Simultaneous analysis of T cell clonality and cytokine production in rheumatoid arthritis using three-colour flow cytometry

Bakakos, Petros; Pickard, C.; Wong, Winnie; Ayre, K R; Madden, J.; Frew, Anthony J.; Hodges, Elizabeth; Cawley, M. I. D.; Smith, J. L.

doi:10.1046/j.1365-2249.2002.01868.x

Cited by 10 publications

(7 citation statements)

References 55 publications

(44 reference statements)

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“…Several lines of evidence suggest that T cells play an important role in the pathogenesis of RA and MS. A skewed TCR repertoire was observed in RA patients, but none of the Vβ genes was found to be consistently overexpressed in all, or a subgroup, of RA patients. 2,4,19 Although several putative autoantigens have been implicated as candidate antigens in RA (collagen, proteoglycans, heat-shock proteins [HSPs]) and MS (myelin components), the "disease-triggering" antigen (or antigens) has not been identified. 20 These findings support the concept that autoimmune diseases are not caused by a single autoantigen, but rather result from a general dysfunction of peripheral immune system tolerance or homeostasis mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with T‐cell‐ mediated AIDs show immune system abnormalities that resemble the typical characteristics of immune dysfunction described in the elderly. Several research groups have observed T‐cell clonal expansions in the peripheral blood of rheumatoid arthritis (RA) patients 1‐4. Others have reported a population of T cells in RA patients with signs of replicative stress 2‐6.…”

Section: Introductionmentioning

confidence: 99%

“…Several research groups have observed T-cell clonal expansions in the peripheral blood of rheumatoid arthritis (RA) patients. [1][2][3][4] Others have reported a population of T cells in RA patients with signs of replicative stress. [2][3][4][5][6] An important aspect of immunosenescence is thymic involution, 7 during which the epithelial space (where T-cell maturation and selection take place) is replaced by fatty tissue.…”

Section: Introductionmentioning

confidence: 99%

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Premature Immunosenescence in Rheumatoid Arthritis and Multiple Sclerosis Patients

Thewissen

Linsen

Somers

et al. 2005

Annals of the New York Academy of Sciences

118

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Patients suffering from T cell mediated autoimmune diseases (AIDs) show immune abnormalities that resemble the typical characteristics of immune dysfunction described in the elderly. In addition, the incidence of AIDs increases with advancing age. To evaluate whether rheumatoid arthritis (RA) and multiple sclerosis (MS) patients have suffered from a premature immunosenescence, we measured two indicators of aging. The number of T cell receptor excision circles (TRECs) and the percentage of CD4+CD28 null T cells were studied in peripheral blood mononuclear cells (PBMC) of 60 RA patients, 32 MS patients and 40healthy controls (HC). TREC numbers were decreased in RA and MS patients as compared to age-matched HC indicating premature thymic involution. Moreover, a subset of these patients contained age-inappropriate high frequencies of CD4+CD28 null T cells. This study provides evidence of a premature senescence of the immune system in both RA and MS patients.Premature aging could be a risk factor for developing autoimmunity in genetically prone individuals in a susceptible environment.2

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Premature Immunosenescence in Rheumatoid Arthritis and Multiple Sclerosis Patients

Thewissen

Linsen

Somers

et al. 2005

Annals of the New York Academy of Sciences

118

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“…With increasing disease duration a number of phenotypic and functional T cell defects have been described in RA including hyporesponsiveness of T cells to stimulation, a decline in naive CD4+ T cells and a disturbance in the naive T cell receptor (TCR) repertoire indicated by a loss of TCR diversity and clonal expansion of a proportion of T cells [3][4][5]. The capacity of lymphocytes to clonally expand may be mediated, at least in part, through the upregulation of telomerase.…”

Section: Introductionmentioning

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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“…However, this mechanism induces replicative stress on peripheral T cells. Several research groups have observed T cell clonal expansions in the peripheral blood of RA patients (7–10) and have reported a population of T cells with signs of replicative stress in RA patients (8–12). Replicatively stressed cells have lost the expression of the major costimulatory molecule CD28, accompanied by phenotypic and functional changes (13).…”

mentioning

confidence: 99%

Premature aging of the immune system in children with juvenile idiopathic arthritis

Prelog

Schwarzenbrunner

Sailer‐Höck

et al. 2008

Arthritis & Rheumatism

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Objective. Juvenile idiopathic arthritis (JIA) is an autoimmune disease of the young. The pathogenesis is not completely understood. Premature aging, associated thymic involution, and compensatory autoproliferation could play important roles in the pathogenesis of autoimmunity. We undertook this study to determine whether patients with JIA demonstrate premature immunosenescence.Methods. To test this hypothesis, we measured 3 indicators of aging: the percentages and total counts of peripheral blood naive T cells, the frequency of T cell receptor excision circles (TRECs) in naive T cells, and telomeric erosion and Ki-67 expression as estimates of the replicative history of homeostatic proliferation.Results. JIA patients showed an accelerated loss of CD4؉,CD45RA؉,CD62L؉ naive T cells with advancing age and a compensatory increase in the number of CD4؉,CD45RO؉ memory T cells. JIA patients demonstrated a significantly decreased frequency of TRECs in CD4؉,CD45RA؉ naive T cells compared with agematched healthy donors (P ‫؍‬ 0.002). TREC numbers correlated with age only in healthy donors (P ‫؍‬ 0.0001).Telomeric erosion in CD4؉,CD45RA؉ naive T cells was increased in JIA patients (P ‫؍‬ 0.01). The percentages of Ki-67-positive CD4؉,CD45RA؉ naive T cells were increased in JIA patients (P ‫؍‬ 0.001) and correlated with disease duration (P ‫؍‬ 0.003), which was also an independent factor contributing to telomeric erosion (P ‫؍‬ 0.04).Conclusion. Our findings suggest that ageinappropriate T cell senescence and disturbed T cell homeostasis may contribute to the development of JIA. In patients with JIA, dysfunction in the ability to reconstitute the T cell compartment should be considered when exploring new therapeutic strategies.

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Simultaneous analysis of T cell clonality and cytokine production in rheumatoid arthritis using three-colour flow cytometry

Cited by 10 publications

References 55 publications

Premature Immunosenescence in Rheumatoid Arthritis and Multiple Sclerosis Patients

Premature Immunosenescence in Rheumatoid Arthritis and Multiple Sclerosis Patients

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

Premature aging of the immune system in children with juvenile idiopathic arthritis

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