Elevated proportions of recent thymic emigrants in children and adolescents with type 1 diabetes.

It is unclear, whether pediatric patients with type 1 diabetes (T1DM) show immunological alterations typically found in autoimmune conditions resembling immune dysfunction of the thymus, such as decrease of naïve T cells, lower T cell receptor excision circle (TREC) numbers, telomeric erosion, and diminished interleukin-7 (IL-7) levels. Furthermore, it is unknown, whether long-term therapy with insulin, a thymic growth factor, interferes with these changes. Therefore, the aim of this study was to analyze the quantity of the naïve T cell subset and its TREC content, relative telomere length (RTL) of naïve T cells, and peripheral IL-7 levels in patients with recent-onset T1DM (n = 5), long-standing T1DM (n = 33), and age-matched healthy donors (HD) (n = 37). In long-standing T1DM, TREC numbers/CD8+CD45RA+ T cells were enhanced (p < 0.01) compared to HD and correlated with disease duration (p < 0.02), an independent factor for increased thymic output (p < 0.01), and insulin dosage at blood withdrawal (p < 0.05). IL-7 serum levels were elevated in long-standing T1DM (p < 0.001) and positively correlated with TREC numbers (p < 0.01) and disease duration (p < 0.0001). RTLs in CD8+CD45RA+ T cells were significantly increased compared to HD (p < 0.02). Our data suggest that longterm insulin therapy may serve as a driving factor for thymic function and rejuvenation of the naïve T cell compartment. The ability of the immune system to reconstitute the naïve T cell compartment under well-adjusted insulin therapy may be of major importance for recognition of new antigens, response to vaccinations, and defense of infectious complications.

Quantitative alterations of CD8+ T cells in juvenile idiopathic arthritis patients in remission.

The study was aimed to investigate whether quantities of CD8(+) T cell subsets are normal in juvenile idiopathic arthritis (JIA) patients with disease remission compared to age-matched healthy donors (HD) and whether chronological age may have an impact on proportions of naive CD8(+) T cells. CD8(+) T cell subsets were analyzed in 17 JIA patients and 32 age-matched HD by flow cytometry. JIA patients showed lower CD3(+)CD8(+) T cells compared to HD. Total counts of CD8(+)CD28(+) and CD8(+)CD28(+)CD45RA(+) T cells were inversely correlated to chronological age in JIA patients and HD. In JIA patients, percentages of CD8(+)CD28(+)CD45RA(+) T cells and of CD62L-expressing CD8(+)CD28(+)CD45RA(+) T cells showed a negative correlation with age. The trend to lower CD28(+)CD45RA(+) T cell proportions in aged JIA patients in remission may reflect a disturbed T cell homeostasis independently of disease activity and may be due to an intrinsic effect in reconstitution of the peripheral T cells.

Accumulation of CD8+CD45RA+CD62L+ T cells in acute chylothorax in neonates.

BACKGROUND: Acute chylothorax in neonates is a rare disease but results in significant loss of lymphatic cells. OBJECTIVES: The purpose of the study was to determine whether acute chylothorax in neonates results in quantitative changes of lymphocyte subpopulations in peripheral blood and chyle. METHODS: 6 neonates who had acute chylothorax after thoracic surgery due to transposition of the great arteries were prospectively enrolled in the study. Peripheral blood mononuclear cells (PBMC) and chylous fluid mononuclear cells (CFMC) including CD45RA+ and CD45RO+ T cells and the expression of the lymphocyte homing marker CD62L were investigated by fluorescence-activated cell sorting. RESULTS: In chyle, CD3+CD45RA+ T cells were significantly increased compared to peripheral blood (PMBC: median 65.8% of CD3+; range 32.3-76.9% vs. CFMC: 90.3%; 68.6-94.4%) (p = 0.02). In chyle, changes of percentages of the CD45RA+ were limited to CD8-expressing T cells (CD8+CD45RA+: PBMC: 77.3%; 69.3-85.6% vs. CFMC: 93.2%; 86.3-98.5%) (p = 0.02). The CD8+CD45RA+ were mainly CD62L+ (PBMC: 59.4%; 31.6-62.0% vs. CFMC: 87.8%; 62.7-90.7%) (p = 0.02). CONCLUSIONS: The study gives evidence that acute chylothorax in neonates results in immunophenotypic alterations and accumulation of certain T-cell subpopulations in the pleural cavity. Although limited by small numbers of patients due to the rare manifestation of the disease, we were able to demonstrate an abundance of CD8+CD45RA+ T cells expressing CD62L in the chyle compared to peripheral blood. However, whether CD62L expression may contribute to the accumulation of CD8+CD45RA+ T cells in chyle and whether quantitative changes of these specific cells are of clinical relevance has to be determined.

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

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 age-matched 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 age-inappropriate 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.

Indications for a disturbed peripheral T-cell homeostasis in juvenile idiopathic arthritis (JIA): absent expansion of CD28 T-cells and no decrease of naive T-cells in cytomegalovirus-positive patients with JIA.

OBJECTIVE: To investigate the influence of latent cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections on CD28-expressing T-cell subpopulations and replicative senescence of naive T-cells as a marker for aging of the immune system in children with juvenile ideopathic arthritis (JIA). METHODS: T-cell subpopulations were analyzed from 24 patients with JIA and 61 healthy age-matched controls by fluorescence activated cell sorting. Relative telomere length (RTL) in CD4+CD28+CD45RA+ (naive) T-cells was measured by quantitative polymerase chain reaction. RESULTS: Although confirming known data of expansions of CD28- T-cells and tendency of decreasing naive T-cells in CMV-seropositive healthy individuals, our findings did not show a marked influence of latent EBV or CMV infection on CD28-expressing T-cells in patients with JIA. In contrast, CMV was an independent factor for loss of CD28, regardless of age, in healthy controls. Irrespective of serology results for CMV or EBV, patients with JIA showed signficantly decreased RTL compared to age-matched controls. Regression lines for RTL and age revealed decreased RTL with advancing age in CMV-positive and EBV-positive subjects. The evidence that findings for CMV-positive JIA patients did not resemble the findings of healthy CMV-positive controls, namely expansion of CD28- T-cells and decrease of naive T-cells, may support the theory of a disturbed peripheral T-cell homeostasis in JIA. CONCLUSION: Diminished mechanisms of T-cell homeostasis and premature aging of the immune system may play a role in the pathogenesis of JIA.