Characterization and clinical relevance of circulating CD4+CD28- T cells in Graves' disease.

During autoimmune disease the fraction of CD4+CD28- T cells in the peripheral blood of has been found to be elevated. In the present study, peripheral blood was collected from 61 patients with Graves' disease (GD) and 30 healthy control participants. Serum concentrations of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4) and thyrotropin receptor autoantibody (TRAb) were measured and peripheral blood mononuclear cell (PBMC) surface expression of CD4 and CD28 molecules was detected by flow cytometry. CD4+CD28- cells were sorted from six patients undergoing subtotal thyroidectomy and cultured ex vivo. The influence of TSH pretreated thyroid follicular cells on CD4+CD28- cell proliferation was evaluated using the agonist CD40 mAb 5C11, the blocking CD40L mAb 4F1 or B7-1 mAb 4E5 in 3H-TdR assays. Our data showed that the fraction of CD4+CD28- T cells was higher in GD patients than healthy donors (10.21%±8.56% vs. 2.33%±1.94%; P<0.001), and further elevated in 24 of 61 patients with Graves' ophthalmopathy (GO) (7.00±6.57% vs. 15.21±8.96%; P<0.001). A higher proportion of CD4+CD28- cells was detected in patients with degree II or III goiter than those with degree I goiter (11.53±9.18% vs. 6.11±3.97%; P<0.05 and 14.50±10.41% vs. 6.11±3.97%; P<0.01). The percentage of CD4+CD28- T cells correlated positively with serum levels of FT3 (r=0.354, P<0.01) and TRAb (r=0.304, P<0.05), but did not correlate with serum FT4 or TSH. Ex vivo, 5C11 enhanced proliferation of CD4+CD28+ cells (P<0.05), but did not influence the proliferation of CD4+CD28- cells. 4F1 inhibited the proliferation of both CD4+CD28+ (P<0.05) and CD4+CD28- (P<0.01) cells, and 4E5 inhibited proliferation of CD4+CD28+ cells (P<0.05). The elevation in circulating CD4+CD28- cells in GD patients correlates with disease severity and maybe plays an important role in the pathogenesis of GD.

Wang F ，Chen L ，Shen Q ，Liu T ，Jiang L ，Gu X ，Chen L ，Sun J ，Liu C ... -  《-》

Relationship between CTLA-4 and CD28 molecule expression on T lymphocytes and stimulating and blocking autoantibodies to the TSH-receptor in children with Graves' disease.

The present study was performed to elucidate the relationship between CTLA-4/CD28 molecules and stimulating (TSAb) and blocking (TBAb) antibodies to the TSH-receptor (TSH-R) in Graves' disease. CD28 and CD152 (CTLA-4) are glycoprotein molecules which provide a potent costimulatory signal for T-cell activation and proliferation via interactions with their ligands, B7.1/B7.2 molecules, which are present on the surface of antigen-presenting cells. The aim of the study was to estimate the expression of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152), CD28, B7.1 (CD80), and B7.2 (CD86) molecules on peripheral blood cells in patients with Graves' disease (GD) (n = 55, mean age 15.5 +/- 5.1 years) and nontoxic nodular goiter (NTNG) (n = 55, mean age 15.2 +/- 4.5 years), in comparison with sex and age-matched healthy control subjects (n = 55, mean age 15.2 +/- 3.9 years). The expression of the costimulatory molecules on mononuclear cells was analyzed by three-color flow cytometry using a Coulter EPICS XL cytometer. Detection of TSAb and TBAb to the TSH-R using JPO9 CHO cells in unfractionated serum was measured by a highly sensitive commercial radioimmunoassay. When compared with healthy control subjects and euthyroid patients with GD, untreated patients with GD showed a significant increase of CD152+ (p < 0.001, p < 0.001) and CD28+ (p < 0.01, NS) T lymphocytes, respectively. After 6-12 months of methimazole therapy, the percentage of these cells in the peripheral blood of hyperthyroid patients returned to normal values. In addition, patients with GD showed an increase in the percentage of both B7.1 (3.8%) and B7.2 (18.4%) molecules on activated monocytes, compared to patients with NTNG (0.5% p < 0.05, 2.5% p < 0.01, respectively) and healthy control subjects (0.2% p < 0.05, 0.8% p < 0.003, respectively). In patients with untreated GD there was a statistically significant positive correlation between the expression of CTLA-4 on the surface of peripheral blood T cells and the index of TSAb antibodies (R = 0.54, p < 0.001) as well as a negative correlation with TBAb antibody titer (R = -0.58, p < 0.001). However, no such correlations were noted with regard to CD28 and anti-TPO, anti-TG, and TRAb antibodies. We conclude that changes in the expression of costimulatory molecules on the surface of peripheral blood T cells and their significant relationship with the level of antithyroid antibodies indicate an involvement of these molecules in the pathogenesis of GD.

Bossowski A ，Stasiak-Barmuta A ，Urban M 《hormone research》

CD4+ T cells and the Th1/Th2 imbalance are implicated in the pathogenesis of Graves' ophthalmopathy.

Xia N ，Zhou S ，Liang Y ，Xiao C ，Shen H ，Pan H ，Deng H ，Wang N ，Li QQ ... -  《INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE》

[Analysis of costimulatory molecules (CD28-CTLA-4/B7) expression on chosen mononuclear cells in adolescents with Graves' disease during methimazole therapy].

Bossowski A ，Stasiak-Barmuta A ，Urban M ，Rinderle C ... -  《-》

Analysis of changes in the percentage of B (CD19) and T (CD3) lymphocytes, subsets CD4, CD8 and their memory (CD45RO), and naive (CD45RA) T cells in children with immune and non-immune thyroid diseases.

Bossowski A ，Urban M ，Stasiak-Barmuta A 《JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM》