a major pathway in the elimination of unwanted cells under physiological and disease conditions [18]. Fas and TNF receptors mediate cell death through cytoplasmic death domains (DDs) shared by both receptors [19]. They ...

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“…The importance of activationinduced CD4 + T-lymphocyte apoptosis in the protection against autoimmunity is underlined by the finding that deficiencies in Fas-mediated apoptosis are found in several idiopathic autoimmune diseases (Kovacs et al, 1996;Le Deist et al, 1996;Semra et al, 2002;Bona et al, 2003;Szodoray et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Ability of Trichloroethylene Metabolite to Promote Immune Pathology is Strain-Specific

Blossom

Doss

Gilbert

2006

Journal of Immunotoxicology

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Chronic low-level exposure to the environmental pollutant trichloroethylene has been shown to promote autoimmune disease in association with CD4 + T-lymphocyte activation in lupus-prone MRL +/+ mice. One of the primary metabolites of trichloroethylene, trichloroacetaldehyde hydrate (TCAH), was similarly shown to increase the percentage of IFNγ-producing CD4 + T-lymphocytes when added to the drinking water of MRL +/+ mice. In addition, TCAH-treated MRL +/+ mice developed skin inflammation and alopecia. In the present study TCAH was tested for its ability to accelerate the development of alopecia in C3H/HeJ mice which tend to develop the disorder spontaneously late in life. In contrast to MRL +/+ mice, C3H/HeJ mice treated with TCAH did not develop alopecia at an increased rate. In addition, TCAH did not promote the expansion of activated IFNγ-producing CD4 + Tlymphocytes in C3H/HeJ mice. CD4 + T-lymphocytes from TCAHtreated C3H/HeJ mice, unlike their MRL +/+ counterparts, did not become resistant to activation-induced apoptosis following in vivo exposure to TCAH. Taken together, it appears that the ability of TCAH to promote immune-mediated pathology is strain-specific and may require an autoimmune-prone genetic background.

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Defective CD3-Mediated Cell Death in Activated T Cells from Patients with Systemic Lupus Erythematosus: Role of Decreased Intracellular TNF-α

Cited by 104 publications

References 0 publications

Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Estrogen Upregulates Cyclic AMP Response Element Modulator α Expression and Downregulates Interleukin-2 Production by Human T Lymphocytes

Mitochondrial hyperpolarization: a checkpoint of T-cell life, death and autoimmunity

Ability of Trichloroethylene Metabolite to Promote Immune Pathology is Strain-Specific

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