臺灣博碩士論文加值系統

背景：干擾素調節因子-第一型干擾素(type 1 IFN)- B細胞活化因子?BAFF)的訊息傳導與自體免疫疾病的發病有關，但是，這訊息路徑對自體甲狀腺免疫疾病?AITD?的發病與臨床表徵的影響並不清楚，因此需要進一步去闡明。第八干擾素調節因子?IRF8)，可調控第一型干擾素，它的基因變異，被認為與紅斑性狼瘡及多發性硬化症的發病有關。同時，B細胞活化因子?BAFF)，被第一型干擾素調控，與B細胞功能有關，而它的基因多型性也被發現與紅斑性狼瘡、類風溼性關節炎、乾燥症有關。在本研究中，我們主要著墨在IRF8-type 1 IFN-BAFF的訊息路徑。我們探討中國人IRF8的基因多型性rs17445836 and rs2280381，與BAFF的基因多型性rs1041569 and rs2893321與AITD的相關性。同時，我們也同時探討血清BAFF與 AITD的相關性。
研究方法與材料：共有葛瑞夫茲氏疾病(GD) 278人，橋本氏甲狀腺炎?HT?55人，健康者252人納入IRF8的基因多型性研究。GD 319人，HT83人，健康者369人，收入BAFF的基因多型性研究。另外，我們也收集了170個GD病人，51 HT患者，與124健康者的血清進行血中BAFF蛋白質的分析。我們使用聚合?連鎖反應-限制?片段長度多型性方法與直接定序來決定基因型。我們也測量了病人發病時的甲狀腺功能與甲狀腺自體抗體，包括甲狀腺刺激素自體抗體 (TSHRAb)，抗微粒體抗體(AmiA)，與抗甲狀腺球蛋白抗體(ATA)。
結果：在IRF8的研究中，我們發現HT的病人比之健康者的rs17445836有較低比例的的GA genotype與 A allele(p = 0.028， odds ratio (OR) = 4.71 and p = 0.022， OR = 4.40)。rs17445836 與 rs2280381都與AmiA的產生有關。另外，rs17445836在AITD中與AmiA的濃度有關。在BAFF的研究中，我們發現GD與健康者(p = 0.013， OR = 0.76， and p = 0.017， OR = 0.68)及AITD與健康者(p = 0.009， OR = 0.76 and，p = 0.014， OR = 0.69)的rs2893321的G allele 與AG+GG genotype比例不同。在男性中，rs2893321的AA genotype伴隨著較低濃度的TSHRAb。在男性中，rs2893321的AA genotype伴隨著單一種抗體而女性則較易伴隨這兩種抗體。另外，我們發現血清BAFF在GD、HT及AITD的病人中是升高的。在女性中，血清BAFF與TSHRAb(r = 0.238， p = 0.018) ， AmiA(p = 0.038) ， 及ATA(p = 0.025)濃度都有相關。此外，在女性的active GD中，血清BAFF與游離甲狀腺素(r = 0.430， p = 0.004)及TSHRAb(r = 0.495, p = 0.001)有關，但在inactive GD則無相關。
結論：所有基因多型性與血清蛋白質的研究都高度暗示IRF8-type 1 IFN-BAFF的訊息路徑參與了AITD的發病機轉，這個路徑的破壞有可能誘發AITD或改變AITD的臨床表徵，而這有可能是可以被性荷爾蒙調控的。這些結果提供了未來可以從針對IRF8-type 1 IFN-BAFF的訊息路徑的免疫介入治療AITD病人的重要訊息。

Background: Interferon regulatory factors-type 1 interferon (type 1 IFN)-B-Lymphocyte activating factor (BAFF) signature has been linked to the pathogenesis of autoimmune disease. However, the impact of the signaling pathway on the occurrence and clinical features of autoimmune thyroid disease (AITD) is still unclear and required to be elucidated. The genetic variant of the INF regulatory factor 8 (IRF8), a type 1 INF regulator, is associated with susceptibility to systemic lupus erythematosus (SLE) and multiple sclerosis. At the same time, the B-lymphocyte-activating factor (BAFF) is associated with B-cell functions and is modulated by type 1 INF, and gene polymorphisms of the BAFF have been also linked to SLE, rheumatoid arthritis and Sj?gren''s syndrome. In this study, we mainly focused on the immuno-modulators involved in the IRF8-type 1 IFN-BAFF signaling pathway. We investigated possible associations of the IRF8 polymorphisms (SNP), rs17445836 and rs2280381, and two BAFF SNPs, rs1041569 and rs2893321,with AITD in an ethnic Chinese population. At the same time, we also investigated the association of serum BAFF levels with AITD.
Material and Methods: In total, 278 Graves’ disease (GD) and 55 Hashimoto’s thyroiditis (HT) patients, and 252 healthy controls were enrolled for IRF8 SNP analysis. 319 GD, 83 HT patients, and 369 healthy controls were recruited in the BAFF SNP analysis. At the same time, we collected serum samples from 221 patients with AITD (170 patients with GD, 51 patients with HT) and 124 healthy controls to measure serum BAFF levels. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing were used for genotyping. Thyroid function and thyroid autoantibody (TAb) levels, including of thyroid-stimulating hormone receptor antibody (TSHRAb), anti-microsomal antibody (AmiA) and antithyroglobulin antibody (ATA), were measured at baseline.
Results: In IRF8 analysis, significantly lower frequencies of the GA genotype and A allele of rs17445836 were found in the HT group than in the control group (p = 0.028, odds ratio (OR) = 4.71 and p = 0.022, OR = 4.40, respectively). Both rs17445836 and rs2280381 were associated with the presence of an AmiA. Moreover, rs17445836 was associated the level of AmiA in AITD. In BAFF study, we found there was a significant difference in frequencies of the G allele and AG+GG genotype of rs2893321 between the GD and control groups (p = 0.013, OR = 0.76, and p = 0.017, OR = 0.68, respectively) and between the AITD and control groups (p = 0.009, OR = 0.76, and, p = 0.014, OR = 0.69, respectively). The AA genotype of rs2893321 was associated with low titers of TSHRAb (p = 0.015) in males but not in females. The AA genotype of rs2893321 was associated with the presence of two different types of TAb (TSHRAb and Hashimoto’s autoantibody (ATA or AmiA) in females and with that of one type in males. In serum BAFF protein analysis, we found that serum BAFF levels were higher in the GD, HT, and AITD groups than in the control group. Significant correlations were observed between BAFF and TSHRAb levels (r = 0.238, p = 0.018), between BAFF and AmiA levels (p = 0.038), and between BAFF and ATA titers (p = 0.025) in women but not in men. In addition, serum BAFF levels were significantly associated with free thyroxine (r = 0.430, p = 0.004) and TSHRAb (r = 0.495, p = 0.001) levels in women with active GD but not in those with inactive GD.
Conclusions: All of the genetic and serum protein results highly suggested that the IRF8-type 1 IFN-BAFF signaling could participate in the pathogenesis of AITD and the disruption of the pathway could trigger the AITD and modulate the phenotypes of AITD, which could be controlled by sex hormone. The results offer the important information that that AITD patients might benefit from the immunological intervention targeting to IRF8-type 1 IFN-BAFF pathway.

