CMV-Seropositivity in Patients With Hashimoto's Thyroiditis
Naive T cell subpopulations are significantly altered in patients at the onset of T cell mediated autoimmune disorders, such as diabetes mellitus type 1 and juvenile idiopathic arthritis (JIA). These alterations are reminiscent of immunological changes found in the elderly during the aging of the immune system (immunosenescence), such as the switch from the CD45RA + to the CD45RO + T cell phenotype and a decrease in thymic function with increased compensatory mechanisms. Patients with rheumatoid arthritis and JIA demonstrated increased CD28-negative T cells, an erosion of telomere length as a marker of replicative senescence and a loss of T cell receptor excision circles (TRECs) as a parameter of thymic function and peripheral proliferation of naive T cells. TRECs are stable circular DNA fragments that are created during T cell receptor rearrangement in the thymus and have been described to be an indicator of thymic production. TRECs are not replicating during mitosis. Therefore, TREC numbers are as much influenced by peripheral cell turnover as by the influx of newly generated TREC-positive T cells from the thymus.
Latent Cytomegalovirus (CMV) infection was shown to be a driving factor for T cell differentiation. The majority of CMV-specific T cells are included within the CD28-negative T cell subpopulation. CMV-seropositive healthy individuals demonstrated accelerated loss of CD28 expression, which was not seen in CMV-seropositive JIA patients.
Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disorder of the thyroid gland associated with diffuse lymphoid infiltration, inflammatory destruction of follicular cells and auto-antibodies against thyroid-specific self-antigens. However, the etiopathogenesis of HT is far from being clearly understood. Previous studies have shown significant alterations of the peripheral B and T cell subpopulations in HT with a restricted T-cell-receptor repertoire and a suggested role of CD25+ regulatory T cells in balancing immune tolerance.
Thus, the present study was aimed to assess whether patients with HT show proportional alterations of the peripheral T cell subpopulations as found in other T cell-mediated autoimmune diseases. In order to investigate the different T cell subpopulations, T cells were characterized by expression of CD3 and either CD4 or CD8, B cells by CD19 and natural killer (NK) cells by CD3-CD16/56+. HLA-DR was used as an activation marker of T cells. CD28 is a co-stimulatory molecule, which is lost through differentiation of T cells. CD45RO mainly defines the memory T cell subset, expression of CD45RA activated naive T cells expressing the CD62L lymphocyte homing factor. High expression of CD25 in combination with CD62L is characteristic for regulatory CD4+ T cells, and in low amounts also for naive T cells.
A further aim was to investigate the replicative history of CD45RA + expressing T cells by assessment of TRECs and relative telomere length (RTL) and the association with CMV-seropositivity. In our study, dilution of TRECs was used to estimate the thymus output and the peripheral proliferative history of the CD45RA-expressing T cell pool, which contains recent thymic emigrants (usually high TREC numbers), pre-existing peripheral, naive T cells (usually low TREC numbers due to peripheral replication and dilution of TRECs) and a small amount of differentiated effector T cells (usually TREC-negative).
Background
Naive T cell subpopulations are significantly altered in patients at the onset of T cell mediated autoimmune disorders, such as diabetes mellitus type 1 and juvenile idiopathic arthritis (JIA). These alterations are reminiscent of immunological changes found in the elderly during the aging of the immune system (immunosenescence), such as the switch from the CD45RA + to the CD45RO + T cell phenotype and a decrease in thymic function with increased compensatory mechanisms. Patients with rheumatoid arthritis and JIA demonstrated increased CD28-negative T cells, an erosion of telomere length as a marker of replicative senescence and a loss of T cell receptor excision circles (TRECs) as a parameter of thymic function and peripheral proliferation of naive T cells. TRECs are stable circular DNA fragments that are created during T cell receptor rearrangement in the thymus and have been described to be an indicator of thymic production. TRECs are not replicating during mitosis. Therefore, TREC numbers are as much influenced by peripheral cell turnover as by the influx of newly generated TREC-positive T cells from the thymus.
Latent Cytomegalovirus (CMV) infection was shown to be a driving factor for T cell differentiation. The majority of CMV-specific T cells are included within the CD28-negative T cell subpopulation. CMV-seropositive healthy individuals demonstrated accelerated loss of CD28 expression, which was not seen in CMV-seropositive JIA patients.
Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disorder of the thyroid gland associated with diffuse lymphoid infiltration, inflammatory destruction of follicular cells and auto-antibodies against thyroid-specific self-antigens. However, the etiopathogenesis of HT is far from being clearly understood. Previous studies have shown significant alterations of the peripheral B and T cell subpopulations in HT with a restricted T-cell-receptor repertoire and a suggested role of CD25+ regulatory T cells in balancing immune tolerance.
Thus, the present study was aimed to assess whether patients with HT show proportional alterations of the peripheral T cell subpopulations as found in other T cell-mediated autoimmune diseases. In order to investigate the different T cell subpopulations, T cells were characterized by expression of CD3 and either CD4 or CD8, B cells by CD19 and natural killer (NK) cells by CD3-CD16/56+. HLA-DR was used as an activation marker of T cells. CD28 is a co-stimulatory molecule, which is lost through differentiation of T cells. CD45RO mainly defines the memory T cell subset, expression of CD45RA activated naive T cells expressing the CD62L lymphocyte homing factor. High expression of CD25 in combination with CD62L is characteristic for regulatory CD4+ T cells, and in low amounts also for naive T cells.
A further aim was to investigate the replicative history of CD45RA + expressing T cells by assessment of TRECs and relative telomere length (RTL) and the association with CMV-seropositivity. In our study, dilution of TRECs was used to estimate the thymus output and the peripheral proliferative history of the CD45RA-expressing T cell pool, which contains recent thymic emigrants (usually high TREC numbers), pre-existing peripheral, naive T cells (usually low TREC numbers due to peripheral replication and dilution of TRECs) and a small amount of differentiated effector T cells (usually TREC-negative).
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