甲亢的分类及其免疫相关问题
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Cappa, M., Bizzarri, C. & Crea, F. Autoimmune thyroid diseases in children. J Thyroid Res 2011, 675703.
Genetic factors
------ATDs susceptibility genes 1. Immune modulating genes HLA-DR, CTLA-4, CD40, and PTPN22 2. Thyroid specific genes thyroglobulin and TSH receptor genes
Hyperthyroidism
Classification and Immune Assiciated Problems
By 郭浩
Three common disorders that cause hyperthyroidism 造成甲亢的三种常见病 • Graves disease
Causes:Autoimmune自身免疫 Thyroid-stimulating immunoglobulins甲状腺刺激性免疫球蛋白
The sensitivity of two frequently used serum anti-TSHr antibody assays is cited to be 75–96% for TBII (a competitive binding assay with TSH) and 85–100% for TSAb measurements (a bioassay of TSH receptor activation)
为了帮助保护您的隐私，PowerPoint 禁止自动下载此外部图片。若要下载并显示此图片，请单击消息栏中的 “选项”，然后单击 “启用外部内容 ”。
Harrison's Endocrinology(2nd,2010)
Toxic multinodular goiter
------Hyperthyroidism （T3 toxicosis, low TSH） ） with negative TRAb ------Enlarged thyroid gland with multiple small nodules ------Subclinical hyperthyroidism is frequently prolonged
Autoimmune Thyroiditis
------A diffusely enlarged, nontender thyroid gland ------elevated TSH (typically over 5 or 10IU/mL) ------low FT4 ------positive anti-TPO antibodies ------Lymphocytic infiltration
The Japan Endocrine Society Advance Publication doi: 10.1507/endocrj. EJ11-0202
Thyroid Autonomy
Functioning of the thyroid gland independently of the normal pituitary–thyroid negative feedback control mechanism
The Japan Endocrine Society Advance Publication doi: 10.1507/endocrj. EJ11-0202
Toxic adenoma
------Hyperthyroidism（T3 toxicosis, low TSH）with （ ） negative TRAb ------One large nodule ------Subclinical hyperthyroidism can last years
Biondi, B. & Kahaly, G. J. Nat. Rev. Endocrinol. 6, 431–443 (2010)
Pathogenesis
------Self-reactive CD4 T cells recruit cytotoxic CD8 T cells as well as autoreactive B cells into the thyroid ------Direct cytotoxicity by CD8 T cells is believed to be the main mechanism of hypothyroidism ------TBAb, anti-TPO antibodies, anti-TG antibodies, antibodies against the sodium-iodine symporter
Hale Waihona Puke Baidu
Davies, T. F. Infection and autoimmune thyroid disease. J Clin Endocrinol Metab 93, 674-6 (2008).
Relation Between Autoimmune Diseases
• Autoimmune polyglandular syndrome • Coexisting of ATD, Type 1 diabetes, Addison’s disease, celiac disease… Why and How？ ？
Cappa, M., Bizzarri, C. & Crea, F. Autoimmune thyroid diseases in children. J Thyroid Res 2011, 675703.
GD versus AT
------Common points:
Thyroid reactive T cells escape tolerance and infiltrate the thyroid; Antibodies
Causes: Nonautoimmune（同上） Activating mutations in thyrotropin receptor or G protein
Prevalence worldwide varies between 1% and 5%
Biondi, B. & Kahaly, G. J. Nat. Rev. Endocrinol. 6, 431–443 (2010)
It should be noted that 10–15% of the general population are positive for anti-TPO antibodies and that low titers (less than 1/100 by agglutination methods or less than 100IU/L by immunoassays) are less specific for ATDs
• Toxic multinodular goiter 毒性多结节性甲状腺肿
Causes: Nonautoimmune非自身免疫 Activating mutations in thyrotropin receptor or G protein 促甲状腺素受体或者G蛋白基因的激活性突变
• Toxic adenoma 毒性腺瘤
TSHR (G蛋白偶联受体) gene mutations:
------The majority of the mutations are located in transmembrane helix (TMH) 6 and TMH 2, and several mutations are located in intracellular loop (ICL) 3. ------These domains are reported to have an important role in the basal activation of cAMP production.