1. Abstract in Chinese-------------------------------------------------------------------i-ii
2. Abstract in English--------------------------------------------------------------------iii-v
3. Introduction----------------------------------------------------------------------------1-7
3.1. The synthesis of thyroid hormone and thyroid autoantigen------------1
3.2 The immune system---------------------------------------------------------------1-3
3.3. Autoimmune thyroid disease (AITD)-----------------------------------------3-4
3.4. Interferon regulatory factor 8 (IRF8)----------------------------------------4-6
3.5. B-Lymphocyte-activating factor (BAFF)------------------------------------6-7
3.6. Aim of the thesis------------------------------------------------------------------8
4. Materials and methods---------------------------------------------------------------9-12
4.1. Subjects----------------------------------------------------------------------------9
4.2. Genotyping-------------------------------------------------------------------------9-10
4.3. Serum BAFF protein measurement-------------------------------------------10
4.4. Laboratory analyses-------------------------------------------------------------10-11
4.5. Statistical analysis----------------------------------------------------------------11-12
5. Results-----------------------------------------------------------------------------------13-23
5.1. IRF8 SNP study------------------------------------------------------------------13-16
5.1.1 Demographic data of the GD, HT and control groups----------------13
5.1.2 SNP association analysis-----------------------------------------------------13-14
5.1.3 Associations of rs17445836 and rs2280381 with the presence of the AmiA and ATA in AITD----------------------------------------------------------------14
5.1.4 Prevalence of rs17445836 and rs2280381 in GD without the AmiA and ATA, GD with the AmiA or ATA, and HT-------------------------------------------14-15
5.1.5 Associations of rs17445836 and rs2280381 with thyroid function at the baseline and clinical outcomes of GD and HT patients---------------------------15
5.1.6 Associations of rs17445836 and rs2280381 with TSHRAb and AmiA titers------------------------------------------------------------------------------------------15
5.1.7. Multivariate logistic regression analysis for susceptibility to HT----15-16
5.2. BAFF SNP study--------------------------------------------------------------------16-20
5.2.1 Demographic data of the GD, HT, AITD, and control groups--------16
5.2.2 SNP association analysis------------------------------------------------------16-17
5.2.3 Associations of rs1041569 and rs2893321with TSHRAb and AmiA titers------------------------------------------------------------------------------------------18
5.2.4 Prevalences of rs1041569 and rs2893321 with diversity of autoantibody production in AITD-----------------------------------------------------------------------18-19
5.2.5 Associations of rs2893321 and rs1041569 with serum BAFF protein levels-----------------------------------------------------------------------------------------19
5.2.6 Multivariate logistic regression analysis for susceptibility to GD, HT, and AITD-----------------------------------------------------------------------------------20
5.3. Serum BAFF study-----------------------------------------------------------------20-23
5.3.1 Demographic data of the GD, HT, AITD, and control groups-------20-21
5.3.2 Serum BAFF level comparison---------------------------------------------21
5.3.3 Association of BAFF protein levels with thyroid function at baseline---21
5.3.4 Association of BAFF protein levels with TSHRAb, AmiA, and ATA titers------------------------------------------------------------------------------------------21-22
5.3.5. Association of BAFF protein levels with TSHRAb and FT4 levels in active and inactive GD-------------------------------------------------------------------22-23
6. Discussion-------------------------------------------------------------------------------24-32
7.Conclusion and perspective----------------------------------------------------------32-34
8. Reference--------------------------------------------------------------------------------34-41
8.Tables and Figures---------------------------------------------------------------------42-73
9.Appendix---------------------------------------------------------------------------------74-76

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