Graves’ Disease: A Host Defense Mechanism Gone Awry

Kohn, Leonard D.; Napolitano, Giorgio; Singer, Dinah S.; Molteni, Monica; Scorza, Raffaella; Shimojo, Naoki; Kohno, Yoichi; Mozes, Edna; Nakazato, Minoru; Ulianich, Luca; Chung, Hai Won; Matoba, Hana; Saunier, Bertrand; Suzuki, Koichi; Schuppert, Frank; Saji, Motoyasu

doi:10.3109/08830180009088516

Cited by 30 publications

(36 citation statements)

References 62 publications

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“…Firstly, the Shimojo model supports the hypothesis proposed by Bottazzo et al more than two decades ago [25] that has since been evaluated extensively by others [26]. In their hypothesis, thyroid cells in autoimmune thyroid diseases aberrantly express MHC class II antigen and, as non-professional antigen-presenting cells, present thyroid-specific autoantigens to naïve T cells, leading to thyroid autoimmune reaction.…”

Section: Implications Of Animal Models In Disease Pathogenesissupporting

confidence: 63%

Animal Models of Graves' Hyperthyroidism

Nagayama

2005

Endocr J

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Abstract. Graves' disease is a common organ-specific autoimmune disease characterized by overstimulation of the thyroid gland with agonistic anti-thyrotropin (TSH) receptor autoantibodies, which leads to hyperthyroidism and diffuse hyperplasia of the thyroid gland. Several groups including us have recently established several animal models of Graves' hyperthyroidism using novel immunization approaches, such as in vivo expression of the TSH receptor by injecting syngeneic living cells coexpressing the TSH receptor, the major histocompatibility complex (MHC) class II antigen and a costimulatory molecule, or genetic immunization using plasmid or adenovirus vectors coding the TSH receptor. This breakthrough has made it possible for us to study the pathogenesis of Graves' disease in more detail and has provided important insights into our understanding of disease pathogenesis. The important new findings that have emerged include: (i) the shed A subunit being the major autoantigen for TSAb, (ii) the significant role played by dendritic cells (DCs) as professional antigen-presenting cells in initiating disease development, (iii) contribution of MHC and particularly non-MHC genetic backgrounds in disease susceptibility, and (iv) influence of some particular infectious pathogens on disease development. However, the data regarding Th1/Th2 balance of TSH receptor-specific immune response or the association of Graves' hyperthyroidism with intrathyroidal lymphocytic infiltration are rather inconsistent. Future studies with these models will hopefully lead to better understanding of disease pathogenesis and help develop novel strategies for treatment and ultimately prevention of Graves' disease in humans.

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Section: Implications Of Animal Models In Disease Pathogenesissupporting

confidence: 63%

Animal Models of Graves' Hyperthyroidism

Nagayama

2005

Endocr J

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“…Cytotoxic T cells such as NK cells could have an early regulatory role in innate and adaptive immunity. HLA class I molecules are recognized by NK cells through killer immunoglobulin-like receptors (KIR) [17,18]. Recent studies have indicated that an HLA-class I/KIR complex is associated with the pathogenesis and susceptibility of type-1 diabetes mellitus [19,20,21], psoriatic arthritis [22], ankylosing spondylitis [23], hepatitis B [24], and hepatitis C [25].…”

Section: Discussionmentioning

confidence: 99%

Association of HLA Alleles with Autoimmune Thyroid Disease in Korean Children

et al. 2011

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Backgrounds: Data regarding genetics of Hashimoto’s disease (HD) and Graves’ disease (GD) in Korean children are lacking. Methods: 73 patients with autoimmune thyroid disease (AITD; HD 32, GD 41) were recruited. We analyzed human leukocyte antigen (HLA) class I and HLA-DRB1 by PCR-SSP, and compared them with those of 159 controls. Results: In AITD, the allele frequencies of HLA-A*02, -B*46, -Cw*01 and -DRB1*08 were higher and those of HLA-A*30, -B*07, -Cw*07 and -DRB1*01 were lower than in controls. In HD, those of HLA-B*46 and -Cw*01 were higher and those of HLA-DRB1*01 and -Cw*07 were lower than in controls. In GD, those of HLA-A*02, -B*46, -Cw*01 and -DRB1*08 were higher and those of HLA-DRB1*07 and -Cw*07 were lower than in controls. Between HD and GD, there were no significant differences in allele frequencies. The risk of AITD in the presence of both HLA-B*46 and -Cw*01 is higher than in the presence of either allele alone. Conclusion: The susceptible and protectable alleles in HD are similar to those in GD. Coexistence of HLA-B*46 and -Cw*01 may be a genetic gene marker for early-onset AITD in Koreans.

