Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Immunologic Research
Published in: Immunologic Research 2/2015

01-06-2015

Elevated follicular helper T Cells and expression of IL-21 in thyroid tissues are involved in the pathogenesis of Graves’ disease

Authors: Jin Zhang, Meng Ren, Hua Zeng, Ying Guo, Zhenwu Zhuang, Zhimei Feng, Haiyan Yan, Mingtong Xu, Weiwen Liang, Chuan Yang, Hua Cheng, Helin Ding, Li Yan

Published in: Immunologic Research | Issue 2/2015

Login to get access

Abstract

The follicular helper T cell (Tfh) and IL-21 have been shown to play an important role in many autoimmune diseases. However, less is known about their role in Graves’ disease (GD). This study aimed to investigate the expression of Tfhs and related factors (IL-21, IL-21R, CXCR5, and CXCL13) in GD thyroid tissues and to explore the effect of IL-21 on thyroid follicular cells (TFCs). The expression of Tfh-related factors in GD and normal thyroid tissues was validated using immunohistochemistry, real-time polymerase chain reaction and Western blotting. Confocal microscopy confirmed the presence of Tfh and IL-21R on CD4+T-/CD19+B cell in GD thyroid tissues. Furthermore, the effect of IL-21 on cAMP production in TFCs upon thyroid-stimulating antibody (TSAb) stimulation was also examined by an in vitro bioassay. The increased expression of Tfh-related factors was observed in GD thyroid tissues compared to control subjects. Confocal microscopy further confirmed the presence of Tfhs and the expression of IL-21R on CD4+T cells and CD19+B cells in GD thyroid tissues. Moreover, the expression of IL-21mRNA in GD thyroid tissues was correlated with the levels of thyroid autoantibodies. Additionally, IL-21 could indirectly promote cAMP production upon TSAb stimulation in TFCs when cooperating with lymphocytes, and GD TFCs were more sensitive to IL-21 stimulation than normal TFCs. There is increased expression of Tfhs and related factors (IL-21, IL-21R, CXCR5, and CXCL13) in GD thyroid tissues, and the expression of IL-21mRNA in GD thyroid tissues was found to correlate with the serum levels of thyroid autoantibodies and thyroid hormones. Moreover, IL-21 could indirectly enhance the biological activity of TFCs upon TSAb stimulation when cooperating with lymphocytes in vitro, particularly in GD TFCs, suggesting that Tfh and IL-21 might be involved in the pathogenesis of GD.
Literature
1.
2.
Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 2008;29:127–37.CrossRefPubMed
3.
Ozaki K, Spolski R, Feng CG, Qi CF, Cheng J, Sher A, Morse HR, Liu C, Schwartzberg PL, Leonard WJ. A critical role for IL-21 in regulating immunoglobulin production. Science. 2002;298:1630–4.CrossRefPubMed
4.
Rodriguez-Bayona B, Ramos-Amaya A, Bernal J, Campos-Caro A, Brieva JA. Cutting edge: IL-21 derived from human follicular helper T cells acts as a survival factor for secondary lymphoid organ, but not for bone marrow, plasma cells. J Immunol. 2012;188:1578–81.CrossRefPubMed
5.
Ettinger R, Sims GP, Fairhurst AM, Robbins R, Da SY, Spolski R, Leonard WJ, Lipsky PE. IL-21 induces differentiation of human naive and memory B cells into antibody-secreting plasma cells. J Immunol. 2005;175:7867–79.CrossRefPubMed
6.
Pene J, Gauchat JF, Lecart S, Drouet E, Guglielmi P, Boulay V, Delwail A, Foster D, Lecron JC, Yssel H. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J Immunol. 2004;172:5154–7.CrossRefPubMed
7.
Vinuesa CG, Tangye SG, Moser B, Mackay CR. Follicular B helper T cells in antibody responses and autoimmunity. Nat Rev Immunol. 2005;5:853–65.CrossRefPubMed
8.
