耶尔森氏菌蛋白在促甲状腺素受体自身抗体产生中分子模拟机制的研究
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摘要
甲状腺是人体的重要内分泌器官,它分泌的多种激素参与人体糖、脂和蛋白质以及钙等物质的代谢调控,特别是甲状腺激素,是维持人体正常代谢的核心激素之一。由于这些激素功能的重要性,因此它们的产生和活性都有高度受控的反馈调节机制来保持其正常.这些机制主要包括：下丘脑产生甲状腺释放激素(TRH)从而刺激垂体产生甲状腺刺激激素(TSH), TSH再与甲状腺滤泡细胞上的甲状腺刺激激素受体(TSHR)结合,从而刺激甲状腺激素的产生,这是一种正反馈机制；另外是一种负反馈机制,即甲状腺产生的游离甲状腺激素T3能够通过血液循环作用于下丘脑和垂体,从而反馈抑制TRH和TSH产生的。通过这两种机制来调控甲状腺激素维持在正常水平,既不太多,也不太少,从而发挥正常的调控作用。有很多原因能够引起自身免疫功能的异常,从而破坏这一精细的调控机制而导致甲状腺激素过多或过少,最终产生甲状腺机能亢进或甲状腺机能减退。由自身免疫原因引起的甲状腺疾病即称为自身免疫性甲状腺疾病,它们的共同特征是存在针对多种甲状腺抗原的自身抗体,如TG、TPO和TSHR,而这些蛋白是甲状腺激素产生过程中的关键蛋白。
Graves'disease(GD)是一种常见的器官特异性自身免疫疾病,与桥本氏甲状腺炎(HT)和特发性粘液性水肿(PM)一样都是自身免疫性甲状腺病(AITD)的主要类型,发病率在0.3‰左右,尤以年轻女性多发。AITD都存在不同程度甲状腺组织的淋巴细胞浸润；在病人的血清中都存在甲状腺组织特异的自身抗体,主要包括抗甲状腺球蛋白抗体(TGAb)、抗甲状腺过氧化物酶抗体(TPOAb)和抗促甲状腺激素受体抗体(TRAb)三种,就某种特定疾病而论,超过90%的Graves病(GD)病人存在抗TSHR的自身抗体,接近80%的Graves病(GD)病人存在抗TPO的自身抗体；而超过90%的HT病人有anti-TPO和／或anti-TG的自身抗体。但与anti-TSHR抗体不同,anti-TPO和anti-TG抗体在HT或GD的发病机制中并没有重要意义,但它们能够帮助人们进行鉴别诊断和判断预后。而TRAb在GD、PM和部分HT患者血清中的阳性检出率可高达80%-100%,被认为是导致AITD,特别是GD发病的主要病因和自身抗原,是GD最重要的标志物。作为一种典型的自身免疫性疾病,GD发病机制复杂,特别是TSHR的免疫耐受如何被破坏从而产生TRAb这一过程的确切机制目前仍不明确。现在人们普遍认为遗传因素(HLA-DR, MHC, CTLA-4和PTPN22等)在这一过程中发挥重要作用；但很多证据也表明遗传因素并非是导致自体免疫耐受被破坏而产生抗TSHR抗体从而导致GD发生的唯一原因,感染、辐射、饮食和精神等众多环境因素在机体对甲状腺组织免疫耐受异常、产生TRAb等自身抗体而发病的过程中也发挥重要作用。但这些因素通过何种机制,如何导致免疫系统攻击原本免疫耐受的自体组织器官而导致发病的具体环节目前仍不清楚。在这些环境因素中,感染是众多自身免疫疾病的重要病因,目前认为其破坏免疫耐受的重要机制之一就是因细菌、病毒等外来抗原与某些自身组织存在交叉免疫原性,免疫系统产生的针对外来抗原的抗体就会通过分子模拟机制而使原本免疫耐受的自身组织遭到免疫系统攻击。此外还有细菌超抗原活化多克隆T细胞；甲状腺等组织内HLA分子表达增强等破坏自身免疫耐受的机制。
小肠结肠炎耶尔森氏菌(Yersinia enterocolitica, YE)是一种常见的感染因素,有腹泻、心肌炎、反应性关节炎和结节性红斑等肠道内外症状。70年代人们发现GD患者中YE抗体(YEAb)的阳性率与正常对照和非GD组相比明显增高,YE菌体蛋白有稳定的TSH结合位点,而且能够被GD病人免疫球蛋白所识别和结合。我们之前对403例GD患者的研究也发现63%的GD患者伴YE引发的腹泻,应用YE敏感的抗生素治疗后,70%的GD患者腹泻缓解,同时GD病情和复发率也明显降低,这些证据都提示YE与GD关系密切。之前已有研究认为YE的包膜蛋白和脂蛋白与TSHR存在交叉免疫原性,但未能指出是那一种具体的蛋白以及蛋白上被TRAb所识别的具体的抗原表位。尽管与YE感染在GD发病中作用有关的研究已进行了35年,但目前仍未有定论,很多问题仍未能阐明：如YE中有那些蛋白与GD有关；这些蛋白及其不同抗原表位所对应的抗体是否影响甲状腺功能,它们单独或与TSHR抗原表位联合免疫动物后能否导致甲状腺功能异常等。因此更多揭示YE中能够被TRAb识别且其抗体具有功能意义的蛋白、该蛋白上功能相关的抗原表位和其可能的致GD作用,以及它们与其它TSHR抗原表位的关系将有助于人们对YE与GD关系和GD发病机制的深入理解,也有助于对GD的诊断及预后判定、免疫干预治疗；而且,对人们深入理解免疫耐受形成和破坏的机制、感染在糖尿病等其它与自体免疫密切相关的疾病中的作用,也具有重要的指导意义。
技术的进步使我们除了噬菌体展示肽库,肽探针扫描和x-ray/MRI技术等经典表位作图技术外,还能够利用免疫蛋白组学的技术,更加方便和高效的确定YE中完全未知的TRAb抗原蛋白,并确定功能相关的抗原表位。在这些技术的帮助下,我们利用GD患者的血清以及多种抗原表位位于TSHR的ECD内的商业化单克隆抗体与YE总蛋白进行Western blot,发现在不同病人之间存在共同的阳性条带,将该条带剪切下来,经膜上酶解和质谱鉴定后,发现该条带是YE蛋白中理论分子量为42KD的外膜孔蛋白F(ompF)。在这一研究结果的基础上,我们构建了它的表达载体,研究结果表明表达纯化后的ompF蛋白不仅仍能与原单抗结合,也能被经GD病人的抗血清所识别,这进一步确证了我们之前的研究结果。我们进一步利用蛋白抗原性分析的相应生物信息学工具,并在已知同源蛋白空间结构的基础上,通过蛋白空间结构同源建模工具得到了TSHR和ompF蛋白的空间结构,利用这些数据,我们经过综合分析发现ompF上至少存在5个潜在抗原表位,而且这些表位都在蛋白结构的表面,其中ompF上能够被anti-hTSHR antibody所识别的抗原表位是位于190到197位间的氨基酸序列(DALGNVTS).