Increased frequency of in vivo hprt gene-mutated T cells in the peripheral blood of patients with systemic sclerosis

P. P. Sfikakis, J. Tesar, S. Theocharis, Gary Klipple, G. C. Tsokos

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Objectives - Activated T lymphocytes are involved in the pathogenesis of scleroderma (systemic sclerosis, SSc); such cells rapidly divide in vivo and are thus theoretically subject to random mutation more frequently than resting cells. To study whether SSc is associated with rapidly expanding T cell clones the frequency was determined of in vivo mutated T cells (MF) at the hypoxanthine guanine phosphoribosyl transferase (hprt) gene in the peripheral blood from patients with SSc. Specific clinical or serological associations were also investigated. Methods - Peripheral blood lymphocytes from 16 healthy individuals and 20 patients with SSc were cultured using an hprt clonal assay; mutated and wild T cell clones were established to assess individual values of T cell MF. T cell clones were further expanded in vitro and their phenotype was determined by standard immunofluorescence technique. Enzyme-linked immunosorbent assays were used for simultaneous measurements of plasma levels of soluble Interleukin-2 receptors (s-IL-2R) and Intercellular adhesion molecule-l (s-ICAM-1). Results - Mean (SD) value of T cell MF in patients with SSc was 2.5-fold higher than the normal mean (SD) value [10.6 (6.6) x 10-6 v [4.4 (2.8) x 10-6, p = 0.0007]. Eleven of 20 patients with SSc (55%) had T cell MF values greater than two SD above the normal mean value. The majority (84%) of mutated T cells had a helper/inducer, memory phenotype while 12% were cytotoxic/suppressor T cells. There was no association between T cell MF and the extent of skin involvement or the duration of Raynaud's phenomenon. High individual T cell MF values were not related to a possible concurrent immune overactivity as assessed by plasma levels of s-IL-2R and s-ICAM-1. Patients with long standing skin disease, however, had almost double T cell MF values than patients with early skin disease [(13.6 (7.4)) x 10-6 v (7.5 (4.3)) x 10-6, p = 0.03], suggesting that increased T cell MF in SSc may reflect an ongoing process of chronic in vivo T cell proliferation and/or prolonged survival. Conclusion - Increased in vivo T cell mutation in patients with SSc suggests that excessive division and/or survival of T cell clones contribute to the pathology in SSc; this approach can be used in further investigations to identify the stimulus that is triggering T cell activation in this disease.

Original languageEnglish (US)
Pages (from-to)122-127
Number of pages6
JournalAnnals of the Rheumatic Diseases
Volume53
Issue number2
DOIs
StatePublished - Jan 1 1994

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Hypoxanthine
T-cells
Systemic Scleroderma
Guanine
Transferases
Blood
Genes
T-Lymphocytes
Clone Cells
Skin
Interleukin-2 Receptors
Intercellular Adhesion Molecule-1
Skin Diseases
Assays
Phenotype
Plasmas
Immunosorbents
Raynaud Disease
Mutation
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Increased frequency of in vivo hprt gene-mutated T cells in the peripheral blood of patients with systemic sclerosis. / Sfikakis, P. P.; Tesar, J.; Theocharis, S.; Klipple, Gary; Tsokos, G. C.

In: Annals of the Rheumatic Diseases, Vol. 53, No. 2, 01.01.1994, p. 122-127.

Research output: Contribution to journalArticle

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abstract = "Objectives - Activated T lymphocytes are involved in the pathogenesis of scleroderma (systemic sclerosis, SSc); such cells rapidly divide in vivo and are thus theoretically subject to random mutation more frequently than resting cells. To study whether SSc is associated with rapidly expanding T cell clones the frequency was determined of in vivo mutated T cells (MF) at the hypoxanthine guanine phosphoribosyl transferase (hprt) gene in the peripheral blood from patients with SSc. Specific clinical or serological associations were also investigated. Methods - Peripheral blood lymphocytes from 16 healthy individuals and 20 patients with SSc were cultured using an hprt clonal assay; mutated and wild T cell clones were established to assess individual values of T cell MF. T cell clones were further expanded in vitro and their phenotype was determined by standard immunofluorescence technique. Enzyme-linked immunosorbent assays were used for simultaneous measurements of plasma levels of soluble Interleukin-2 receptors (s-IL-2R) and Intercellular adhesion molecule-l (s-ICAM-1). Results - Mean (SD) value of T cell MF in patients with SSc was 2.5-fold higher than the normal mean (SD) value [10.6 (6.6) x 10-6 v [4.4 (2.8) x 10-6, p = 0.0007]. Eleven of 20 patients with SSc (55{\%}) had T cell MF values greater than two SD above the normal mean value. The majority (84{\%}) of mutated T cells had a helper/inducer, memory phenotype while 12{\%} were cytotoxic/suppressor T cells. There was no association between T cell MF and the extent of skin involvement or the duration of Raynaud's phenomenon. High individual T cell MF values were not related to a possible concurrent immune overactivity as assessed by plasma levels of s-IL-2R and s-ICAM-1. Patients with long standing skin disease, however, had almost double T cell MF values than patients with early skin disease [(13.6 (7.4)) x 10-6 v (7.5 (4.3)) x 10-6, p = 0.03], suggesting that increased T cell MF in SSc may reflect an ongoing process of chronic in vivo T cell proliferation and/or prolonged survival. Conclusion - Increased in vivo T cell mutation in patients with SSc suggests that excessive division and/or survival of T cell clones contribute to the pathology in SSc; this approach can be used in further investigations to identify the stimulus that is triggering T cell activation in this disease.",
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T1 - Increased frequency of in vivo hprt gene-mutated T cells in the peripheral blood of patients with systemic sclerosis

AU - Sfikakis, P. P.

