Identification of thyroid stimulating hormone receptor-specific T cells in Graves' disease thyroid using autoantigen-transfected Epstein-Barr virus-transformed B cell lines.

Mullins, Raymond J; Cohen, S. B. A.; Webb, Louise M. C.; Chernajovsky, Yuti; Dayan, Colin; Londei, Marco; Feldmann, Marc

doi:10.1172/jci118034

Cited by 52 publications

(30 citation statements)

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“…These results suggest that Th1-associated T lymphocytes in peripheral blood were profoundly reduced in patients who had both diseases, compared with either disease alone. Since the pathogenesis of Graves' disease is linked to production of thyrotropin (TSH) receptor antibodies (TRAb) that stimulates the thyroid follicular cell TSH receptor, humoral immunity plays a crucial role in the pathogenesis of Graves' disease [9,10,12,13]. However, a recent study demonstrated the recruitment of CXCR3-expressing Th1 lymphocytes in the thyroid glands of patients at the initial phase of Graves' disease [14], suggesting Th1 dominance within the thyroid gland, rather than Th2, at the onset of illness.…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of Graves' disease is linked to the production of thyrotropin (TSH) receptor (TSHR) antibodies (TRAb), which overstimulates thyroid cells, to result in hyperthyroidism [9]. A previous study demonstrated TSHRspecific T-cell clones in thyroid gland affected by Graves' disease; these were characterized as Th0/Th2 clones on the basis of an increased ratio of IL-4 to IFN-γ [10]. Thus, dominance of humoral immunity (Th2) has been suggested in Graves' disease.…”

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confidence: 99%

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Profound Reduction in T-helper (Th) 1 lymphocytes in Peripheral Blood from Patients with Concurrent Type 1 Diabetes and Graves' Disease

et al. 2006

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Abstract. Type 1 diabetes likely is mediated by T-helper (Th) 1 lymphocytes, while Graves' disease may involve Th2 predominance. We investigated the balance between Th1 and Th2 cells and between Th1-and Th2-associated chemokine receptor expression on peripheral lymphocytes in subjects including patients with coexisting type 1 diabetes and Graves' disease. Peripheral blood mononuclear cells of all subjects were examined by flow cytometry for intracellular cytokines (IFN-γ for Th1; IL-4 for Th2) and expression of the chemokine receptors CXCR3 (Th1-associated) and CCR4 (Th2-associated). Plasma concentrations of interferon-inducible protein (IP)-10, a CXCR3 ligand, and thymus and activationregulated chemokine (TARC), a CCR4 ligand, were measured by enzyme-linked immunosorbent assays. IFN-γ producing-T lymphocytes were significantly fewer in patients with coexisting type 1 diabetes and Graves' disease (12.4 ± 6.8%, n = 6) than in healthy control subjects (19.9 ± 4.1%, n = 6; P<0.01) or patients with type 2 diabetes (19.1 ± 4.5%, n = 5; P<0.05). We found no significant difference in IFN-γ-producing T lymphocytes between healthy controls and patients with only type 1 diabetes (n = 8) or Graves' disease (n = 5). Plasma IP-10 concentrations were significantly higher in patients with coexisting type 1 diabetes and Graves' disease than in control subjects (106.3 ± 30.48 vs. 66.7 ± 25.3 pg/ml, P = 0.0343). Considering only patients with type 1 diabetes alone, duration of diabetes correlated positively with IFN-γ-producing T lymphocytes (r = 0.773, P = 0.0242) and the ratio of CXCR3 to CCR4 receptor expression (r = 0.947, P = 0.0004). In conclusion, Th1-associated T lymphocytes were fewer in peripheral blood from patients having both type 1 diabetes and Graves' disease than in those with either disease alone. Numbers of peripheral Th1 lymphocytes increased with increasing time from onset of type 1 diabetes in patients with type 1 diabetes alone.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Profound Reduction in T-helper (Th) 1 lymphocytes in Peripheral Blood from Patients with Concurrent Type 1 Diabetes and Graves' Disease

et al. 2006

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“…Graves' disease is characterized by persistent infiltration of the thyroid gland by lymphocytes composed mainly of CD4C and CD8C lymphocytes (4). A previous study demonstrated that thyroid glands affected by Graves' disease contained TSHR-specific T-cell clones that were characterized as Th2 on the basis of an increased ratio of IL-4 to IFN-g (5). Further, an in vitro study of cultured whole bloods from Graves' disease patients showed an increase in Th2-associated cytokine production (6).…”

Section: Introductionmentioning

confidence: 99%

Changes in expression of T-helper (Th) 1- and Th2-associated chemokine receptors on peripheral blood lymphocytes and plasma concentrations of their ligands, interferon-inducible protein-10 and thymus and activation-regulated chemokine, after antithyroid drug administration in hyperthyroid patients with Graves’ disease