为了进一步检测我们发现的ompF蛋白上这些与TSHR可能存在交叉免疫反应的抗原表位的功能意义,我们又进一步制备了ompF相应抗原表位的多克隆抗体,发现该多克隆抗体能够使人原代甲状腺滤泡细胞和稳定表达人TSHR的CHO细胞的细胞内cAMP升高,具有一定的TSAb活性。然而,YE在GD发病中的作用是一个十分复杂的问题,仍需要在很多领域进行大量细致深入的研究,本研究的结果为进一步的深入研究提供了线索。以此为基础,我们可以利用基于亲和纯化和质谱技术的epitope extraction和epitope excision技术对于ompF蛋白中能被anti-hTSHR抗体所识别的抗原表位以及不同抗原表位所产生的抗体的功能意义进行更加精确和详尽的研究。另外,ompF、lipoproteins, envelope proteins andYOP等已发现的与TSHR具有交叉免疫原性的YE蛋白在GD发病和诱导TRAb产生中的确切作用和相互关系也需要进一步的深入研究。只有在这些深入分子水平的研究的基础上,才能明确YE在TRAb产生和GD发生和发展中的作用,对GD的诊断、预后及免疫干预治疗都具有重要的意义,而且也有助于人们深入理解免疫耐受形成和破坏的机制、感染在其它与自体免疫密切相关的疾病中的作用。
Graves'disease (GD) is the main type of autoimmune thyroid disease (AITD). It afflicts up to 30 per 100,000 of the population, especially young women. Thyroid-specific autoantibodies are frequently found in the serum of GD patients, while over 90% of patients with GD have anti-thyrotropin receptor (TSHR) autoantibodies (TRAb). Some TRAb are thyroid-timulating antibodies (TSAb) that can bind to the TSHR and stimulate the thyroid to produce excessive thyroid hormone resulting in hyperthyroidism. TSAbs are considered to be the primary cause of thyroid dysfunction and also the most important autoantibody and immunological hallmark in GD. Although a lot of information is known regarding the characteristics of TRAb in patient serum and on GD pathology, the mechanism of loss of immune tolerance to TSHR and how TRAbs are induced are not fully understood. Many studies have suggested that susceptibility is determined by genetic factors (e.g., HLA-DR alleles and CTLA-4 polymorphisms), which play important roles in the pathogenesis of GD, similar to other autoimmune diseases. Nevertheless, many evidences suggest that genetics cannot totally account for susceptibility to GD, and genes are not the only factor in the disturbance of autoimmune tolerance to TSHR and the induction of autoantibodies resulting in GD. Non-genetic and environmental factors including infection, irradiation, iodine, smoking and stress may have secondary causative roles that are likely very important. Yersinia enterocolitica (YE) is a common intestinal infection with symptoms of diarrhea, myocarditis, reactive arthritis and erythema nodosum. Yersinia enterocolitica (YE) infection played an important causative role in the pathogenesis of Graves'disease (GD) through molecular mimicry. However, the specific YE proteins and epitopes recognized by anti-thyrotropin receptor (TSHR) autoantibodies (TRAb) have not been fully clarified, resulting in conflicting results from clinical research. Our aim was to explore the roles of YE