Increased activation‐induced cell death in peripheral lymphocytes of rheumatoid arthritis patients: the mechanism of action

Tang, Xiaolei; Yocum, David E.; Dejonghe, David; K, Nordensson; Lake, Douglas F.; Richard, John

doi:10.1111/j.1365-2567.2004.01888.x

Cited by 12 publications

(18 citation statements)

References 63 publications

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“…As expected, the T cell proliferative response in this patient group seemed to be impaired. It has been demonstrated that lymphocytes from RA patients have an increased sensitivity to die from AICD [28]. A fraction of the proliferative restricted cells may thus undergo apoptosis in response to stimulation.…”

Section: Discussionmentioning

confidence: 99%

Impaired activation-induced telomerase activity in PBMC of early but not chronic rheumatoid arthritis patients

et al. 2005

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Although telomerase activity is important in normal immune function, it is unclear whether telomerase or telomerase (dys)regulation plays a role in the pathogenic immune response in autoimmune diseases like rheumatoid arthritis (RA). In this study we evaluated the dynamics of the activation-induced human Telomerase Reverse Transcriptase (hTERT) response in RA patients and non-RA controls. The expression of the catalytic subunit of telomerase, hTERT, was measured in PBMC of RA patients and controls after in vitro stimulation with anti-CD3 monoclonal antibody (mAb) using real-time PCR. Anti-CD3 mAb stimulation induced activation and proliferation of the T cells in all populations studied. In early RA patients with a disease duration of less than a year, the activation-induced hTERT mRNA levels were found to be reduced as compared to healthy controls (HC). Chronic RA patients, with a disease duration of more than one year, did not show these impaired hTERT mRNA levels after stimulation with anti-CD3 mAb. Decreased hTERT mRNA levels were also found in multiple sclerosis patients and patients suffering from flu-like symptoms, indicating that these deviations are not disease-specific. The impaired activation-induced hTERT response in PBMC may be a general response of the immune cells in cases of acute or chronic immuneactivation, presumably to control unwanted clonal expansions and to maintain the diversity of the TCR repertoire. Our results also indicate that clonal T cell expansions, described in RA, are probably not mediated by an elevated potency to express hTERT.1

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Section: Discussionmentioning

confidence: 99%

Impaired activation-induced telomerase activity in PBMC of early but not chronic rheumatoid arthritis patients

et al. 2005

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“…Previous studies support the idea that a failure of T cell AICD is also involved in the pathogenesis of RA [10][11][12][13]. However, the impaired AICD in RA synovium might be ascribed to a soluble survival signal from CD14 + cells, or to an aberrant expression of Fas-like IL-1β-converting enzyme-inhibitory protein (FLIP) [12,13]. These alternative models have been controversial.…”

Section: Introductionmentioning

confidence: 96%

“…In support of this notion, mutations in Fas or Fas ligand (FasL) result in a systemic lupus-like autoimmune disease in mice and humans [7][8][9], implying a critical role for AICD in the maintenance of self-tolerance. Previous studies support the idea that a failure of T cell AICD is also involved in the pathogenesis of RA [10][11][12][13]. However, the impaired AICD in RA synovium might be ascribed to a soluble survival signal from CD14 + cells, or to an aberrant expression of Fas-like IL-1β-converting enzyme-inhibitory protein (FLIP) [12,13].…”

Section: Introductionmentioning

confidence: 97%

Engagement of CD44 up-regulates Fas Ligand expression on T cells leading to activation-induced cell death

et al. 2006

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Activation-induced cell death (AICD) plays a pivotal role in self-tolerance by deleting autoreactive T cells, but a defect of AICD results in expansion of autoreactive T cells and is deeply involved in the pathogenesis of rheumatoid arthritis. Although the process of AICD is mainly mediated by Fas Ligand (FasL)/Fas signaling, it remains unclear what induces FasL expression on T cells. In the present study, we found that CD44 was the most potent stimulator of FasL expression on human peripheral T cells. CD44 cross-linking rapidly up-regulated FasL expression on the T cell surface by delivery from the cytoplasm without new FasL protein synthesis. This up-regulation of FasL was mediated by activation of a tyrosine kinase, IP3 receptor-dependent Ca(2+) mobilization and actin cytoskeletal rearrangements. Furthermore, AICD induced by CD3 restimulation was inhibited by hyaluronidase as well as by soluble Fas, indicating an interaction between membrane-bound hyaluronan and the cell surface CD44 was involved in the up-regulation of FasL expression on T cells and subsequent AICD. We therefore propose that the engagement of CD44 on T cells can eliminate autoreactive T cells by expression of FasL and FasL-mediated AICD.

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“…Peripheral tolerance is the most important mechanism that helps in preventing the host immune system from responding to peripheral self-antigens. Activationinduced cell death (AICD) of lymphocytes is the critical mechanism responsible for eliminating peripheral activated lymphocytes in the immune system and maintaining peripheral immune tolerance [4,5]. It is a kind of cell death induced by death receptors, in which FAS-associated death domain protein (FADD) is recruited mainly through the interaction of Fas and Fas ligand (FasL).…”

Section: Introductionmentioning

confidence: 99%

Resistance to activation-induced cell death and elevated FLIPL expression of CD4+ T cells in a polyI:C-induced primary biliary cirrhosis mouse model

et al. 2009

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Primary biliary cirrhosis (PBC) is a type of organ-specific autoimmune disease in which immune tolerance is impaired by an unknown mechanism. We established a PBC animal model by injecting C57BL/6 mice with polyI:C to study activation-induced cell death (AICD) in CD4+ T lymphocytes and changes of apoptosis-associated molecules as a first step to understand the immune tolerance of PBC mice. Obvious inflammatory cell infiltration was observed in the portal area of the liver tissues in model mice and antimitochondrial antibodies (AMA) positive rate was 80%. The AICD level in both splenic and hepatic CD4+ T cells in the model group were all lower than those in controls, and in the model group the level for hepatic CD4+ T cells were significantly lower than that for splenic CD4+ T cells. Quantitative PCR revealed that FasL mRNA and TRAIL expression in CD4+ T cells in the model group decreased significantly compared with that in the control group. Western blots revealed that the expression of the anti-apoptotic protein FLIP(L) in the model group increased significantly with the FLIP(L) expression in hepatic CD4+ T cells significantly higher than that in splenic CD4+ T cells. There was a positive linear correlation between the number of infiltrated portal areas and relative expression of FLIP(L) in splenic CD4+ T cells in model group. There were no obvious changes for caspase-8 in either group. These results show that the anti-apoptotic ability of CD4+ T lymphocytes play an important role in immune tolerance in the PBC mouse model, and elevated FLIP(L) expression may enhance this ability. The inhibition of FasL and TRAIL expression may also help enhance this anti-apoptotic ability in CD4+ T lymphocytes and contribute to the aggravation of portal area inflammation.

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Increased activation‐induced cell death in peripheral lymphocytes of rheumatoid arthritis patients: the mechanism of action

Cited by 12 publications

References 63 publications

Impaired activation-induced telomerase activity in PBMC of early but not chronic rheumatoid arthritis patients

Impaired activation-induced telomerase activity in PBMC of early but not chronic rheumatoid arthritis patients

Engagement of CD44 up-regulates Fas Ligand expression on T cells leading to activation-induced cell death

Resistance to activation-induced cell death and elevated FLIPL expression of CD4+ T cells in a polyI:C-induced primary biliary cirrhosis mouse model

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