Regulatory T-Cells in Graves' Orbitopathy: Baseline Findings and Immunomodulation by Anti-T Lymphocyte Globulin

Kahaly, George J.; Shimony, Orly; Gellman, Yechiel N.; Lytton, Simon D.; Eshkar-Sebban, Lora; Rosenblum, Nir; Refaeli, Efrat; Kassem, Sameer; Ilany, Jacob; Naor, David

doi:10.1210/jc.2010-1424

Cited by 56 publications

(37 citation statements)

References 29 publications

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“…In the present study, we observed an enhanced frequency of peripheral Th17 cells in patients with HT than in control subjects; however, the proportions of peripheral Treg cells in patients with HT were significantly higher than in control subjects. This suggests a compensatory attempt to overcome or reduce the autoimmunity by accelerating Treg cell activity (37). This is a notable finding as it has previously been hypothesized that the opposite roles of Th17, Treg cells and alteration of Th17/Treg may participate in the pathogenesis of HT (10,34).…”

Section: Discussionmentioning

confidence: 72%

Immunological changes of T helper cells in flow cytometer‑sorted CD4+ T cells from patients with Hashimoto's thyroiditis

et al. 2018

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Abstract. Recent incidence rates for Hashimoto's thyroiditis (HT) and hypothyroidism are higher than those of previous studies. Previous studies indicated that T helper cells may have a major role in the pathogenesis and development of HT, but there is no consensus in the literature. The aim of the present study was to explore the peripheral T helper cell response in the different stages of HT. In this cross-sectional study, we performed flow cytometry analysis to determine the various T cell subsets of 389 patients with HT (34 patients with HT who developed overt hypothyroidism, and 148 patients with HT who developed subclinical hypothyroidism), as well as 51 healthy controls. Anti-thyroid antibodies, and thyroid function were measured. The findings demonstrated that the proportion of peripheral Th1 cells was significantly lower in patients with HT than in healthy euthyroid controls (P<0.001), and the proportion of peripheral Th2, Treg cells was significantly higher in patients with HT than in healthy euthyroid controls (P<0.001). Therefore the Th1/Th2 ratio was significantly lower in HT patients than in healthy euthyroid controls (P<0.001). The Th17/Treg ratio in HT patients was significantly lower than that control subjects (P<0.001). Th1 proportions in patients with overt hypothyroidism HT were significantly higher than in subclinical hypothyroidism HT patients (P=0.031). In conclusion, the findings of the present study demonstrated that there is an increased immune deviation of Th1 lymphocytes and compensatory accelerating activity of Treg cells in HT, and the peripheral Th1 cells from the HT patients correlated to the developmental stage of hypothyroidism.

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Section: Discussionmentioning

confidence: 72%

Immunological changes of T helper cells in flow cytometer‑sorted CD4+ T cells from patients with Hashimoto's thyroiditis

et al. 2018

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“…Treg cells function via negative costimulatory molecules, induction of anti-inflammatory signal transduction pathways in T cells and antigen-presenting cells, direct or indirect destruction of effector cells or antigen-presenting cells, and secretion of suppressive cytokines [6]. Tregs are involved in the maintenance of immunological self-tolerance through active suppression of self-reactive lymphocytes, and are considered an essential element in the suppression of autoimmune disorders.…”

Section: Introductionmentioning

confidence: 99%

Treatment of Graves’ disease with methimazole in children alters the proliferation of Treg cells and CD3+ T lymphocytes

Klatka

Kaszubowska

Grywalska

et al. 2014

Folia Histochem Cytobiol.

