Shortening of telomeres: Evidence for replicative senescence of T cells derived from patients with Wegener's granulomatosis

Vogt, Saskia; Iking‐Konert, Christof; Hug, Friederike; Andrássy, K.; Hänsch, Gertrud Maria

doi:10.1046/j.1523-1755.2003.00037.x

Cited by 42 publications

(32 citation statements)

References 27 publications

(1 reference statement)

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“…These abnormalities include lymphopenia [15], a high number of activated T lymphocytes in peripheral blood [16], skewing of Th1 to Th2 responses [17] and senescence of CD28 -lymphocytes in the CD8 + subpopulation [18]. Our results also demonstrate beneficial effects of DSG on T cells by inhibiting T cell receptor-mediated T cell proliferation and cytokine production in both Th1 and Th2 T cells.…”

Section: Discussionsupporting

confidence: 61%

In vivoeffects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis

Kälsch

Schmitt

Breedijk

et al. 2006

Clinical and Experimental Immunology

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Summary 15-Deoxyspergualin (DSG)is an alternative treatment modality for Wegener's granulomatosis (WG) patients refractory to conventional treatment. Nevertheless, it is unclear how DSG modulates disease activity in these patients. This study was conducted to investigate which parameters of adaptive and acquired immunity were influenced during two subsequent cycles of DSG treatment. Emphasis was put upon T cell and monocyte activation, neutrophil function and surface expression of proteinase-3 (PR-3). Anti-CD3/anti-CD28 and interleukin (IL)-15/IL-7-mediated T cell proliferation were assessed by fluorescence activated cell sorter (FACS) analysis using carboxyfluorescein succinimidyl ester (CSFE) labelling. Interferon (IFN)-g and IL-10 production were determined in the supernatants of these cultures by enzyme-linked immunosorbent assay. Monocyte activation was assessed in lipopolysaccharide (LPS)-stimulated whole blood, using tumour necrosis factor (TNF)-a as read-out. Neutrophil function was determined by measuring oxidative burst, chemotaxis and phagocytosis. T cell activation markers and PR3 expression were measured by FACS. All parameters were determined directly before and after each DSG cycle. Anti-CD3/anti-CD28-mediated T cell proliferation was reduced directly after DSG treatment. Directly before a subsequent cycle of DSG was started, T cell proliferation was increased. Similar findings were observed for IFN-g and IL-10 production by T cells. DSG did not influence IL-15/IL-7-mediated T cell proliferation. LPS-mediated TNF-a production was also impaired directly after DSG treatment. No influence on T cell activation markers, neutrophil function and surface PR-3 expression was observed in peripheral blood of these patients. Our data demonstrate that DSG influences T cell and monocyte activation in a reversible fashion. Although DSG causes neutropenia in these patients, it does not influence neutrophil function.

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Section: Discussionsupporting

confidence: 61%

In vivoeffects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis

Kälsch

Schmitt

Breedijk

et al. 2006

Clinical and Experimental Immunology

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“…However, we have not observed any significant correlation between telomere shortening and ROS or DFI levels in men. It may be possible that shorter telomeres are associated with replicative senescence and may lead to pre or post implantation losses or results in meiotic segregation abnormalities in germ cells that may lead to aneuploid fetus which may itself result in RPL [35][36][37]. Aneuploidies are the major cause of RPL and telomeres shortening associated with impaired microtubular movement may also impair chromosome segregation.…”

Section: Discussionmentioning

confidence: 99%

Analysis of telomere length in couples experiencing idiopathic recurrent pregnancy loss

Thilagavathi

Mishra

Kumar

et al. 2013

J Assist Reprod Genet

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Purpose Telomere length plays a significant role in various disorders; however, its role in idiopathic recurrent pregnancy loss (iRPL) is not known. The objective of this study was to assess telomere length in peripheral blood leukocytes in couples experiencing unexplained recurrent pregnancy loss (iRPL). Methods The study included 25 couples experiencing iRPL and 20 controls. The mean relative telomere length was measured by quantitative Real Time PCR (Q-PCR) based assay, which measures the average ratio of telomere repeat copy number to a single copy gene (36B4) copy number (T/S ratio) in each sample. Results The relative leukocyte mean telomere length (T/S) in both men and women from iRPL group was significantly lower (p<0.05) when compared to controls. A significant (P<0.05) negative correlation was found between age and leukocyte telomere length (T/S ratio). Among the sperm parameters seminal volume was found to be negatively (r = −0.4679) associated with the telomere T/S ratio. The DNA fragmentation index of sperm showed positive correlation (r=0.4744) with telomere length. In this preliminary study, we found that shorter telomere length in both men and women may be associated with early pregnancy loss. Conclusion In conclusion, shorter telomere length in both male and female partners appears to play a role in the idiopathic recurrent pregnancy loss. Loss of telomeric DNA due to oxidative stress needs further analysis. Analysis of telomere length in germ cells are needed to further substantiate the findings of this study.

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“…Aberrant TL has been described in a number of autoimmune syndromes ( table 1 ) such as systemic lupus erythematosus [116] , systemic sclerosis [117] , RA [118] , insulin-dependent diabetes mellitus [119] , Wegener's granulomatosis [120] , atopic dermatitis, and psoriasis [121] . In autoimmune syndromes, increasing evidence is making the general model that autoreactive T cells undergo excessive proliferation, leading to telomeric erosion and loss, less satisfactory.…”

Section: Telomere Loss In Autoimmunitymentioning

confidence: 99%

Telomeres and Immunological Diseases of Aging

et al. 2009

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A defining feature of the eukaryotic genome is the presence of linear chromosomes. This arrangement, however, poses several challenges with regard to chromosomal replication and maintenance. To prevent the loss of coding sequences and to suppress gross chromosomal rearrangements, linear chromosomes are capped by repetitive nucleoprotein structures, called telomeres. Each cell division results in a progressive shortening of telomeres that, below a certain threshold, promotes genome instability, senescence, and apoptosis. Telomeric erosion, maintenance, and repair take center stage in determining cell fate. Cells of the immune system are under enormous proliferative demand, stressing telomeric intactness. Lymphocytes are capable of upregulating telomerase, an enzyme that can elongate telomeric sequences and, thus, prolong cellular lifespan. Therefore, telomere dynamics are critical in preserving immune function and have become a focus for studies of immunosenescence and autoimmunity. In this review, we describe the role of telomeric nucleoproteins in shaping telomere architecture and in suppressing DNA damage responses. We summarize new insights into the regulation of telomerase activity, hereditary disorders associated with telomere dysfunction, the role of telomere loss in immune aging, and the impact of telomere dysfunction in chronic inflammatory disease.

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Shortening of telomeres: Evidence for replicative senescence of T cells derived from patients with Wegener's granulomatosis

Abstract: Our data provide evidence that a portion of T cells had undergone replicative senescence, which in turn indicates clonal expansion of T cells as consequence of activation.

Cited by 42 publications

References 27 publications

In vivoeffects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis

In vivoeffects of cyclic administration of 15-deoxyspergualin on leucocyte function in patients with Wegener's granulomatosis

Analysis of telomere length in couples experiencing idiopathic recurrent pregnancy loss

Telomeres and Immunological Diseases of Aging

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