Signal transduction in Sjögren's syndrome T cells. Abnormalities associated with a newly described human A‐type retrovirus

Flescher, Eliezer; Dauphinée, Michael J.; Fossum, Donna; Ledbetter, Jeffrey A.; Talal, Norman

doi:10.1002/art.1780350912

Cited by 8 publications

(4 citation statements)

References 33 publications

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“…A link between Ca2+ influx, phospholipid hydrolysis and polyamines has been reported by us and other investigators [27,[34][35][36][37]. We found that polyamines inhibited Ca2+ influx in Balb/c splenic T-cells in a cell-specific manner [27], the CD4 subset being more susceptible to the inhibitory effect of polyamines than the CD8 subset.…”

Section: Discussionsupporting

confidence: 79%

“…Polyamine-mediated inhibition of the phospholipid-sensitive Ca2+-dependent protein kinase C has also been reported [35]. It is possible that the effect of polyamines might be exerted through their oxidation products [36]. Furthermore, polyamines may react with biological membranes and induce a variety of effects including the promotion of membrane fusion and inhibition of the association of protein kinases with the membranes [37].…”

Section: Discussionmentioning

confidence: 99%

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Defective signal-transduction pathways in T-cells from autoimmune MRL-lpr/lpr mice are associated with increased polyamine concentrations

Gunnia¹,

Seibold²,

Thomas³

1995

Biochemical Journal

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We previously reported that difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, exerted significant beneficial effects on the lifespan and disease expression of MRL-lpr/lpr mice, which spontaneously develop a lupus-like syndrome. Polyamine levels in splenic T-cells of MRL-lpr/lpr mice were significantly higher than those of Balb/c mice. In the present investigation, we examined the role of endogenous polyamines in transmembrane Ca2+ influx, generation of InsP3 and tyrosine phosphorylation of the p56lck protein in concanavalin A-stimulated splenic T-cells. Cytosolic free calcium concentrations ([Ca2+]i) in concanavalin A-stimulated T-cells of MRL-lpr/lpr and Balb/c mice were 250 +/- 25 and 450 +/- 42 nM respectively. Treatment of MRL-lpr/lpr mice with DFMO increased [Ca2+]i to 360 +/- 30 nM (P < 0.05). InsP3 levels of concanavalin A-stimulated MRL-lpr/lpr splenic T-cells were only 20% higher than those of unstimulated controls, whereas those of Balb/c T-cells were 90% higher. DFMO treatment increased InsP3 levels in concanavalin A-treated MRL-lpr/lpr T-cells to 67%. Western-blot analysis showed a 7-fold higher level of p56lck phosphorylation of MRL-lpr/lpr splenic T-cells than that of Balb/c mice. DFMO treatment reduced tyrosine phosphorylation of p56lck of MRL-lpr/lpr mice significantly (P < 0.001). Two-colour flow-cytometric analysis revealed no significant difference in the CD4+/CD8+ ratio in splenic T-cells of MRL-lpr/lpr mice after DFMO treatment. Polyamine levels in splenocytes were significantly reduced by DFMO treatment. These data show that DFMO treatment could alter signal-transduction pathways of splenic T-cells of MRL-lpr/lpr mice. Increased levels of polyamines in T-cells of untreated lpr mice contribute to defective signal-transduction pathways and the pathogenesis of lupus-like symptoms.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Defective signal-transduction pathways in T-cells from autoimmune MRL-lpr/lpr mice are associated with increased polyamine concentrations

Gunnia¹,

Seibold²,

Thomas³

1995

Biochemical Journal

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“…A preliminary report by Flescher et al (1991) showed that anti-CD-3-induced intracellular Ca2+ mobilization in normal human peripheral lymophocytes was suppressed by spermidine. They also found significantly decreased Ca2+ influx in T-cells of rheumatoid-arthritis patients that contained constitutively higher levels of polyamines than that of normal lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of calcium signalling in murine splenocytes by polyamines: differential effects on CD4 and CD8 T-cells

