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

Abstract

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.

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

“…The present study confirmed that plasma concentrations of IP-10, the ligand for CXCR3, were significantly higher in hyperthyroid patients with Graves' disease than in control subjects (13)(14)(15)(16). Furthermore, plasma IP-10 decreased to concentrations resembling those in control subjects when a euthyroid state had been restored by MMI treatment.…”

High Risk First Degree Relatives of Type 1 Diabetics: An Association with Increases in CXCR3+T Memory Cells Reflecting an Enhanced Activity of Th1 Autoimmune Response

“…In addition, we demonstrated that the onset of T1D is characterized by the decreases in CXCR3 + Th1 memory T subsets, presumably reflecting possible recruitment of those cells in pancreatic tissue, in agreement with the findings reported previously [21, 26, 27]. …”

“…In this context, the study done in adults with T1D in whole blood samples showed initial decrease in CXCR3/CCR4 expression ratio on CD4 + T cells [27]. Simultaneously, recently published study revealed interesting data about lower expression of Th1-associated chemokine receptors on circulated CD4 + but not on CD8 + T cells in T1D, suggesting suboptimal helper function at onset of the disease [26].…”

“…Recently, higher circulating levels of IP-10, IFN- γ and IL-18 were reported in patients with T1D, LADA, and FDRs positive for islet autoantibodies [27, 36–40], suggesting that IP-10 level might represent clinical marker of Th1 autoimmune response. These data implicate proinflammatory changes in cellular immunity in prediabetics which is in line with our observations.…”

Long-Term IKK2/NF-κB Signaling in Pancreatic β-Cells Induces Immune-Mediated Diabetes

“…However, autoimmune diabetes was prevented by Ccl22-mediated regulatory T-cell recruitment in another study (43). Furthermore, no significant difference in plasma Ccl17 was detected in type 1 diabetes patients (44). Yet, this study was conducted in a very small cohort of diabetic Japanese subjects, which certainly does not exclude a different pattern in other patient subsets.…”