The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: An association analysis in Caucasian and Japanese cohorts

Ban, Yoshiyuki; Tozaki, Teruaki; Tobe, Takashi; Ban, Yoshio; Jacobson, Eric S.; Concepcion, Erlinda; Tomer, Yaron

doi:10.1016/j.jaut.2007.02.016

Cited by 132 publications

(88 citation statements)

References 56 publications

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“…Many peripheral tolerance mechanisms, such as regulatory T cells and the danger signal theory, have been described in both animal modles and humna (22)(23)(24)(25)(26)(27). Most, if not all, of those mechanisms prevent autoimmune diseases by manipulation of naïve self-reactive T cells.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

Robertson

Arends

et al. 2008

Journal of Autoimmunity

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Different susceptibility to anti-GBM glomerulonephritis (GN) among animal strains has been reported. Using our rat model for T cell-mediated anti-GBM GN, this study initiated an investigation on the mechanism related with GN-susceptibility. Anti-GBM GN was induced either though immunization with the nephritogenic T cell epitope pCol(28-40) from Col4α3NC1 or through the transfer of specific T cells. WKY rats were highly susceptible to GN while immuno-compatible LEW rats were GN-resistant. GN-resistance in LEW rats was not associated immune response to pCol (28-40). First, both strains mounted a Th1 T cell response to pCol(28-40) with identical specificities; transfer of T cells from LEW to WKY rats induced glomerular injury. Second, co-transfer of antibody from WKY to LEW failed to induce GN. Time-course studies revealed that LEW rats did develop T cell-mediated inflammation in glomeruli at early stages similar to WKY rats, as evidenced by histopathology, proteinuria, CD4 + T cell infiltration in glomeruli, and glomerular expression of inflammatory molecules. However, glomerular inflammation in LEW rats was transient followed by a full recovery. Thus, GN-resistance in LEW rats was due to its ability to contain early T cell-mediated autoimmune glomerular damage. Our model may reveal a potential tolerance mechanism after autoimmune tissue damage has been initiated.

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Section: Discussionmentioning

confidence: 99%

Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

Robertson

Arends

et al. 2008

Journal of Autoimmunity

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“…Mutations in FOXP3 result in the fatal immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Polymorphisms in FOXP3 have been associated with AITD in Caucasians (especially with Graves' disease developing below the age of 30 years) but not in Japanese (29,30). The location of FOXP3 on the X chromosome might contribute to the female preponderance of AITD.…”

Section: Genetic Factorsmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

Effraimidis

Wiersinga

2014

European Journal of Endocrinology

289

196

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The last 10 years have seen some progress in understanding the etiology of autoimmune thyroid disease (AITD). The female preponderance can now be explained -at least in part -by fetal microchimerism and X-chromosome inactivation. The number of identified susceptibility genes for AITD is increasing (among others now including TSHR, TG, HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, and FOXP3), but these genes together probably do not explain more than about 10% of the heritability of AITD. As twin studies indicate that genes contribute for 70% of AITD, it follows that there must be many more loci, each of them contributing a little. While the genetic studies have clarified why various autoimmune diseases so often cluster in the same patient, the molecular mechanism of action of these genetic polymorphisms (frequently located in introns) has hardly been explained. Polymorphisms in AITD susceptibility genes may become helpful in clinical practice, e.g. in assessing risk of recurrent Graves' hyperthyroidism (GH) after a course of antithyroid drugs. Moderate alcohol intake decreases the risk on overt GH and overt Hashimoto's hypothyroidism. Current smokers -as well known -are at increased risk for Graves' disease, but -surprisingly -at diminished risk for Hashimoto's thyroiditis. Low selenium and low vitamin D levels might increase the risk of developing AITD, but data are still inconclusive. Current options for preventive interventions in subjects at risk to develop AITD are very limited.

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“…It has been documented that regulatory T (Treg) cells play an important role in preventing autoimmune responses and are involved in the maintenance of homeostatic mechanisms that suppress autoreactive T cell proliferation and promote autoreactive T cell anergy (3)(4)(5). Natural CD4 + CD25 + Treg cells, which are the major component of Treg cells, develop in the thymus and represent a subpopulation of ∼10% of the peripheral CD4 + T cells (6).…”

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confidence: 99%

Impairment of Regulatory Capacity of CD4+CD25+ Regulatory T Cells Mediated by Dendritic Cell Polarization and Hyperthyroidism in Graves’ Disease

Mao

Shu

Xiao

et al. 2011

The Journal of Immunology

126

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Graves’ disease (GD) is one of the most common autoimmune diseases. The immune dysfunction in GD involves the generation of thyroid-stimulating hormone receptor (TSHR) autoantibodies that presumably arise consequent to interactions among dendritic cells (DCs), T cells, and regulatory T (Treg) cells. However, the immunological mechanisms of interactions between them that lead to the induction and regulation of this autoimmune disease are poorly defined. In this study, we investigated whether DCs are the main cause of the defective activity of Treg cells in GD patients. We found a significant decrease in the percentage of circulating CD4+CD25+FOXP3+ Treg cells in untreated GD patients (uGD), which was negatively correlated with the concentration of TSHR autoantibodies. uGD-derived DCs were polarized to increase the number of plasmacytoid DCs (pDCs) and conferred the ability to abrogate the suppressive function of Treg cells through inducing apoptosis of CD4+CD25+ Treg cells in an IFN-α–dependent manner, and elevated thyroid hormones further exacerbated the effect. The nucleotide UDP, which inhibits IFN-α secretion of pDCs through P2Y6 receptor signaling, restored the suppressive function of CD4+CD25+ Treg cells. Collectively, uGD-derived DCs through pDC polarization and elevated thyroid hormones act in concert to impair the regulatory capacity of Treg cells, facilitating the production of TSHR autoantibodies in the pathogenesis of GD.

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The regulatory T cell gene FOXP3 and genetic susceptibility to thyroid autoimmunity: An association analysis in Caucasian and Japanese cohorts

Cited by 132 publications

References 56 publications

Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

Spontaneous recovery from early glomerular inflammation is associated with resistance to anti-GBM glomerulonephritis: tolerance and autoimmune tissue injury

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

Impairment of Regulatory Capacity of CD4+CD25+ Regulatory T Cells Mediated by Dendritic Cell Polarization and Hyperthyroidism in Graves’ Disease

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