------Differences:
AT——apoptosis of thyroid cells GD——activation of TSHr-reactive B cells (TSAb)
------Coexist, Transformation ------Common and different gene loci
Autoimmune Thyroid Disease
Graves disease
------A diffusely enlarged, nontender thyroid gland ------Lymphocytic infiltration ------Subclinical hyperthyroidism is of short duration ------Severe clinical manifestations of thyrotoxicosis ------Accumulation of glycosaminoglycans in the orbital connective tissue and skin ------T3 and T4 toxicosis with low TSH
Biondi, B. & Kahaly, G. J. Nat. Rev. Endocrinol. 6, 431–443 (2010)
N ENGL J MED 364;20 NEJM.ORG MAY 19, 2011
Pathogenesis
------Environmental and Genetic Factors ------TSH receptor stimulating immunoglobulins (TSIs or TSAb)
Lehuen, A., Diana, J., Zaccone, P. & Cooke, A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 10, 501-13（2010）.
Immune Tolerance
Elimination, via apoptosis, of T and B cells with a high avidity to self ------ Thymus or peripheral tissues Immunosuppression of Treg cells (via menbrane and soluble TGF-β) ------ Peripheral tissues
T1DM
定义：Ⅰ型糖尿病是以选择性胰岛β细胞损伤为主
要特征的一种慢性自身免疫病。其病因复杂，与 遗传因素和环境因素（如病毒等）均有关。发病 机制为Th1细胞介导的自身免疫反应 细胞介导的自身免疫反应，在CTL和非 细胞介导的自身免疫反应 特异性免疫系统细胞的参与下，造成胰岛B细胞 的损伤，进而使胰岛素合成减少，三大营养物质 代谢紊乱。
Davies, T. F. Infection and autoimmune thyroid disease. J Clin Endocrinol Metab 93, 674-6 (2008).
Immune modulating genes
------CTLA-4、PTPN22 a major negative regulator of T-cell activation ------CD40 expressed on B cells and other APCs； B-cell activation
------Others: anti-TPO antibodies, anti-TG antibodies, antibodies against the sodium-iodine symporter
Cappa, M., Bizzarri, C. & Crea, F. Autoimmune thyroid diseases in children. J Thyroid Res 2011, 675703.
Genetic factors
------ATDs susceptibility genes 1. Immune modulating genes HLA-DR, CTLA-4, CD40, and PTPN22 2. Thyroid specific genes thyroglobulin and TSH receptor genes
Hyperthyroidism
Classification and Immune Assiciated Problems
By 郭浩
Three common disorders that cause hyperthyroidism 造成甲亢的三种常见病 • Graves disease
Causes:Autoimmune自身免疫 Thyroid-stimulating immunoglobulins甲状腺刺激性免疫球蛋白
The sensitivity of two frequently used serum anti-TSHr antibody assays is cited to be 75–96% for TBII (a competitive binding assay with TSH) and 85–100% for TSAb measurements (a bioassay of TSH receptor activation)
为了帮助保护您的隐私，PowerPoint 禁止自动下载此外部图片。若要下载并显示此图片，请单击消息栏中的 “选项”，然后单击 “启用外部内容 ”。
Harrison's Endocrinology(2nd,2010)
Toxic multinodular goiter
------Hyperthyroidism （T3 toxicosis, low TSH） ） with negative TRAb ------Enlarged thyroid gland with multiple small nodules ------Subclinical hyperthyroidism is frequently prolonged
Autoimmune Thyroiditis
------A diffusely enlarged, nontender thyroid gland ------elevated TSH (typically over 5 or 10IU/mL) ------low FT4 ------positive anti-TPO antibodies ------Lymphocytic infiltration
The Japan Endocrine Society Advance Publication doi: 10.1507/endocrj. EJ11-0202
Thyroid Autonomy
Functioning of the thyroid gland independently of the normal pituitary–thyroid negative feedback control mechanism
The Japan Endocrine Society Advance Publication doi: 10.1507/endocrj. EJ11-0202
Toxic adenoma
------Hyperthyroidism（T3 toxicosis, low TSH）with （ ） negative TRAb ------One large nodule ------Subclinical hyperthyroidism can last years
Biondi, B. & Kahaly, G. J. Nat. Rev. Endocrinol. 6, 431–443 (2010)
Pathogenesis
------Self-reactive CD4 T cells recruit cytotoxic CD8 T cells as well as autoreactive B cells into the thyroid ------Direct cytotoxicity by CD8 T cells is believed to be the main mechanism of hypothyroidism ------TBAb, anti-TPO antibodies, anti-TG antibodies, antibodies against the sodium-iodine symporter
Hale Waihona Puke Baidu
Davies, T. F. Infection and autoimmune thyroid disease. J Clin Endocrinol Metab 93, 674-6 (2008).