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“…Finally, 90K induces MHC class I expression (15,16), and the concomitant suppression of both 90K and MHC class I by TSH has been suggested as a mechanism to preserve selftolerance and prevent autoimmunity (16,25,26,28). On the basis of these considerations, we suggest that induction of 90K by USFs may be another mechanism through which these transcription factors activate immune responses.…”

Section: Discussionmentioning

confidence: 91%

Upstream Stimulatory Factor Regulates Constitutive Expression and Hormonal Suppression of the 90K (Mac-2BP) Protein

et al. 2007

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We previously reported that hormones important for the normal growth and function of FRTL-5 rat thyroid cells, TSH, or its cAMP signal plus insulin or IGF-I, could transcriptionally suppress constitutive and ␥-interferon (IFN)-increased synthesis of the 90K protein (also known as Mac-2BP). Here we cloned the 5-flanking region of the rat 90K gene and identified a minimal promoter containing an interferon response element and a consensus E-box or upstream stimulator factor (USF) binding site, which are highly conserved in both the human and murine genes. We show that suppression of constitutive and ␥-IFN- The function of 90K is not known, although several lines of evidence support a role for the protein in the host immune defense. First, 90K is a member of a family of transmembrane or secreted glycoproteins containing a scavenger receptor, cysteine-rich domain (9, 10). Proteins containing a scavenger receptor, cysteine-rich domain are expressed by immunocompetent cells (B and T lymphocytes, macrophages) and are implicated in immune defense (9, 11-13). Second, in vitro generation of cytotoxic effector cells (natural killer and lymphokine-activated killer) has been observed after exposure of peripheral blood mononuclear cells (PBMCs) to 90K (9). Third, 90K increases cytokine production by PBMCs (9, 12) and accessory cells (12,14). Finally, 90K increases major histocompatibility (MHC) class I antigen expression in human breast cancer cells (15).A rat 90K was recently cloned (16) and found to be homologous to human 90K (9, 10) and to mouse adherent macrophage protein (also known as CyCap, Cyclophilin C associated protein) (17,18). In rat thyroid FRTL-5 cells, 90K is increased by ␥-interferon (IFN), as in humans and mice, and acts in an autocrine or paracrine/exocrine manner to increase MHC class I (16). Hormones that regulate the growth and function of FRTL-5 cells, particularly TSH/cAMP plus insulin/IGF-I (19 -23), coordinately decrease MHC class I and 90K expression (16).The ability of TSH/cAMP plus insulin/IGF-I to decrease MHC class I (24) has been explained by a complex, interlocking array of trans factors and cis elements (25-30). In contrast, the mechanisms involved in hormonal suppression of 90K are unknown.Here we report the cloning of the 5Ј flanking region of the rat 90K gene and the identification of the critical regulatory element responsible for the suppression of 90K expression by TSH/cAMP plus insulin/IGF-I. We show that this element controls basal expression of 90K, is conserved in the human and mouse promoter, and corresponds to an E-box that is sensitive to regulation by the basic helix-loop-helix leucine zipper proteins, upstream stimulator factor (USF)-1 and -2.

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Graves’ Disease: A Host Defense Mechanism Gone Awry

Cited by 30 publications

References 62 publications

Animal Models of Graves' Hyperthyroidism

Animal Models of Graves' Hyperthyroidism

Association of HLA Alleles with Autoimmune Thyroid Disease in Korean Children

Upstream Stimulatory Factor Regulates Constitutive Expression and Hormonal Suppression of the 90K (Mac-2BP) Protein

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