Thomas¹,

Gunnia²,

Yurkow

et al. 1993

Biochemical Journal

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Transmembrane Ca2+ influx is recognized as a universal second messenger that transduces T-cell activation signals to cytoplasm and nucleus, thereby stimulating transcription and cell division. To examine the role of endogenous factors that regulate mitogenic Ca2+ signalling of T-cells, we measured the concanavalin (Con) A-induced increase in cytoplasmic free calcium ([Ca2+]i) in spleen cells of BALB/c mice, using flow cytometry with an indicator dye, Indo-1 acetoxymethyl ester (Indo-1/AM). Con A is a polyclonal activator of T-cells. Unstimulated splenocytes had a [Ca2+]i of 100 nM. [Ca2+]i increased with Con A in a dose-dependent manner up to a concentration of 50 micrograms/ml. In the presence of 50 micrograms/ml Con A, [Ca2+]i was 350 nM. Natural polyamines (putrescine, spermidine and spermine) inhibited Con-A-induced Ca2+ influx in a dose-dependent manner. Putrescine was the most effective polyamine in desensitizing the Ca2+ signal, and decreased [Ca2+]i from 350 nM in the absence of putrescine to 250 nM in the presence of 100 microM putrescine. This effect was not mimicked by structurally related homologues or inorganic cations, suggesting a specific structural effect of the polyamine. H.p.l.c. analysis showed that polyamines were internalized during incubation of cells in vitro. In experiments using monoclonal anti-CD4 and anti-CD8 antibodies, we found a differential effect of putrescine on Ca2+ influx in CD4 and CD8 subpopulations of T cells. For CD4+ cells, [Ca2+]i decreased from 625 nM to 420 nM in the presence of 500 microM putrescine, whereas [Ca2+]i was not affected by putrescine in CD8+ cells. These data suggest that natural polyamines have cell-specific effects on mitogen-stimulated Ca(2+)-influx in T-cell subsets.

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“…The genome encoding HIAP-I has not been characterized; however, cells expressing these RVLPs are reported to have reduced protein kinase C activation and IL-2 production and to express reduced levels of CD4 and increased levels of MHC class II in comparison to normal H9 cells (143). In addition, stimulation of the same cells with phorbol myristate acetate resulted in an increased production of RVLPs, although these RVLPs appeared as cytoplasmic clusters of particles of smaller diameter (approximately 33 nm) (112) and are therefore unlikely to be the same particles observed originally.…”

Section: Human Intracisternal A-type Particlesmentioning

confidence: 99%

Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease

Voisset

Weiss

Griffiths

2008

Microbiol Mol Biol Rev

143

156

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SUMMARY Retroviruses are an important group of pathogens that cause a variety of diseases in humans and animals. Four human retroviruses are currently known, including human immunodeficiency virus type 1, which causes AIDS, and human T-lymphotropic virus type 1, which causes cancer and inflammatory disease. For many years, there have been sporadic reports of additional human retroviral infections, particularly in cancer and other chronic diseases. Unfortunately, many of these putative viruses remain unproven and controversial, and some retrovirologists have dismissed them as merely “human rumor viruses.” Work in this field was last reviewed in depth in 1984, and since then, the molecular techniques available for identifying and characterizing retroviruses have improved enormously in sensitivity. The advent of PCR in particular has dramatically enhanced our ability to detect novel viral sequences in human tissues. However, DNA amplification techniques have also increased the potential for false-positive detection due to contamination. In addition, the presence of many families of human endogenous retroviruses (HERVs) within our DNA can obstruct attempts to identify and validate novel human retroviruses. Here, we aim to bring together the data on “novel” retroviral infections in humans by critically examining the evidence for those putative viruses that have been linked with disease and the likelihood that they represent genuine human infections. We provide a background to the field and a discussion of potential confounding factors along with some technical guidelines. In addition, some of the difficulties associated with obtaining formal proof of causation for common or ubiquitous agents such as HERVs are discussed.

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Signal transduction in Sjögren's syndrome T cells. Abnormalities associated with a newly described human A‐type retrovirus

Cited by 8 publications

References 33 publications

Defective signal-transduction pathways in T-cells from autoimmune MRL-lpr/lpr mice are associated with increased polyamine concentrations

Defective signal-transduction pathways in T-cells from autoimmune MRL-lpr/lpr mice are associated with increased polyamine concentrations

Inhibition of calcium signalling in murine splenocytes by polyamines: differential effects on CD4 and CD8 T-cells

Human RNA “Rumor” Viruses: the Search for Novel Human Retroviruses in Chronic Disease

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