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Studies on experimental autoimmune thyroiditis in mice and rats with thyroglobulin and thyroglobulin peptides

机译：甲状腺球蛋白和甲状腺球蛋白肽对小鼠和大鼠实验性自身免疫性甲状腺炎的研究

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Experimental autoimmune thyroiditis (EAT) induced in mice or rats with thyroglobulin (Tg) emulsified in complete Freund's adjuvant (CFA) has been a model system to understand the immunopathogenesis of Hashimoto's thyroiditis (HT). I have demonstrated, by the immunotargeting approach, that adjuvant-free challenge of mice with small doses of mTg conjugated to monoclonal antibodies (MAbs) specific for class II MHC (I-Ak) expressed on APC, induces an mTg-specific IgG response in CBA (H-2k) but not in B6 (H-2b) mice. Priming of CBA mice with mTg conjugated to an irrelevant MAb (control) did not elicit an autoimmune response. Despite the induction of an mTg-specific IgG response, mononuclear cell infiltration of the thyroid was not detected in CBA mice thus indicating a clear divergence in the requirements for autoantibody (AAb) production and the requirements for disease. These findings may help elucidate the role of various APC subsets in autoimmunity and facilitate study of the initial events that trigger autoreactivity outside a CFA-induced granuloma site. -- Investigation in rats of the immunopathogenicity of a 17mer homologous (rat) Tg peptide, rTgP1 (2495-2511), revealed that TgP1-priming of F334, WKY and WF rats elicits lymph node cell (LNC) proliferative responses to the peptide in vitro without concomitant specific primary IgG responses. LNC proliferative assays demonstrated that specific CD4⁺ T cells recognize TgP1 in the context of class II MHC and that TgP1 contains cryptic T cell epitope(s). Strong TgP1-specific IgG responses were not observed despite the presence of EAT in rats. These results provide the first evidence that a self-Tg peptide, TgP1, is immunopathogenic in rats. In contrast to 17mer TgP1, examination in rats of the immunopathogenicity of an 18mer rTg peptide, rTgP2 (2695-2713) revealed that TgP2- priming of rats induced specific LNC proliferative responses in F344, WKY but not in WF rats, although concomitant specific IgG responses were elicited in all three rat strains. Thyroiditis was readily induced in F344 rats both by direct challenge with TgP2 and by adoptive transfer with TgP2- specific T cells (CD4⁺, CD8⁻, TCR α/β⁺) indicating that peptide-induced rat EAT is a CD4⁺ T cell-mediated disease. Specific T cells recognize TgP2 in the context of class II molecules in an MHC-unrestricted fashion and TgP2 contains non-dominant T cell determinants. The TgP2-specific IgG (day 28) readily binds intact rTg and such binding could be abrogated by free peptide indicating the absence of "determinant spreading". These results indicate that TgP2 is pathogenic in rats but differs in its immunogenicity from that of TgP1. -- Class II rat thyrocytes (IFN-γ treated), to address their putative APC function in TgP2-mediated EAT, were examined by testing their ability to present endogenous Tg epitope to the TgP2-specific cloned T cells. Both unpulsed or peptide pulsed class II+ thyrocytes failed to activate the hybridoma (assessed by IL-2 release) suggesting that thyrocytes by themselves do not function as APC in vitro. The findings that both glutaraldehyde fixation and irradiation of spleenocytes abolished their capacity to present TgP2 leading to activation of the 8F7-5 hybridoma raised the possibility that thyrocytes may be deficient in the expression of certain costimulatory molecules. These findings have implications for understanding Ag-presentation in thyroid autoimmunity. -- Examination of the relative serological immunodominance of the pathogenic TgP1 and TgP2 peptides revealed contrasting findings. Priming of F344 rats either with homologous or heterologous Tgs did not elicit TgP1-specific IgG responses indicating the non-dominance of TgP1. In contrast, homologous Tg-priming elicited TgP2-specific IgG response. The immunogenicity of the TgP2 epitope(s) on heterologous Tgs varied dramatically, being highest on bovine Tg, intermediate on mouse Tg and undetectable on human and porcine Tgs although peptide-specific IgG readily cross-reacted with Tgs of various species. Epitope analysis of heterologous Tg-primed sera revealed that TgP2-reactivity is directed to distinct B epitopes within TgP2. These data provide the first evidence in EAT that variable immunodominance may partially explain why distinct Tg epitopes are recognized by MAbs in various species/Tg combinations and may have implications in serological screening of pathogenic Tg epitopes.
