Decreased Frequencies of Peripheral Blood CD4+CD25+CD127–Foxp3+ in Patients with Graves’ Disease and Graves’ Orbitopathy: Enhancing Effect of Insulin Growth Factor-1 on Treg Cells

Abstract

Graves' orbitopathy (GO) is characterized by orbital T cell infiltration. We evaluated the regulatory T (Treg) cell fractions induced with IGF-1 in Graves' disease (GD) with and without GO. Peripheral blood mononuclear cells (PBMCs) were obtained from 13 patients with GD without eye manifestations; 10 patients with active GO; and 12 patients with nodular goiter (NG). All the patients from GD, GO, and NG were subclinical hyperthyroid. We analyzed the expression of Treg cell markers (CD4, CD25, CD127, Foxp3) on T cells and their ability to respond to IGF-1 stimulation. In patients with GD without GO, we found lowered percentages of CD4 Foxp3 cells, as compared to nodular goiter 1.77 vs. 5.42% (p=0.0276). Similarly, significantly reduced frequencies of CD4CD25CD127Foxp3 and CD4CD25CD127 cells were observed in GD patients as compared to nodular goiter patients with hyperthyreosis, (0.7 vs. 1.48%) (p=0.0071) and (14.5 vs. 37.2%) (p=0.0051), respectively. In GO with active GO, only the percentage of CD4CD25CD127 cells was found to be decreased versus nodular goiter (9.35 vs. 37.2) (p=0.0275). Stimulation of PBMC derived from GO patients with IGF-1 resulted in significant increase of frequency of both CD4 Foxp3 and CD4CD25CD127 Foxp3 cells. Decreased frequencies of peripheral blood CD4CD25CD127Foxp3 in patients with GD and GO could be an useful marker of autoimmune process and perhaps a possible target for future therapies. This is the first study demonstrating Treg-enhancing effects of IGF-1. Thus IGF-1 can be accounted for modulating Treg cell-related action in GO.

Search of reference biomarkers reflecting orbital tissue remodeling in the course of Graves’ orbitopathy

“…Interestingly, IGF-1 promotes cell proliferation and lipid accumulation within orbital adipose tissue-derived stromal cells from patients with GO [11]. Recently we revealed that IGF-1 stimulation of peripheral blood mononuclear cells (PBMC) derived from GO patients resulted in significant increase of Treg frequency, thus demonstrating Treg-enhancing effects of IGF-1 [21]. This effect of IGF-1 may also impact Treg numbers locally within the orbital tissue from GO and therefore we compared the expression pattern of the IGF-1R with that of Foxp-3 in this current study.…”

Analysis of Regulatory T Cell Subsets and Their Expression of Helios and PD-1 in Patients with Hashimoto Thyroiditis

“…Various studies have demonstrated that Tregs play an important role in preventing autoimmunity and restraining responses of effector T cells, but the frequency and function of Tregs in the progression of AITD are discrepant [4, 25, 26]. Defective Tregs frequency has been widely reported to exist in Graves' disease [27–32], while less evidence is available regarding Tregs in HT. In this regard, we assessed the classical CD4 + CD25 + Foxp3 + Tregs number and two key functional indicators in HT patients and HC.…”

40 YEARS OF IGF1: IGF1 receptor and thyroid-associated ophthalmopathy

“…In transgenic mice over-expressing IGF-II, thymic cellularity was substantially increased and the frequency of normal T cells was increased, exhibiting a skew toward CD4 + lymphocytes (Kooijman, et al 1995b). IGF-I treatment of peripheral blood mononuclear cells from patients with GD could enhance the frequency of CD25 + Foxp3 + regulatory T cells (Pawlowski, et al 2017). IGF-I produced by bone marrow stromal cells stimulates the development of pro-B cells (Landreth, et al 1992).…”