Telomere length in Hepatitis C

Kitay-Cohen, Yona; Goldberg‐Bittman, Lilach; Hadary, Ruth; Fejgin, Moshe D.; Amiel, Aliza

doi:10.1016/j.cancergencyto.2008.08.006

Cited by 33 publications

(23 citation statements)

References 23 publications

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“…In ataxia-telangiectasia, a progeric immunodeficiency disorder, telomere attrition is caused by the defects in genetic mechanisms that ensure telomere maintenance [22]. A cause of accelerated telomere shortening in lymphocytes, independent on genetic background, is chronic stimulation by infectious agents, as for example cytomegalovirus [20], HCV [23] or HIV [24] infection. Patients with CVID are continuously stimulated by an array of microorganisms that chronically infect the respiratory tract and the intestine.…”

Section: Discussionmentioning

confidence: 99%

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

et al. 2011

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A subset of patients with common variable immunodeficiency (CVID), group 1a of the Freiburg classification, is characterized by increased B cells expressing low levels of CD21 (CD21 low ), lymphoproliferation and autoimmunity. The CD21 low B cells have been shown to be profoundly anergic, and defects of BCR-mediated calcium signaling and of T cells have been described in CVID 1a. We found that also the classical naïve B cells from CVID 1a patients, but not from CVID non-1a patients, proliferated poorly. The B cells of CVID 1a patients had a reduced capacity to divide reminiscent of the proliferative arrest associated with replicative senescence. Thus, we investigated whether lymphocyte dysfunction in CVID 1a was related to telomere-dependent replicative senescence, and found that both the B and the T cells from CVID 1a patients had significantly shorter telomeres compared with B and T cells from CVID non-1a patients. Telomere lengths in B and T cells were significantly correlated, indicating that the rate of telomere attrition in lymphocytes is an individual characteristic of CVID patients. Our findings suggest that telomere-dependent replicative senescence contributes to the immune dysfunction of CVID 1a patients, and may provide an important clue for a better understanding of the pathogenesis of CVID.Key words: Anergy . IntroductionCommon variable immunodeficiency (CVID) is a heterogeneous disorder characterized by reduced antibody levels with low to normal numbers of circulating B cells [1]. Only a small proportion of CVID patients can be classified by the underlying genetic defect [2], and current classifications are mainly based on the B-cell phenotype [3,4]. A subset of CVID is hallmarked by the expansion of an unusual population of B cells with reduced expression of CD21 (CD21 low ); these patients are classified as CVID group 1a according to the Freiburg study [3]. Clinically, CVID 1a is characterized by a late onset, autoimmunity and benign polyclonal lymphoproliferation [3,4]. In addition, several T-cell abnormalities have been described in CVID 1a patients [5]. 854The CD21 low B cells of CVID patients express an array of inhibitory receptor and fail to proliferate in response to BCRdependent and -independent stimuli [6,7]. However, anergy is not limited to CD21 low B cells, since all mature B cells from CVID 1a patients fail to flux calcium upon BCR triggering [8]. CD21 low B cells are also increased in patients with HIV infection [9], systemic lupus erythematosus [10], or mixed cryoglobulinemia secondary to HCV infection [11,12], all conditions characterized by B-cell hyperactivation. Although the CD21 low B cells of patients with HIV infection or HCV-associated mixed cryoglobulinemia have mutated immunoglobulin genes [10][11][12], the CD21 low B cells of CVID 1a patients are unmutated and mostly autoreactive [6,7]. Similarly to those of patients with CVID, the CD21 low B cells of patients with HIV infection are profoundly anergic to B-cell stimuli [9].In this study, we observed that the B cells fr...

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Section: Discussionmentioning

confidence: 99%

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

et al. 2011

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“…Normal cells, adjacent to SCC, reportedly have shortened telomeres suggesting that reduction of telomere length could be related to malignant transformation 43 . Inflammatory diseases with a proclivity for malignant transformation such as Barrett’s esophagitis 11 , ulcerative colitis 44 , and hepatitis 45, 46 all show substantial decreases in telomere length. Telomere shortening is associated with aneuploidy both in human cancer as well as in the mouse model 47, 48 .…”

Section: Discussionmentioning

confidence: 99%

Graft-versus-Host Disease: Role of Inflammation in the Development of Chromosomal Abnormalities of Keratinocytes

Sloand

Pfannes

Ling

et al. 2010

Biology of Blood and Marrow Transplantation

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Graft-versus-host disease (GVHD) is a major risk factor for secondary malignancy after hematopoietic stem cell transplantation. Squamous cell carcinoma (SCC) of the skin and mucous membranes are especially frequent in this setting where aneuploidy and tetraploidy are associated with aggressive disease. The current study is directed to the mechanism of neoplasia in this setting. Un-manipulated keratinocytes from areas of oral GVHD in 9 patients showed tetraploidy in 10–46% of cells when examined by florescence in situ hybridization (FISH). Keratinocytes isolated from biopsy sites of GVHD but not from normal tissue showed even greater numbers of tetraploid cells (mean 78%, range 15–85%; N=9) after culture. To mimic the inflammatory process in GVHD, allogeneic HLA- mismatched lymphocytes were mixed with normal keratinocytes. After two weeks, substantial numbers of aneuploid and tetraploid cells were evident in cultures with lymphocytes and with purified CD8 but not CD4 cells. Telomere length was substantially decreased in the lymphocyte-treated sample. No mutations were present in p53 gene, although haploinsufficiency for p53 due to loss of chromosome 17 was common in cells exposed to lymphocytes. These findings suggest that in GVHD, inflammation and repeated cell division correlates with the development of karyotypic abnormalities.

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“…Oligoclonality of CD8+ lymphocytes in HCV infection is associated with increased fibrosis and reduced responses to antiviral therapy [19]. Kitay-Cohen et al demonstrated that viraemic HCV is associated with short peripheral leucocyte telomeres, although no relation to clinical or treatment outcome was explored [20].…”

Section: Introductionmentioning

confidence: 99%

CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection

Hoare

Gelson

Das

et al. 2010

Journal of Hepatology

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Background & AimsIncreasing age is associated with impaired immune function and in chronic HCV infection specifically, with progressive fibrosis, liver failure, HCC and impaired responses to antiviral therapy. T-lymphocyte telomere length declines with age. We hypothesised that shorter T-lymphocyte telomere length would be associated with poor clinical outcome in HCV infection.MethodsCirculating T-lymphocyte telomere length, an objective measure of immune senescence, was measured by flow-FISH in 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls in relation to clinical outcome.ResultsShorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p = 0.003), independent of male sex (p = 0.04), CMV positivity (p = 0.003), previous HBV infection (p = 0.007), and age (p = ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p <0.001), portal tract inflammatory grade (p = 0.035), prothrombin time (p <0.001) and bilirubin (p = 0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p = 0.009) with an age-adjusted hazard ratio of 0.93 (0.90–0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p = 0.001) independent of other factors.ConclusionsCD4+ T-lymphocyte telomere length, independent of age, was related to inflammatory grade, fibrosis stage, laboratory indices of severity, subsequent hepatic decompensation and treatment outcome in patients with chronic HCV infection.

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Telomere length in Hepatitis C

Cited by 33 publications

References 23 publications

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

Telomere‐dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency

Graft-versus-Host Disease: Role of Inflammation in the Development of Chromosomal Abnormalities of Keratinocytes

CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection

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