Abnormal T cell signal transduction in systemic lupus erythematosus

Kammer, Gary M.; Perl, András; Richardson, Bruce C.; Tsokos, George C.

doi:10.1002/art.10192

Cited by 134 publications

(107 citation statements)

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“…Second, MHP might occur through calciumactivated dephosphorylation of cytochrome c oxidase [44]. Phosphorylation of cytochrome c oxidase is mediated by protein kinase A (PKA); thus, deficiency of PKA could also contribute to MHP in SLE [45]. Third, inhibition of the enzymatic activity of F 0 F 1 -ATPase would decrease utilization of the electrochemical gradient and cause ΔΨ m hyperpolarization, ATP depletion and ADP accumulation.…”

Section: Mhp and Atp Depletion Predispose Lupus T Cells To Necrosismentioning

confidence: 99%

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

Perl

Gergely

Nagy

et al. 2004

Trends in Immunology

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220

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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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Section: Mhp and Atp Depletion Predispose Lupus T Cells To Necrosismentioning

confidence: 99%

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

Perl

Gergely

Nagy

et al. 2004

Trends in Immunology

Self Cite

220

142

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“…Nontranslated downstream region of the ζ chain gene is shorter, which may account for decreased messenger RNA stability. Several of the mutations were located in the 3 immunoreceptor tyrosine activation motifs, or the GTP binding domain, and this could lead to functional alterations in the TCR zeta chain [2,14].…”

Section: Abnormal Tcr Activation and Ca 2+ Signaling In Slementioning

confidence: 99%

“…Current evidence suggests that a central role in initiating disease is played by underlying defects in T lymphocyte antigen receptormediated signaling that lead to B cell hyper-responsiveness, increased spontaneous and decreased activation-induced apoptosis, skewed cytokine production, and breakdown of immunological tolerance [1][2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…It follows that disturbances of mitochondrial function will lead to disruption of cell function, expressed as disease. It is widely accepted that apoptotic abnormalities contribute to the pathogenesis of SLE [1][2][3]. Recently, enhanced spontaneous and diminished activation-induced apoptosis has been found to be associated with abnormal TCR activation, increased mitochondrial biogenesis, persistent mitochondrial hyperpolarization (MHP), ATP depletion, and overproduction of nitric oxide (NO).…”

Section: Introductionmentioning

confidence: 99%

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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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“…We and others have shown that lupus T cells display signalling patterns characteristic of hyper-responsiveness and altered expression of molecules regulated by CTLA-4, such as unregu-lated TCRz phosphorylation and increased expression of lipid microdomain-associated glycosphingolipid (GM1) [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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CTLA‐4 is a critical gatekeeper of T‐cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA‐4 in SLE. Our results reveal increased CTLA‐4 expression in FOXP3− responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA‐4 was unable to regulate T‐cell proliferation, lipid microdomain formation and phosphorylation of TCR‐ζ following CD3/CD28 co‐stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co‐stimulation, there was no parallel increase in CTLA‐4 expression, which would normally provide a break on T‐cell proliferation. These defects were associated with exclusion of CTLA‐4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA‐4 dysfunction as a potential cause for abnormal T‐cell activation in patients with SLE, which could be targeted for therapy.

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Abnormal T cell signal transduction in systemic lupus erythematosus

Cited by 134 publications

References 125 publications

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

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

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

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

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