in the pathogenesis of GD and identify the YE proteins and epitopes that are similar to the TSHR and are recognized by TRAb. Assays of YEAb, TRAb, TGAb and TMAb as well as cross-absorption and two-way immunodiffusion were performed in 120 patients with GD. Utilizing mass spectrometry and the bioinformatics tools of protein structure modeling and epitope prediction, we identified the YE protein and its epitope, which was recognized by TRAb and was similar to TSHR. Our clinical study showed that YE infection was significantly related to the production of TRAb and the relapse of GD. We demonstrated for the first time that the YE protein ompF shared cross-immunogenicity with a leucine rich domain of TSHR. The epitope recognized by anti-hTSHR antibody is located within the ompF region of amino acids 190-197. Our results showed that YE ompF is involved in the production of TRAb and the pathogenesis of GD through molecular mimicry. These findings are potentially important for understanding the role molecular mimicry plays in the disturbance of immune tolerance and the induction of autoimmunity to the TSHR.
Graves'disease(GD)是一种常见的器官特异性自身免疫疾病,与桥本氏甲状腺炎(HT)和特发性粘液性水肿(PM)一样都是自身免疫性甲状腺病(AITD)的主要类型,发病率在0.3‰左右,尤以年轻女性多发。AITD都存在不同程度甲状腺组织的淋巴细胞浸润；在病人的血清中都存在甲状腺组织特异的自身抗体,主要包括抗甲状腺球蛋白抗体(TGAb)、抗甲状腺过氧化物酶抗体(TPOAb)和抗促甲状腺激素受体抗体(TRAb)三种,就某种特定疾病而论,超过90%的Graves病(GD)病人存在抗TSHR的自身抗体,接近80%的Graves病(GD)病人存在抗TPO的自身抗体；而超过90%的HT病人有anti-TPO和／或anti-TG的自身抗体。但与anti-TSHR抗体不同,anti-TPO和anti-TG抗体在HT或GD的发病机制中并没有重要意义,但它们能够帮助人们进行鉴别诊断和判断预后。而TRAb在GD、PM和部分HT患者血清中的阳性检出率可高达80%-100%,被认为是导致AITD,特别是GD发病的主要病因和自身抗原,是GD最重要的标志物。作为一种典型的自身免疫性疾病,GD发病机制复杂,特别是TSHR的免疫耐受如何被破坏从而产生TRAb这一过程的确切机制目前仍不明确。现在人们普遍认为遗传因素(HLA-DR, MHC, CTLA-4和PTPN22等)在这一过程中发挥重要作用；但很多证据也表明遗传因素并非是导致自体免疫耐受被破坏而产生抗TSHR抗体从而导致GD发生的唯一原因,感染、辐射、饮食和精神等众多环境因素在机体对甲状腺组织免疫耐受异常、产生TRAb等自身抗体而发病的过程中也发挥重要作用。但这些因素通过何种机制,如何导致免疫系统攻击原本免疫耐受的自体组织器官而导致发病的具体环节目前仍不清楚。在这些环境因素中,感染是众多自身免疫疾病的重要病因,目前认为其破坏免疫耐受的重要机制之一就是因细菌、病毒等外来抗原与某些自身组织存在交叉免疫原性,免疫系统产生的针对外来抗原的抗体就会通过分子模拟机制而使原本免疫耐受的自身组织遭到免疫系统攻击。此外还有细菌超抗原活化多克隆T细胞；甲状腺等组织内HLA分子表达增强等破坏自身免疫耐受的机制。
小肠结肠炎耶尔森氏菌(Yersinia enterocolitica, YE)是一种常见的感染因素,有腹泻、心肌炎、反应性关节炎和结节性红斑等肠道内外症状。70年代人们发现GD患者中YE抗体(YEAb)的阳性率与正常对照和非GD组相比明显增高,YE菌体蛋白有稳定的TSH结合位点,而且能够被GD病人免疫球蛋白所识别和结合。我们之前对403例GD患者的研究也发现63%的GD患者伴YE引发的腹泻,应用YE敏感的抗生素治疗后,70%的GD患者腹泻缓解,同时GD病情和复发率也明显降低,这些证据都提示YE与GD关系密切。之前已有研究认为YE的包膜蛋白和脂蛋白与TSHR存在交叉免疫原性,但未能指出是那一种具体的蛋白以及蛋白上被TRAb所识别的具体的抗原表位。尽管与YE感染在GD发病中作用有关的研究已进行了35年,但目前仍未有定论,很多问题仍未能阐明：如YE中有那些蛋白与GD有关；这些蛋白及其不同抗原表位所对应的抗体是否影响甲状腺功能,它们单独或与TSHR抗原表位联合免疫动物后能否导致甲状腺功能异常等。因此更多揭示YE中能够被TRAb识别且其抗体具有功能意义的蛋白、该蛋白上功能相关的抗原表位和其可能的致GD作用,以及它们与其它TSHR抗原表位的关系将有助于人们对YE与GD关系和GD发病机制的深入理解,也有助于对GD的诊断及预后判定、免疫干预治疗；而且,对人们深入理解免疫耐受形成和破坏的机制、感染在糖尿病等其它与自体免疫密切相关的疾病中的作用,也具有重要的指导意义。