AU - Tesar, J.

AU - Theocharis, S.

AU - Klipple, Gary

AU - Tsokos, G. C.

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N2 - Objectives - Activated T lymphocytes are involved in the pathogenesis of scleroderma (systemic sclerosis, SSc); such cells rapidly divide in vivo and are thus theoretically subject to random mutation more frequently than resting cells. To study whether SSc is associated with rapidly expanding T cell clones the frequency was determined of in vivo mutated T cells (MF) at the hypoxanthine guanine phosphoribosyl transferase (hprt) gene in the peripheral blood from patients with SSc. Specific clinical or serological associations were also investigated. Methods - Peripheral blood lymphocytes from 16 healthy individuals and 20 patients with SSc were cultured using an hprt clonal assay; mutated and wild T cell clones were established to assess individual values of T cell MF. T cell clones were further expanded in vitro and their phenotype was determined by standard immunofluorescence technique. Enzyme-linked immunosorbent assays were used for simultaneous measurements of plasma levels of soluble Interleukin-2 receptors (s-IL-2R) and Intercellular adhesion molecule-l (s-ICAM-1). Results - Mean (SD) value of T cell MF in patients with SSc was 2.5-fold higher than the normal mean (SD) value [10.6 (6.6) x 10-6 v [4.4 (2.8) x 10-6, p = 0.0007]. Eleven of 20 patients with SSc (55%) had T cell MF values greater than two SD above the normal mean value. The majority (84%) of mutated T cells had a helper/inducer, memory phenotype while 12% were cytotoxic/suppressor T cells. There was no association between T cell MF and the extent of skin involvement or the duration of Raynaud's phenomenon. High individual T cell MF values were not related to a possible concurrent immune overactivity as assessed by plasma levels of s-IL-2R and s-ICAM-1. Patients with long standing skin disease, however, had almost double T cell MF values than patients with early skin disease [(13.6 (7.4)) x 10-6 v (7.5 (4.3)) x 10-6, p = 0.03], suggesting that increased T cell MF in SSc may reflect an ongoing process of chronic in vivo T cell proliferation and/or prolonged survival. Conclusion - Increased in vivo T cell mutation in patients with SSc suggests that excessive division and/or survival of T cell clones contribute to the pathology in SSc; this approach can be used in further investigations to identify the stimulus that is triggering T cell activation in this disease.

AB - Objectives - Activated T lymphocytes are involved in the pathogenesis of scleroderma (systemic sclerosis, SSc); such cells rapidly divide in vivo and are thus theoretically subject to random mutation more frequently than resting cells. To study whether SSc is associated with rapidly expanding T cell clones the frequency was determined of in vivo mutated T cells (MF) at the hypoxanthine guanine phosphoribosyl transferase (hprt) gene in the peripheral blood from patients with SSc. Specific clinical or serological associations were also investigated. Methods - Peripheral blood lymphocytes from 16 healthy individuals and 20 patients with SSc were cultured using an hprt clonal assay; mutated and wild T cell clones were established to assess individual values of T cell MF. T cell clones were further expanded in vitro and their phenotype was determined by standard immunofluorescence technique. Enzyme-linked immunosorbent assays were used for simultaneous measurements of plasma levels of soluble Interleukin-2 receptors (s-IL-2R) and Intercellular adhesion molecule-l (s-ICAM-1). Results - Mean (SD) value of T cell MF in patients with SSc was 2.5-fold higher than the normal mean (SD) value [10.6 (6.6) x 10-6 v [4.4 (2.8) x 10-6, p = 0.0007]. Eleven of 20 patients with SSc (55%) had T cell MF values greater than two SD above the normal mean value. The majority (84%) of mutated T cells had a helper/inducer, memory phenotype while 12% were cytotoxic/suppressor T cells. There was no association between T cell MF and the extent of skin involvement or the duration of Raynaud's phenomenon. High individual T cell MF values were not related to a possible concurrent immune overactivity as assessed by plasma levels of s-IL-2R and s-ICAM-1. Patients with long standing skin disease, however, had almost double T cell MF values than patients with early skin disease [(13.6 (7.4)) x 10-6 v (7.5 (4.3)) x 10-6, p = 0.03], suggesting that increased T cell MF in SSc may reflect an ongoing process of chronic in vivo T cell proliferation and/or prolonged survival. Conclusion - Increased in vivo T cell mutation in patients with SSc suggests that excessive division and/or survival of T cell clones contribute to the pathology in SSc; this approach can be used in further investigations to identify the stimulus that is triggering T cell activation in this disease.

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