Finch DK, Ettinger R, Karnell JL, Herbst R, Sleeman MA. Effects of CXCL13 inhibition on lymphoid follicles in models of autoimmune disease. Eur J Clin Invest. 2013;43:501–9.CrossRefPubMed
9.
King C, Tangye SG, Mackay CR. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol. 2008;26:741–66.CrossRefPubMed
10.
11.
Terrier B, Costedoat-Chalumeau N, Garrido M, Geri G, Rosenzwajg M, Musset L, Klatzmann D, Saadoun D, Cacoub P. Interleukin 21 correlates with T cell and B cell subset alterations in systemic lupus erythematosus. J Rheumatol. 2012;39:1819–28.CrossRefPubMed
12.
Liu R, Wu Q, Su D, Che N, Chen H, Geng L, Chen J, Chen W, Li X, Sun L. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis Res Ther. 2012;14:R255.CrossRefPubMedCentralPubMed
13.
Tzartos JS, Craner MJ, Friese MA, Jakobsen KB, Newcombe J, Esiri MM, Fugger L. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am J Pathol. 2011;178:794–802.CrossRefPubMedCentralPubMed
14.
Zhu C, Ma J, Liu Y, Tong J, Tian J, Chen J, Tang X, Xu H, Lu L, Wang S. Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease. J Clin Endocrinol Metab. 2012;97:943–50.CrossRefPubMed
15.
Ben-Skowronek I, Sierocinska-Sawa J, Szewczyk L, Korobowicz E. Interaction of lymphocytes and thyrocytes in Graves’ disease and nonautoimmune thyroid diseases in immunohistochemical and ultrastructural investigations. Horm Res. 2009;71:350–8.CrossRefPubMed
16.
Zhang J, Zeng H, Ren M, Yan H, Xu M, Feng Z, Liang W, Yang C, Cheng H, Ding H, Yan L. Interleukin-21 is associated with disease activity in patients with Graves’ disease. Endocrine. 2014;46:539–48.CrossRefPubMed
17.
Caraccio N, Giannini R, Cuccato S, Faviana P, Berti P, Galleri D, Dardano A, Basolo F, Ferrannini E, Monzani F. Type I interferons modulate the expression of thyroid peroxidase, sodium/iodide symporter, and thyroglobulin genes in primary human thyrocyte cultures. J Clin Endocrinol Metab. 2005;90:1156–62.CrossRefPubMed
18.
Karlsson FA, Dahlberg PA. Thyroid stimulating antibodies (TSAb) in patients with Graves’ disease undergoing antithyroid drug treatment: indicators of activity of disease. Clin Endocrinol (Oxf). 1981;14:579–85.CrossRef
19.
Neumann S, Pope A, Geras-Raaka E, Raaka BM, Bahn RS, Gershengorn MC. A drug-like antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves’ orbital fibroblasts. Thyroid. 2012;22:839–43.CrossRefPubMedCentralPubMed
20.
Takasu N, Yamashiro K, Ochi Y, Sato Y, Nagata A, Komiya I, Yoshimura H. TSBAb (TSH-stimulation blocking antibody) and TSAb (thyroid stimulating antibody) in TSBAb-positive patients with hypothyroidism and Graves’ patients with hyperthyroidism. Horm Metab Res. 2001;33:232–7.CrossRefPubMed
21.
Ochi Y, Yamashiro K, Takasu N, Kajita Y, Sato Y, Nagata A. Sensitive assay to detect thyroid stimulating antibody (TSAb) in the presence of thyroid stimulation blocking antibody (TSBAb) in serum. Horm Metab Res. 2001;33:115–20.CrossRefPubMed
22.
Guan LJ, Wang X, Meng S, Shi LF, Jiang WJ, Xiao L, Shi XH, Xu J, Zhang JA. Increased IL-21/IL-21R expression and its proinflammatory effects in autoimmune thyroid disease. Cytokine. 2015;72:160–5.CrossRefPubMed
23.
Aust G, Sittig D, Becherer L, Anderegg U, Schutz A, Lamesch P, Schmucking E. The role of CXCR5 and its ligand CXCL13 in the compartmentalization of lymphocytes in thyroids affected by autoimmune thyroid diseases. Eur J Endocrinol. 2004;150:225–34.CrossRefPubMed
24.
Zeng H, Yan H, Zhang Z, Fang W, Ding R, Huang L, Chen M, Zhang J. Association between IL-21 gene rs907715 polymorphisms and Graves’ disease in a Southern Chinese population. Exp Ther Med. 2014;8:213–8.PubMedCentralPubMed
25.
