Disease activity in multiple sclerosis correlates with T lymphocyte expression of the inhibitor of apoptosis proteins

Semra, Y K; Seidi, Osheik; Sharief, Mohammed

doi:10.1016/s0165-5728(01)00464-7

Cited by 36 publications

(19 citation statements)

References 44 publications

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“…Knowledge of these mechanisms could be translated to therapeutic technologies for diseases such as MS (Sohur et al, 2006). Furthermore, increased AP expression in the T cells of MS patients correlates with disease activity, whereas interferon-β therapy decreases IAP expression in these cells (Semra et al, 2002; Sharief et al, 2002). This implicates IAP expression as an important regulator of T-cell survival in, and thus pathology of, MS.…”

Section: Discussionmentioning

confidence: 99%

Fas activation increases neural progenitor cell survival

Knight

Scharf

Mao-Draayer

2009

J of Neuroscience Research

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Although there is a sizable amount of research focusing on adult neural progenitor cells (NPCs) as a therapeutic approach for many neurodegenerative diseases, including multiple sclerosis, little is known about the pathways that govern NPC survival and apoptosis. Fas, a member of the death receptor superfamily, plays a well-characterized role in the immune system, but its function in neural stem cells remains uncertain. Our study focuses on the effects of Fas on NPC survival in vitro. Activation of Fas by recombinant Fas ligand (FasL) did not induce apoptosis in murine NPCs in culture. In fact, both an increase in the amount of viable cells and a decrease in apoptotic and dying cells were observed with FasL treatment. Our data indicate that FasL-mediated adult NPC neuroprotection is characterized by a reduction in apoptosis, but not increased proliferation. Further investigation of this effect revealed that the antiapoptotic effects of FasL are mediated by the up-regulation of Birc3, an inhibitor of apoptosis protein (IAP). Conversely, the observed effect is not the result of altered caspase activation or FLIP (Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein) up-regulation, which is known to inhibit caspase-8-mediated cell death in T cells. Our data indicate that murine adult NPCs are resistant to FasL-induced cell death. Activation of Fas increased cell survival by decreasing apoptosis through Birc3 up-regulation. These results describe a novel pathway involved in NPC survival.

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Section: Discussionmentioning

confidence: 99%

Fas activation increases neural progenitor cell survival

Knight

Scharf

Mao-Draayer

2009

J of Neuroscience Research

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“…Defective T cell apoptosis has been attributed to many factors including elevated soluble CD95 (29), over expression of the caspase 8 inhibitor, FLIP in T cells (30), increased IAP (18,31), and Bcl-X L (32). Diminished autoimmune T cell responsiveness to apoptotic triggers may be due to differential induction of proapoptotic stimuli, reflecting variations in costimulator environment or affinity for MHC ϩ Ag, or due to failure to mount the caspase activation and/or execution sequence due to defects in pathways such as Fas or TRAIL (14,33,34).…”

Section: Discussionmentioning

confidence: 99%

X-linked Inhibitor of Apoptosis Regulates T Cell Effector Function

Zehntner

Bourbonnière

Moore

et al. 2007

The Journal of Immunology

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To understand how the balance between pro- and anti-apoptotic signals influences effector function in the immune system, we studied the X-linked inhibitor of apoptosis (XIAP), an endogenous regulator of cellular apoptosis. Real-time PCR showed increased XIAP expression in blood of mice with experimental autoimmune encephalomyelitis, correlating with disease severity. Daily administration (10 mg/kg/day i.p.) of a 19-mer antisense oligonucleotide specific for XIAP (ASO-XIAP) abolished disease-associated XIAP mRNA and protein expression, and given from day of onset, alleviated experimental autoimmune encephalomyelitis and prevented relapses. Prophylactic treatment also reduced XIAP expression and prevented disease. Random or 5-base mismatched ASO was not inhibitory, and ASO-XIAP did not affect T cell priming. In ASO-XIAP-treated animals, infiltrating cells and inflammatory foci were dramatically reduced within the CNS. Flow cytometry showed an 88–93% reduction in T cells. The proportion of TUNEL+ apoptotic CD4+ T cells in the CNS was increased from <1.6 to 26% in ASO-XIAP-treated mice, and the proportion of Annexin V-positive CD4+ T cells in the CNS increased. Neurons and oligodendrocytes were not affected; neither did apoptosis increase in liver, where XIAP knockdown also occurred. ASO-XIAP increased susceptibility of T cells to activation-induced apoptosis in vitro. Our results identify XIAP as a critical controller of apoptotic susceptibility of effector T cell function.

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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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Disease activity in multiple sclerosis correlates with T lymphocyte expression of the inhibitor of apoptosis proteins

Cited by 36 publications

References 44 publications

Fas activation increases neural progenitor cell survival

Fas activation increases neural progenitor cell survival

X-linked Inhibitor of Apoptosis Regulates T Cell Effector Function

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

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