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Almost all cases of hyperthyroidism in children result from Graves' disease (GD). Recent studies have confirmed a significant role of T regulatory cells (Tregs) in the development of autoimmune diseases. However, the interactions between T cell responses and Treg proliferation in GD are still poorly understood. The aim of this study was to assess the proliferation of Treg cells (Tregs) and CD3+ T lymphocytes isolated from 50 children with GD before and after treatment with the thyreostatic drug methimazole (MMI). The proliferation rates, measured by methyl-3H-thymidyne incorporation, of CD3+ cells and Tregs stimulated with mitogen phorbol 12-myristate 13-acetate (PMA) were compared with those of unstimulated cells. The proliferation rates of both PMA-stimulated and unstimulated CD3+ cells prior to treatment with MMI were significantly higher than after treatment. Simultaneously, the proliferation rates of both PMA-stimulated and unstimulated Tregs were significantly lower before MMI treatment. Moreover, we observed higher cell proliferation rates of unstimulated and PMA-stimulated Tregs before the initiation of MMI therapy and after treatment in patients who had no relapse of hyperthyroidism. There was a positive correlation between the CD3+ cells proliferation rate before MMI treatment and fT3, as well as fT4 concentration in peripheral blood. The proliferation rates of CD3+ T cells before and after MMI treatment positively correlated with the TSI index. Thus, children suffering from Graves' disease presented lower Tregs proliferative potential compared with CD3+ T cells. Cocultures of CD3+ T cells and Tregs showed that Tregs were not capable of efficiently inhibiting the proliferation of CD3+ T cells in GD patients. Conclusions. MMI treatment reduced the proliferative activity of CD3+ T cells in pediatric GD patients and increased the proliferation rate of Tregs. We suggest that Treg cells that are partly dysfunctional in GD disease are probably suppressed by CD3+ T cells and that methimazole exerts some immunomodulatory effects.

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“…In murine models and humans, quantitative and functional alterations in T regs have been related to the development and maintenance of many organ-specific and systemic autoimmune diseases [2, [8][9][10][11][12][13][14][15][16]. In particular, defects in FOXP3 gene, IL-2Ra signalling pathway and inhibitory markers, such as cytotoxic T lymphocyteassociated protein-4 (CTLA-4) or programmed cell death protein-1 (PD-1), as well as over-expression of T-bet or signal transducer and activator of transcription-3 (STAT-3), appear to be critical in the loss of suppressive function or stability in different T helper type 1 (Th1)-and Th17-dominated autoimmune settings, such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus (SLE) [17].…”

Section: T Cells [2-4] Through Diverse Mechanisms Thatmentioning

confidence: 99%

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

Romo-Tena

Aparicio‐Vera

Alcocer‐Varela

et al. 2017

Clinical and Experimental Immunology

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Summary T cells from systemic lupus erythematosus (SLE) patients display a wide array of anomalies in peripheral immune tolerance mechanisms. The role of ubiquitin ligases such as Cbl-b has been described recently in these phenomena. However, its role in resistance to suppression phenotype in SLE has not been characterized, which was the aim of the present study. Thirty SLE patients (20 with active disease and 10 with complete remission) and 30 age- and sex-matched healthy controls were recruited. Effector (CD4+CD25–) and regulatory (CD4+CD25+) T cells (Tregs) were purified from peripheral blood mononuclear cells (PBMCs) by magnetic selection. Suppression assays were performed in autologous and allogeneic co-cultures and analysed by a flow cytometry assay. Cbl-b expression and lysine-63 (K63)-specific polyubiquitination profile were assessed by Western blotting. We found a defective Cbl-b expression in Tregs from lupus patients in contrast to healthy controls (1·1 ± 0·9 versus 2·5 ± 1·8, P = 0·003), which was related with resistance to suppression (r = 0·633, P = 0·039). Moreover, this feature was associated with deficient K63 polyubiquitination substrates and enhanced expression of phosphorylated signal transducer and activation of transcription 3 (pSTAT-3) in Tregs from lupus patients. Our findings support that Cbl-b modulates resistance to suppression by regulating the K63 polyubiquitination profile in lupus Tregs. In addition, defective K63 polyubiquitination of STAT-3 is related to increased pSTAT-3 expression, and might promote the loss of suppressive capacity of Tregs in lupus patients.

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Regulatory T-Cells in Graves' Orbitopathy: Baseline Findings and Immunomodulation by Anti-T Lymphocyte Globulin

Abstract: This study is the first to show that PBMCs of patients with GO substantially increase Treg cells in both frequency and potency after in vitro incubation with rATG.

Cited by 56 publications

References 29 publications

Immunological changes of T helper cells in flow cytometer‑sorted CD4+ T cells from patients with Hashimoto's thyroiditis

Immunological changes of T helper cells in flow cytometer‑sorted CD4+ T cells from patients with Hashimoto's thyroiditis

Treatment of Graves’ disease with methimazole in children alters the proliferation of Treg cells and CD3+ T lymphocytes

Lys63-polyubiquitination by the E3 ligase casitas B-lineage lymphoma-b (Cbl-b) modulates peripheral regulatory T cell tolerance in patients with systemic lupus erythematosus

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