Vol 58, No 1 (2020)
Original paper
Published online: 2020-03-16
Search of reference biomarkers reflecting orbital tissue remodeling in the course of Graves’ orbitopathy
Abstract
Introduction. Graves’ orbitopathy (GO) is a complication in Graves’ disease (GD) that causes disfigurement and sometimes blindness. The pathogenesis of GO remains unknown, while its symptoms demonstrate dependence between the thyroid gland and the orbit. The ongoing inflammatory process in retrobulbar tissue results in its remodeling characterized by increased volume of the orbital contents involving adipose tissue, with fibrosis and adipogenesis as predominant features. This study was aimed at the immunohistochemical verification of potential contribution and correlation between orbital expressions of IGF-1R, CD34, Foxp-3, PPAR-γ and CD4, CD68, TGF-β, FGF-β in severe and mild (long-lasting) GO. Material and methods. Forty-one orbital tissue specimens — 22 patients with severe GO, 9 patients with mild GO and 10 patients undergoing blepharoplasty as a control group — were processed by routine immunohistochemistry. Results. Increased IGF-1R, CD34 and Foxp-3 expression was found in both severe and mild GO, yet a significant correlation between CD34 and CD4, CD68, TGF-β, FGF-β expressions was observed in long-lasting GO. Conclusions. CD34 expression is proposed to be the marker of orbital tissue remodeling in the course of mild GO.
Keywords: Graves’ orbitopathyCD34IGF-1RPPAR-gCD68TGF-bFGF-bFoxp-3tissue remodelingautoimmunityIHC
References
- Wang Y, Smith TJ. Current concepts in the molecular pathogenesis of thyroid-associated ophthalmopathy. Invest Ophthalmol Vis Sci. 2014; 55(3): 1735–1748.
- Smith T, Hegedüs L. Graves’ Disease. New England Journal of Medicine. 2016; 375(16): 1552–1565.
- Douglas RS, Afifiyan NF, Hwang CJ, et al. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2010; 95(1): 430–438.
- Smith TJ, Padovani-Claudio DA, Lu Y, et al. Fibroblasts expressing the thyrotropin receptor overarch thyroid and orbit in Graves' disease. J Clin Endocrinol Metab. 2011; 96(12): 3827–3837.
- Li He, Fitchett C, Kozdon K, et al. Independent adipogenic and contractile properties of fibroblasts in Graves' orbitopathy: an in vitro model for the evaluation of treatments. PLoS One. 2014; 9(4): e95586.
- Gillespie EF, Papageorgiou KI, Fernando R, et al. Increased expression of TSH receptor by fibrocytes in thyroid-associated ophthalmopathy leads to chemokine production. J Clin Endocrinol Metab. 2012; 97(5): E740–E746.
- Krieger CC, Place RF, Bevilacqua C, et al. TSH/IGF-1 Receptor Cross Talk in Graves' Ophthalmopathy Pathogenesis. J Clin Endocrinol Metab. 2016; 101(6): 2340–2347.
- Khong JJ, McNab AA, Ebeling PR, et al. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. Br J Ophthalmol. 2016; 100(1): 142–150.
- Wiersinga WM. Autoimmunity in Graves' ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors? J Clin Endocrinol Metab. 2011; 96(8): 2386–2394.
- Tsui S, Naik V, Hoa N, et al. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves' disease. J Immunol. 2008; 181(6): 4397–4405.
- Zhao P, Deng Y, Gu P, et al. Insulin-like growth factor 1 promotes the proliferation and adipogenesis of orbital adipose-derived stromal cells in thyroid-associated ophthalmopathy. Exp Eye Res. 2013; 107: 65–73.
- Sakaguchi S. Regulatory T cells: history and perspective. Methods Mol Biol. 2011; 707: 3–17.
- Klatka M, Grywalska E, Partyka M, et al. Th17 and Treg cells in adolescents with Graves' disease. Impact of treatment with methimazole on these cell subsets. Autoimmunity. 2014; 47(3): 201–211.