Zhang J, Xiao XW, Zhu FY, Muhali SF, Xiao L, Jiang JW, Shi HX, Zhou HL, Zhang AJ. Polymorphisms of interleukin-21 and interleukin-21-receptor genes confer risk for autoimmune thyroid diseases. BMC Endocr Disord. 2013;13:26.CrossRefPubMedCentralPubMed
26.
Jia HY, Zhang ZG, Gu XJ, Guo T, Cui B, Ning G, Zhao YJ. Association between interleukin 21 and Graves’ disease. Genet Mol Res. 2011;10:3338–46.CrossRefPubMed
27.
Ansel KM, Harris RB, Cyster JG. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity. 2002;16:67–76.CrossRefPubMed
28.
Ansel KM, McHeyzer-Williams LJ, Ngo VN, McHeyzer-Williams MG, Cyster JG. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J Exp Med. 1999;190:1123–34.CrossRefPubMedCentralPubMed
29.
30.
Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, Dong C. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29:138–49.CrossRefPubMedCentralPubMed
31.
Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 2008;29:127–37.CrossRefPubMed
32.
Dien BJ, Gelebart P, Anand M, Zak Z, Hegazy SA, Amin HM, Lai R. IL-21 contributes to JAK3/STAT3 activation and promotes cell growth in ALK-positive anaplastic large cell lymphoma. Am J Pathol. 2009;175:825–34.CrossRef
33.
Ganesh BB, Bhattacharya P, Gopisetty A, Prabhakar BS. Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. J Interferon Cytokine Res. 2011;31:721–31.CrossRefPubMedCentralPubMed
34.
Aust G, Krohn K, Morgenthaler NG, Schroder S, Schutz A, Edelmann J, Brylla E. Graves’ disease and Hashimoto’s thyroiditis in monozygotic twins: case study as well as transcriptomic and immunohistological analysis of thyroid tissues. Eur J Endocrinol. 2006;154:13–20.CrossRefPubMed
35.
36.
Pan D, Shin YH, Gopalakrishnan G, Hennessey J, De Groot LJ. Regulatory T cells in Graves’ disease. Clin Endocrinol (Oxf). 2009;71:587–93.CrossRef
37.
Wang S, Baidoo SE, Liu Y, Zhu C, Tian J, Ma J, Tong J, Chen J, Tang X, Xu H, Lu L. T cell-derived leptin contributes to increased frequency of T helper type 17 cells in female patients with Hashimoto’s thyroiditis. Clin Exp Immunol. 2013;171:63–8.CrossRefPubMedCentralPubMed
38.
39.
Kuchen S, Robbins R, Sims GP, Sheng C, Phillips TM, Lipsky PE, Ettinger R. Essential role of IL-21 in B cell activation, expansion, and plasma cell generation during CD4+ T cell-B cell collaboration. J Immunol. 2007;179:5886–96.CrossRefPubMed
40.
Monteleone G, Pallone F, Macdonald TT. Interleukin-21 as a new therapeutic target for immune-mediated diseases. Trends Pharmacol Sci. 2009;30:441–7.CrossRefPubMed
Metadata
Title
Elevated follicular helper T Cells and expression of IL-21 in thyroid tissues are involved in the pathogenesis of Graves’ disease
Authors
Jin Zhang
Meng Ren
Hua Zeng
Ying Guo
Zhenwu Zhuang
Zhimei Feng
Haiyan Yan
Mingtong Xu
Weiwen Liang
Chuan Yang
Hua Cheng
Helin Ding
Li Yan
Publication date
01-06-2015
Publisher
Springer US
Published in
Immunologic Research / Issue 2/2015
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-015-8647-z

Other articles of this Issue 2/2015

Immunologic Research 2/2015 Go to the issue

OriginalPaper

Development of chimeric candidate vaccine against HPV18: a proof of concept

OriginalPaper

Three conserved MyD88-recruiting TLR residues exert different effects on the human TLR4 signaling pathway

OriginalPaper

STAT4 genetic polymorphisms association with spontaneous clearance of hepatitis B virus infection

OriginalPaper

Decreased expression of microRNA-125a-3p upregulates interleukin-23 receptor in patients with Hashimoto’s thyroiditis

OriginalPaper

Single nucleotide polymorphisms in the FAM167A-BLK gene are associated with polymyositis/dermatomyositis in the Han Chinese population

Interpretive synthesis review article

Mcl-1 is vital for neutrophil survival