CD4+ cells in autoimmune thyroid disease
Abstract
The phenomenon of autoimmunity develops as a result of the triggering factor released by damaged cells. This leads to an infiltration of CD4+ cells involved in stimulating the effector cells cytotoxicity and stimulating the humoral response. One of the most common autoimmune disorders are autoimmune thyroid diseases, including Hashimoto's thyroiditis and Graves's diseases. Helper T lymphocytes, which are divided into Th1, Th2, Tregs, and the relatively new groups Th17, Th22, and Th9, are involved in the pathogenesis of AITD. CD4+ cell subtypes mature and differentiate by specific transcription factors and in a specific interleukin environment. Not only are Th1 and Th2 cells involved in the development of AITD, but also Th17, Th22, and Th9 lymphocytes and their correlation to Tregs lymphocytes. The plasticity of the CD4+ cells is very important, affecting the balance between these cells, as well the factors modulating their phenotypic variability. Patients with AITD have an increased percentage of Th17, Th22, and Th9 cells as well as defective function of Tregs lymphocytes. The balance between Th17 cells (and also other cytotoxic T cells) and Treg cells is also very important. Understanding the role of CD4 cells in the pathogenesis of AITD may be important not only for the development of the knowledge, but also for determining therapeutic targets.
Keywords: CD4+ T cellTh lymphocytesTreg lymphocytesautoimmune thyroid disease
References
- Locatelli F, Rondelli D, Burgio GR. Tolerance and hematopoietic stem cell transplantation 50 years after Burnet's theory. Exp Hematol. 2000; 28(5): 479–489.
- Janeway CA, Janeway CA. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989; 54 Pt 1(9): 1–13.
- Broggi A, Tan Y, Granucci F, et al. Microbe- and danger-induced inflammation. Mol Immunol. 2015; 63(2): 127–133.
- Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994; 12: 991–1045.
- Pradeu T, Cooper EL. The danger theory: 20 years later. Front Immunol. 2012; 3: 287.
- Gonzalez-Diaz SN, Sanchez-Borges M, Rangel-Gonzalez DM, et al. Chronic urticaria and thyroid pathology. World Allergy Organ J. 2020; 13(3): 100101.
- Nanba T, Watanabe M, Inoue N, et al. Increases of the Th1/Th2 cell ratio in severe Hashimoto's disease and in the proportion of Th17 cells in intractable Graves' disease. Thyroid. 2009; 19(5): 495–501.
- Kristensen B. Regulatory B and T cell responses in patients with autoimmune thyroid disease and healthy controls. Dan Med J. 2016; 63(2): B5177.
- Li Q, Wang B, Mu K, et al. The pathogenesis of thyroid autoimmune diseases: New T lymphocytes - Cytokines circuits beyond the Th1-Th2 paradigm. J Cell Physiol. 2019; 234(3): 2204–2216.
- Antonelli A, Ferrari SM, Corrado A, et al. Autoimmune thyroid disorders. Autoimmun Rev. 2015; 14(2): 174–180.
- González-Amaro R, Marazuela M. T regulatory (Treg) and T helper 17 (Th17) lymphocytes in thyroid autoimmunity. Endocrine. 2016; 52(1): 30–38.
- Espinosa JR, Wheaton JD, Ciofani M. In Vitro Differentiation of CD4 T Cell Effector and Regulatory Subsets. Methods Mol Biol. 2020; 2111: 79–89.
- Maier E, Duschl A, Horejs-Hoeck J. STAT6-dependent and -independent mechanisms in Th2 polarization. Eur J Immunol. 2012; 42(11): 2827–2833.
- Gołąb J, Jakóbisiak M, Lasek W. Immunologia. VII, dodruk 2. Wydawnictwo Naukowe PWN, Warszawa 2017.
- Yin L, Zeng C, Yao J, et al. Emerging Roles for Noncoding RNAs in Autoimmune Thyroid Disease. Endocrinology. 2020; 161(8).
- Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol. 2010; 28: 445–489.