- Ban Y, Tozaki T, Tobe T, et al. The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: an association analysis in Caucasian and Japanese cohorts. J Autoimmun. 2007; 28(4): 201–207.
- Pawlowski P, Wawrusiewicz-Kurylonek N, Eckstein A, et al. Disturbances of modulating molecules (FOXP3, CTLA-4/CD28/B7, and CD40/CD40L) mRNA expressions in the orbital tissue from patients with severe graves' ophthalmopathy. Mediators Inflamm. 2015; 2015: 340934.
- Bartalena L, Baldeschi L, Boboridis K, et al. European Group on Graves' Orbitopathy (EUGOGO). The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy. Eur Thyroid J. 2016; 5(1): 9–26.
- Mourits MP, Prummel MF, Wiersinga WM, et al. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf). 1997; 47(1): 9–14.
- Pawlowski P, Reszec J, Eckstein A, et al. Markers of inflammation and fibrosis in the orbital fat/connective tissue of patients with Graves' orbitopathy: clinical implications. Mediators Inflamm. 2014; 2014: 412158.
- Dik WA, Virakul S, van Steensel L. Current perspectives on the role of orbital fibroblasts in the pathogenesis of Graves' ophthalmopathy. Exp Eye Res. 2016; 142: 83–91.
- Smith TJ, Hegedüs L, Douglas RS. Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves' orbitopathy. Best Pract Res Clin Endocrinol Metab. 2012; 26(3): 291–302.
- Pawlowski P, Grubczak K, Kostecki J, et al. 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. Horm Metab Res. 2017; 49(3): 185–191.
- Kahaly GJ, Shimony O, Gellman YN, et al. Regulatory T-cells in Graves' orbitopathy: baseline findings and immunomodulation by anti-T lymphocyte globulin. J Clin Endocrinol Metab. 2011; 96(2): 422–429.
- Bilbao D, Luciani L, Johannesson B, et al. Insulin-like growth factor-1 stimulates regulatory T cells and suppresses autoimmune disease. EMBO Mol Med. 2014; 6(11): 1423–1435.
- Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090): 235–238.
- Schmidt, A., Éliás, S., Joshi, R. N., & Tegnér, J. . In vitro differentiation of human CD4+ FOXP3+ induced regulatory T cells (iTregs) from naïve CD4+ T cells using a TGF-β-containing protocol. J Visual Exp. 2016; 118: e55015.
- Chen H, Mester T, Raychaudhuri N, et al. Teprotumumab, an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J Clin Endocrinol Metab. 2014; 99(9): E1635–E1640.
- Frostad S, Bjerknes R, Abrahamsen JF, et al. Insulin-like growth factor-1 (IGF-1) has a costimulatory effect on proliferation of committed progenitors derived from human umbilical cord CD34+ cells. Stem Cells. 1998; 16(5): 334–342.
- Minich WB, Dehina N, Welsink T, et al. Autoantibodies to the IGF1 receptor in Graves' orbitopathy. J Clin Endocrinol Metab. 2013; 98(2): 752–760.
- Douglas RS, Gianoukakis AG, Kamat S, et al. Aberrant expression of the insulin-like growth factor-1 receptor by T cells from patients with Graves' disease may carry functional consequences for disease pathogenesis. J Immunol. 2007; 178(5): 3281–3287.
- Varewijck AJ, Boelen A, Lamberts SWJ, et al. Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Graves' ophthalmopathy. J Clin Endocrinol Metab. 2013; 98(2): 769–776.
- Alevizaki M, Mantzou E, Cimponeriu A, et al. The Pro 12 Ala PPAR gamma gene polymorphism: possible modifier of the activity and severity of thyroid-associated orbitopathy (TAO). Clin Endocrinol (Oxf). 2009; 70(3): 464–468.
- Smith TJ. TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy. Nat Rev Endocrinol. 2015; 11(3): 171–181.
- Kozdon K, Fitchett C, Rose GE, et al. Mesenchymal Stem Cell-Like Properties of Orbital Fibroblasts in Graves' Orbitopathy. Invest Ophthalmol Vis Sci. 2015; 56(10): 5743–5750.