技术的进步使我们除了噬菌体展示肽库,肽探针扫描和x-ray/MRI技术等经典表位作图技术外,还能够利用免疫蛋白组学的技术,更加方便和高效的确定YE中完全未知的TRAb抗原蛋白,并确定功能相关的抗原表位。在这些技术的帮助下,我们利用GD患者的血清以及多种抗原表位位于TSHR的ECD内的商业化单克隆抗体与YE总蛋白进行Western blot,发现在不同病人之间存在共同的阳性条带,将该条带剪切下来,经膜上酶解和质谱鉴定后,发现该条带是YE蛋白中理论分子量为42KD的外膜孔蛋白F(ompF)。在这一研究结果的基础上,我们构建了它的表达载体,研究结果表明表达纯化后的ompF蛋白不仅仍能与原单抗结合,也能被经GD病人的抗血清所识别,这进一步确证了我们之前的研究结果。我们进一步利用蛋白抗原性分析的相应生物信息学工具,并在已知同源蛋白空间结构的基础上,通过蛋白空间结构同源建模工具得到了TSHR和ompF蛋白的空间结构,利用这些数据,我们经过综合分析发现ompF上至少存在5个潜在抗原表位,而且这些表位都在蛋白结构的表面,其中ompF上能够被anti-hTSHR antibody所识别的抗原表位是位于190到197位间的氨基酸序列(DALGNVTS).为了进一步检测我们发现的ompF蛋白上这些与TSHR可能存在交叉免疫反应的抗原表位的功能意义,我们又进一步制备了ompF相应抗原表位的多克隆抗体,发现该多克隆抗体能够使人原代甲状腺滤泡细胞和稳定表达人TSHR的CHO细胞的细胞内cAMP升高,具有一定的TSAb活性。然而,YE在GD发病中的作用是一个十分复杂的问题,仍需要在很多领域进行大量细致深入的研究,本研究的结果为进一步的深入研究提供了线索。以此为基础,我们可以利用基于亲和纯化和质谱技术的epitope extraction和epitope excision技术对于ompF蛋白中能被anti-hTSHR抗体所识别的抗原表位以及不同抗原表位所产生的抗体的功能意义进行更加精确和详尽的研究。另外,ompF、lipoproteins, envelope proteins andYOP等已发现的与TSHR具有交叉免疫原性的YE蛋白在GD发病和诱导TRAb产生中的确切作用和相互关系也需要进一步的深入研究。只有在这些深入分子水平的研究的基础上,才能明确YE在TRAb产生和GD发生和发展中的作用,对GD的诊断、预后及免疫干预治疗都具有重要的意义,而且也有助于人们深入理解免疫耐受形成和破坏的机制、感染在其它与自体免疫密切相关的疾病中的作用。
Graves'disease (GD) is the main type of autoimmune thyroid disease (AITD). It afflicts up to 30 per 100,000 of the population, especially young women. Thyroid-specific autoantibodies are frequently found in the serum of GD patients, while over 90% of patients with GD have anti-thyrotropin receptor (TSHR) autoantibodies (TRAb). Some TRAb are thyroid-timulating antibodies (TSAb) that can bind to the TSHR and stimulate the thyroid to produce excessive thyroid hormone resulting in hyperthyroidism. TSAbs are considered to be the primary cause of thyroid dysfunction and also the most important autoantibody and immunological hallmark in GD. Although a lot of information is known regarding the characteristics of TRAb in patient serum and on GD pathology, the mechanism of loss of immune tolerance to TSHR and how TRAbs are induced are not fully understood. Many studies have suggested that susceptibility is determined by genetic factors (e.g., HLA-DR alleles and CTLA-4 polymorphisms), which play important roles in the pathogenesis of GD, similar to other autoimmune diseases. Nevertheless, many evidences suggest that genetics cannot totally account for susceptibility to GD, and genes are not the only factor in the disturbance of autoimmune tolerance to TSHR and the induction of autoantibodies resulting in GD. Non-genetic and environmental factors including infection, irradiation, iodine, smoking and stress may have secondary causative roles that are likely