- Piekarski R, Szewczyk L. Rola limfocytów Th17 w cukrzycy typu 1. Pediatric Endocrinol. 2011; 4(37).
- Bedoya SK, Lam B, Lau K, et al. Th17 cells in immunity and autoimmunity. Clin Dev Immunol. 2013; 2013: 986789.
- Romagnani S. Human Th17 cells. Arthritis Res Ther. 2008; 10(2): 206.
- Isailovic N, Daigo K, Mantovani A, et al. Interleukin-17 and innate immunity in infections and chronic inflammation. J Autoimmun. 2015; 60: 1–11.
- Murga-Zamalloa C, Wilcox RA. GATA-3 in T-cell lymphoproliferative disorders. IUBMB Life. 2020; 72(1): 170–177.
- Tindemans I, Serafini N, Di Santo JP, et al. GATA-3 function in innate and adaptive immunity. Immunity. 2014; 41(2): 191–206.
- Maier E, Duschl A, Horejs-Hoeck J. STAT6-dependent and -independent mechanisms in Th2 polarization. Eur J Immunol. 2012; 42(11): 2827–2833.
- Aggarwal S, Ghilardi N, Xie MH, et al. Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem. 2003; 278(3): 1910–1914.
- Rouvier E, Luciani MF, Mattéi MG, et al. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol. 1993; 150(12): 5445–5456.
- Sergejeva S, Lindén A. Impact of IL-17 on cells of the monocyte lineage in health and disease. Endocr Metab Immune Disord Drug Targets. 2009; 9(2): 178–186.
- Harrington LE, Hatton RD, Mangan PR, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005; 6(11): 1123–1132.
- Dumoutier L, Van Roost E, Ameye G, et al. IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes Immun. 2000; 1(8): 488–494.
- Beurel E, Lowell JA, Jope RS, et al. Th17 cells in depression. Brain Behav Immun. 2018; 69: 28–34.
- McGeachy MJ, Bak-Jensen KS, Chen Yi, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007; 8(12): 1390–1397.
- Burgler S, Ouaked N, Bassin C, et al. Differentiation and functional analysis of human T(H)17 cells. J Allergy Clin Immunol. 2009; 123(3): 588–95, 595.e1.
- Sutton CE, Lalor SJ, Sweeney CM, et al. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009; 31(2): 331–341.
- Ochs HD, Oukka M, Torgerson TR. TH17 cells and regulatory T cells in primary immunodeficiency diseases. J Allergy Clin Immunol. 2009; 123(5): 977–83; quiz 984.
- Yasuda K, Takeuchi Y, Hirota K, et al. The pathogenicity of Th17 cells in autoimmune diseases. Semin Immunopathol. 2019; 41(3): 283–297.
- Shao S, Yu X, Shen L. Autoimmune thyroid diseases and Th17/Treg lymphocytes. Life Sci. 2018; 192: 160–165.
- Jogdand GM, Mohanty S, Devadas S. Regulators of Tfh Cell Differentiation. Front Immunol. 2016; 7: 520.
- Law H, Venturi V, Kelleher A, et al. Tfh Cells in Health and Immunity: Potential Targets for Systems Biology Approaches to Vaccination. Int J Mol Sci. 2020; 21(22).
- Veldhoen M, Uyttenhove C, van Snick J, et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008; 9(12): 1341–1346.
- Van Snick J, Goethals A, Renauld JC, et al. Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40). J Exp Med. 1989; 169(1): 363–368.
- He Y, Dong L, Cao Y, et al. IL-9 and Th9 Cells in Tumor Immunity. Adv Exp Med Biol. 2020; 1240: 35–46.
- Rojas-Zuleta WG, Vásquez G. Th9 lymphocytes: A recent history from IL-9 to its potential role in rheumatic diseases. Autoimmun Rev. 2016; 15(7): 649–655.
- Trifari S, Spits H. IL-22-producing CD4+ T cells: middle-men between the immune system and its environment. Eur J Immunol. 2010; 40(9): 2369–2371.