Relation Between Autoimmune Diseases
• Autoimmune polyglandular syndrome • Coexisting of ATD, Type 1 diabetes, Addison’s disease, celiac disease… Why and How？ ？
Cappa, M., Bizzarri, C. & Crea, F. Autoimmune thyroid diseases in children. J Thyroid Res 2011, 675703.
GD versus AT
------Common points:
Thyroid reactive T cells escape tolerance and infiltrate the thyroid; Antibodies
Causes: Nonautoimmune（同上） Activating mutations in thyrotropin receptor or G protein
Prevalence worldwide varies between 1% and 5%
Biondi, B. & Kahaly, G. J. Nat. Rev. Endocrinol. 6, 431–443 (2010)
It should be noted that 10–15% of the general population are positive for anti-TPO antibodies and that low titers (less than 1/100 by agglutination methods or less than 100IU/L by immunoassays) are less specific for ATDs
• Toxic multinodular goiter 毒性多结节性甲状腺肿
Causes: Nonautoimmune非自身免疫 Activating mutations in thyrotropin receptor or G protein 促甲状腺素受体或者G蛋白基因的激活性突变
• Toxic adenoma 毒性腺瘤
TSHR (G蛋白偶联受体) gene mutations:
------The majority of the mutations are located in transmembrane helix (TMH) 6 and TMH 2, and several mutations are located in intracellular loop (ICL) 3. ------These domains are reported to have an important role in the basal activation of cAMP production.
------Differences:
AT——apoptosis of thyroid cells GD——activation of TSHr-reactive B cells (TSAb)
------Coexist, Transformation ------Common and different gene loci
Autoimmune Thyroid Disease
Graves disease
------A diffusely enlarged, nontender thyroid gland ------Lymphocytic infiltration ------Subclinical hyperthyroidism is of short duration ------Severe clinical manifestations of thyrotoxicosis ------Accumulation of glycosaminoglycans in the orbital connective tissue and skin ------T3 and T4 toxicosis with low TSH
Biondi, B. & Kahaly, G. J. Nat. Rev. Endocrinol. 6, 431–443 (2010)
N ENGL J MED 364;20 NEJM.ORG MAY 19, 2011
Pathogenesis
------Environmental and Genetic Factors ------TSH receptor stimulating immunoglobulins (TSIs or TSAb)
Lehuen, A., Diana, J., Zaccone, P. & Cooke, A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 10, 501-13（2010）.
Immune Tolerance
Elimination, via apoptosis, of T and B cells with a high avidity to self ------ Thymus or peripheral tissues Immunosuppression of Treg cells (via menbrane and soluble TGF-β) ------ Peripheral tissues
T1DM
定义：Ⅰ型糖尿病是以选择性胰岛β细胞损伤为主
要特征的一种慢性自身免疫病。其病因复杂，与 遗传因素和环境因素（如病毒等）均有关。发病 机制为Th1细胞介导的自身免疫反应 细胞介导的自身免疫反应，在CTL和非 细胞介导的自身免疫反应 特异性免疫系统细胞的参与下，造成胰岛B细胞 的损伤，进而使胰岛素合成减少，三大营养物质 代谢紊乱。
Davies, T. F. Infection and autoimmune thyroid disease. J Clin Endocrinol Metab 93, 674-6 (2008).
Immune modulating genes
------CTLA-4、PTPN22 a major negative regulator of T-cell activation ------CD40 expressed on B cells and other APCs； B-cell activation
------Others: anti-TPO antibodies, anti-TG antibodies, antibodies against the sodium-iodine symporter
Cappa, M., Bizzarri, C. & Crea, F. Autoimmune thyroid diseases in children. J Thyroid Res 2011, 675703.