very important. Yersinia enterocolitica (YE) is a common intestinal infection with symptoms of diarrhea, myocarditis, reactive arthritis and erythema nodosum. Yersinia enterocolitica (YE) infection played an important causative role in the pathogenesis of Graves'disease (GD) through molecular mimicry. However, the specific YE proteins and epitopes recognized by anti-thyrotropin receptor (TSHR) autoantibodies (TRAb) have not been fully clarified, resulting in conflicting results from clinical research. Our aim was to explore the roles of YE in the pathogenesis of GD and identify the YE proteins and epitopes that are similar to the TSHR and are recognized by TRAb. Assays of YEAb, TRAb, TGAb and TMAb as well as cross-absorption and two-way immunodiffusion were performed in 120 patients with GD. Utilizing mass spectrometry and the bioinformatics tools of protein structure modeling and epitope prediction, we identified the YE protein and its epitope, which was recognized by TRAb and was similar to TSHR. Our clinical study showed that YE infection was significantly related to the production of TRAb and the relapse of GD. We demonstrated for the first time that the YE protein ompF shared cross-immunogenicity with a leucine rich domain of TSHR. The epitope recognized by anti-hTSHR antibody is located within the ompF region of amino acids 190-197. Our results showed that YE ompF is involved in the production of TRAb and the pathogenesis of GD through molecular mimicry. These findings are potentially important for understanding the role molecular mimicry plays in the disturbance of immune tolerance and the induction of autoimmunity to the TSHR.
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2. Rapoport B, McLachlan SM. The thyrotropin receptor in Graves'disease. Thyroid.2007; 17:911-922.
3. Ajjan RA, Weetman AP. Techniques to quantify TSH receptor antibodies. Nat Clin Pract Endocrinol Metab.2008; 4:461-468.
4. Schott M, Scherbaum WA, Morgenthaler NG. Thyrotropin receptor autoantibodies in Graves'disease. Trends Endocrinol Metab.2005; 16:243-248.
5. Weetman AP. Autoimmune Thyroid Disease. Autoimmunity 2004,37(4), 337-340.
6. Tunbridge WM, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young E, Bird T and Smith PA. The spectrum of thyroid disease in a community:the Whickham survey. Clin Endocrinol (Oxf).1977,7(6), 481-493.
7 Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, et al. The incidence of thyroid disorders in the community:a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf).1995,43(1),55-68.
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