- Jia L, Wu C. The biology and functions of Th22 cells. Adv Exp Med Biol. 2014; 841: 209–230.
- Lowes MA, Suárez-Fariñas M, Krueger JG. Immunology of psoriasis. Annu Rev Immunol. 2014; 32: 227–255.
- Tian T, Yu S, Ma D. Th22 and related cytokines in inflammatory and autoimmune diseases. Expert Opin Ther Targets. 2013; 17(2): 113–125.
- Chen Z, Wang Y, Ding Xi, et al. The proportion of peripheral blood Tregs among the CD4+ T cells of autoimmune thyroid disease patients: a meta-analysis. Endocr J. 2020; 67(3): 317–326.
- Sakaguchi S, Mikami N, Wing JB, et al. Regulatory T Cells and Human Disease. Annu Rev Immunol. 2020; 38: 541–566.
- Rodríguez-Muñoz A, Vitales-Noyola M, Ramos-Levi A, et al. Levels of regulatory T cells CD69(+)NKG2D(+)IL-10(+) are increased in patients with autoimmune thyroid disorders. Endocrine. 2016; 51(3): 478–489.
- O'Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010; 327(5969): 1098–1102.
- Zgliczyński W. Wielka Interna. Endokrynologia. Vol II. II. Medical Tribune, Warszawa 2020.
- Pyzik A, Grywalska E, Matyjaszek-Matuszek B, et al. Immune disorders in Hashimoto's thyroiditis: what do we know so far? J Immunol Res. 2015; 2015: 979167.
- Qin Q, Liu P, Liu L, et al. The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto's thyroiditis but not in Graves' disease. Braz J Med Biol Res. 2012; 45(12): 1202–1208.
- Morshed SA, Latif R, Davies TF. Delineating the autoimmune mechanisms in Graves' disease. Immunol Res. 2012; 54(1-3): 191–203.
- Nanba T, Watanabe M, Akamizu T, et al. The -590CC genotype in the IL4 gene as a strong predictive factor for the development of hypothyroidism in Hashimoto disease. Clin Chem. 2008; 54(3): 621–623.
- Fouser LA, Wright JF, Dunussi-Joannopoulos K, et al. Th17 cytokines and their emerging roles in inflammation and autoimmunity. Immunol Rev. 2008; 226: 87–102.
- Korn T, Oukka M, Kuchroo V, et al. Th17 cells: effector T cells with inflammatory properties. Semin Immunol. 2007; 19(6): 362–371.
- Karczewski J, Mazur M, Rychlewska-Hańczewska A, et al. [Role of Th17 lymphocytes in pathogenesis of colorectal cancer]. Postepy Hig Med Dosw (Online). 2014; 68: 42–47.
- Hus I, Maciag E, Roliński J. [The role of Th17 cells in anti-cancer immunity]. Postepy Hig Med Dosw (Online). 2010; 64: 244–250.
- Shi Y, Wang H, Su Z, et al. Differentiation imbalance of Th1/Th17 in peripheral blood mononuclear cells might contribute to pathogenesis of Hashimoto's thyroiditis. Scand J Immunol. 2010; 72(3): 250–255.
- Figueroa-Vega N, Alfonso-Pérez M, Benedicto I, et al. Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto's thyroiditis. J Clin Endocrinol Metab. 2010; 95(2): 953–962.
- Zake T, Skuja S, Kalere I, et al. Upregulated tissue expression of T helper (Th) 17 pathogenic interleukin (IL)-23 and IL-1β in Hashimoto's thyroiditis but not in Graves' disease. Endocr J. 2019; 66(5): 423–430.
- Li C, Yuan J, Zhu YF, et al. Imbalance of Th17/Treg in Different Subtypes of Autoimmune Thyroid Diseases. Cell Physiol Biochem. 2016; 40(1-2): 245–252.