Inukai

Momobayashi²,

Sugawara³

et al. 2007

eur j endocrinol

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Objective: Although Graves' disease is considered an autoantibody-mediated, T-helper 2 (Th2)-dominant disease, Th1-dominance may prevail in its initial phase. We longitudinally investigated Th1/Th2 balance in untreated hyperthyroid patients with Graves' disease after treatment of methimazole (MMI), an antithyroid drug. Design: University clinic outpatients were studied prospectively. Patients: Subjects included 23 untreated hyperthyroid patients with Graves' disease and 17 agematched control subjects. Methods: Before and after treatment, we measured Th1-and Th2-associated chemokine receptors (CXCR)3 and CCR4, on peripheral blood lymphocytes using flow cytometry, as well as plasma concentrations of their ligands, interferon-inducible protein (IP)-10 and thymus and activationregulated chemokine (TARC). Results: The percentage of CXCR3-expressing cells among CD4C T lymphocytes and plasma IP-10 was significantly higher in hyperthyroid Graves' disease patients than in controls. At 12 and 24 weeks after initiation of MMI, percentage of CXCR3-expressing CD4 C T lymphocytes had decreased significantly, while the percentage of CCR4-expressing CD4 C T lymphocytes had increased significantly at 24 weeks. The CXCR3/CCR4 ratio had decreased significantly at 24 weeks. Plasma concentrations of IP-10 had decreased significantly at 12 and 24 weeks. Plasma concentrations of TARC also had decreased significantly at 24 weeks. Conclusions: In hyperthyroid patients with Graves' disease in the active phase, Th1 cells rather than Th2 cells predominated among peripheral blood lymphocytes. After initiation of MMI, an ongoing transition from Th1 to Th2 dominance occurred. 156 623-630 European Journal of Endocrinology

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“…Type 1 diabetes and Hashimoto's thyroiditis represent Th1 dominant diseases [10], while Graves' disease is considered to show Th2 or Th0 dominance. T cells specific for the TSH receptor cloned from Graves' disease lymphoid infiltrates produced relatively little IFN-g and possessed distinct Th0/Th2 characteristics, unlike cloned TPO-responsive cells which have Th1 characteristics [11]. An increased accumulation of transcripts for IFN-g, IL-2, IL-4 and IL-10 has been reported in Graves' disease thyroid glands [12].…”

Section: Introductionmentioning

confidence: 99%

The effects of CD40- and interleukin (IL-4)-activated CD23+ cells on the production of IL-10 by mononuclear cells in Graves’ disease: the role of CD8+ cells

Uchimura

Itoh

Yamamoto

et al. 2002

Clinical and Experimental Immunology

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SUMMARY The possible roles of CD8+ cells in the abnormal T cell-dependent B-cell activation in Graves’ disease were investigated by analysing lymphocyte subsets in peripheral blood mononuclear cells (PBMC) and their production of soluble factors and cytokines such as IL-10 in patients with Graves’ disease, Hashimoto's thyroiditis and normal controls. The PBMC were separated into CD8+ and CD8-depleted cells by magnetic separation columns, and cultured for 7 days with or without anti-CD40 monoclonal antibodies and IL-4. The culture supernatant was assayed for sCD23 and IL-10 using EIA, and the remaining cells were analysed by flow cytometry. Stimulation with anti-CD40 antibody together with IL-4 increased sCD23 levels and the number of CD23+ cells. The latter was further augmented by depletion of CD8+ cells. This combination of B cell stimulants increased production of IL-10 by PBMC from patients with Graves’ disease. The CD40- and IL-4-activated production of IL-10 was decreased by CD8+ cell depletion. In contrast, constitutive production of IL-10 was increased after CD8+ cell depletion in a group of patients with low basal secretion levels (<35 ng/ml). It was, however, decreased in a group with higher basal production levels, but such a relationship was not found in the normal control group. Thus, T cell-dependent B-cell activation via a CD40 pathway activates CD23+ cells, leading to over-production of IL-10 and a shift of the Th1/Th2 balance to Th2 dominance, while CD8+ cells may suppress this activation to counteract the Th2 deviation in Graves’ disease.

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Identification of thyroid stimulating hormone receptor-specific T cells in Graves' disease thyroid using autoantigen-transfected Epstein-Barr virus-transformed B cell lines.

Abstract: IntroductionThe importance of thyrotropin receptor (TSHR) Clin. Invest. 1995. 96:30-37.)

Cited by 52 publications

References 47 publications

Profound Reduction in T-helper (Th) 1 lymphocytes in Peripheral Blood from Patients with Concurrent Type 1 Diabetes and Graves' Disease

Profound Reduction in T-helper (Th) 1 lymphocytes in Peripheral Blood from Patients with Concurrent Type 1 Diabetes and Graves' Disease

The effects of CD40- and interleukin (IL-4)-activated CD23+ cells on the production of IL-10 by mononuclear cells in Graves’ disease: the role of CD8+ cells

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