- Vitales-Noyola M, Ramos-Levi AM, Martínez-Hernández R, et al. Pathogenic Th17 and Th22 cells are increased in patients with autoimmune thyroid disorders. Endocrine. 2017; 57(3): 409–417.
- Hayashi F, Watanabe M, Nanba T, et al. Association of the -31C/T functional polymorphism in the interleukin-1beta gene with the intractability of Graves' disease and the proportion of T helper type 17 cells. Clin Exp Immunol. 2009; 158(3): 281–286.
- Zheng Li, Ye P, Liu C. The role of the IL-23/IL-17 axis in the pathogenesis of Graves' disease. Endocr J. 2013; 60(5): 591–597.
- Ciccia F, Guggino G, Rizzo A, et al. Potential involvement of IL-9 and Th9 cells in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford). 2015; 54(12): 2264–2272.
- Yang Ji, Li Q, Yang X, et al. Interleukin-9 Is Associated with Elevated Anti-Double-Stranded DNA Antibodies in Lupus-Prone Mice. Mol Med. 2015; 21: 364–370.
- Elyaman W, Khoury SJ. Th9 cells in the pathogenesis of EAE and multiple sclerosis. Semin Immunopathol. 2017; 39(1): 79–87.
- Guggino G, Lo Pizzo M, Di Liberto D, et al. Interleukin-9 over-expression and T helper 9 polarization in systemic sclerosis patients. Clin Exp Immunol. 2017; 190(2): 208–216.
- Zivancevic-Simonovic S, Mihaljevic O, Majstorovic I, et al. Cytokine production in patients with papillary thyroid cancer and associated autoimmune Hashimoto thyroiditis. Cancer Immunol Immunother. 2015; 64(8): 1011–1019.
- Chen J, Guan L, Tang L, et al. T Helper 9 Cells: A New Player in Immune-Related Diseases. DNA Cell Biol. 2019; 38(10): 1040–1047.
- Peng Di, Xu B, Wang Ye, et al. A high frequency of circulating th22 and th17 cells in patients with new onset graves' disease. PLoS One. 2013; 8(7): e68446.
- Bai X, Sun J, Wang W, et al. Increased differentiation of Th22 cells in Hashimoto's thyroiditis. Endocr J. 2014; 61(12): 1181–1190.
- Vitales-Noyola M, Serrano-Somavilla A, Martínez-Hernández R, et al. Patients With Autoimmune Thyroiditis Show Diminished Levels and Defective Suppressive Function of Tr1 Regulatory Lymphocytes. J Clin Endocrinol Metab. 2018; 103(9): 3359–3367.
- Marazuela M, García-López MA, Figueroa-Vega N, et al. Regulatory T cells in human autoimmune thyroid disease. J Clin Endocrinol Metab. 2006; 91(9): 3639–3646.
- Rodríguez-Muñoz A, Vitales-Noyola M, Ramos-Levi A, et al. Levels of regulatory T cells CD69(+)NKG2D(+)IL-10(+) are increased in patients with autoimmune thyroid disorders. Endocrine. 2016; 51(3): 478–489.
- Jadidi-Niaragh F, Mirshafiey A. The deviated balance between regulatory T cell and Th17 in autoimmunity. Immunopharmacol Immunotoxicol. 2012; 34(5): 727–739.
- Qin J, Zhou J, Fan C, et al. Increased Circulating Th17 but Decreased CD4Foxp3 Treg and CD19CD1dCD5 Breg Subsets in New-Onset Graves' Disease. Biomed Res Int. 2017; 2017: 8431838.
- Veldhoen M, Hocking RJ, Atkins CJ, et al. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006; 24(2): 179–189.
- Valmori D, Raffin C, Raimbaud I, et al. Human RORγt+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors. Proc Natl Acad Sci U S A. 2010; 107(45): 19402–19407.
- Cosmi L, Maggi L, Santarlasci V, et al. T helper cells plasticity in inflammation. Cytometry A. 2014; 85(1): 36–42.
![](https://journals.viamedica.pl/plugins/generic/popups/images/icons/close.png)