机译：在完全弗氏佐剂（CFA）中乳化的甲状腺球蛋白（Tg）在小鼠或大鼠中诱发的实验性自身免疫性甲状腺炎（EAT）已成为了解桥本甲状腺炎（HT）免疫发病机制的模型系统。我已经通过免疫靶向方法证明了，小剂量的mTg与APC上表达的针对II类MHC（I-Ak）的单克隆抗体（MAb）偶联的小剂量mTg的小鼠无佐剂攻击，可在小鼠体内诱导mTg特异性IgG应答。 CBA（H-2k），但不在B6（H-2b）小鼠中。用偶联至无关MAb的mTg引发CBA小鼠（对照）不会引起自身免疫反应。尽管诱导了mTg特异性IgG反应，但在CBA小鼠中未检测到甲状腺的单核细胞浸润，因此表明自身抗体（AAb）产生需求和疾病需求之间存在明显差异。这些发现可能有助于阐明各种APC亚型在自身免疫中的作用，并有助于研究引发CFA诱导的肉芽肿部位之外的自身反应的初始事件。 -对大鼠的17mer同源（大鼠）Tg肽rTgP1（2495-2511）的免疫致病性研究表明，F334，WKY和WF大鼠的TgP1引发引发了对该肽的淋巴结细胞（LNC）增殖反应。体外没有特异性的初级IgG反应。 LNC增殖试验表明，在II类MHC的背景下，特定的CD4 + T细胞可识别TgP1，并且TgP1包含隐性T细胞表位。尽管在大鼠中存在EAT，但未观察到强烈的TgP1特异性IgG反应。这些结果提供了第一个证据，表明自身Tg肽TgP1在大鼠中具有免疫致病性。与17mer TgP1相比，在大鼠中检查18mer rTg肽rTgP2（2695-2713）的免疫致病性显示，大鼠TgP2引发在F344，WKY中诱导了特异性LNC增殖反应，但在WF大鼠中未诱导，尽管同时存在特异性IgG在所有三种大鼠品系中引起了应答。通过直接攻击TgP2和过继转移TgP2特异性T细胞（CD4CD，CD8⁻，TCRα/β⁺），F344大鼠容易诱发甲状腺炎，这表明肽诱导的大鼠EAT是CD4⁺T细胞，介导的疾病。特定的T细胞在MHC不受限制的II类分子的背景下识别TgP2，而TgP2包含非主要的T细胞决定簇。 TgP2特异性IgG（第28天）很容易结合完整的rTg，并且这种结合可以被游离肽消除，表明不存在“决定簇扩散”。这些结果表明，TgP2在大鼠中是致病的，但其免疫原性与TgP1不同。 -通过测试其将内源性Tg表位呈递给TgP2特异性克隆的T细胞的能力，检查了II类大鼠甲状腺细胞（经IFN-γ处理）在TgP2介导的EAT中的假定APC功能。未脉冲或肽脉冲的II +类甲状腺细胞均未能激活杂交瘤（通过IL-2释放评估），表明甲状腺细胞本身在体外不具有APC的功能。戊二醛固定和脾细胞辐射均消除了它们呈现TgP2的能力，从而导致8F7-5杂交瘤的激活，这增加了甲状腺细胞可能缺乏某些共刺激分子表达的可能性。这些发现对于理解甲状腺自身免疫中的Ag呈递具有启示意义。 -对致病性TgP1和TgP2肽的相对血清学免疫学检查发现了相反的发现。用同源或异源Tgs引发F344大鼠均未引起TgP1特异性IgG反应，表明TgP1不具有优势。相反，同源Tg引发引发TgP2特异性IgG应答。 TgP2表位在异源Tgs上的免疫原性变化很大，在牛Tg上最高，在小鼠Tg上居中，而在人和猪Tgs上则无法检测到，尽管肽特异性IgG容易与各种Tgs交叉反应。异源Tg引发的血清的表位分析表明，TgP2反应性针对TgP2中​​不同的B表位。这些数据提供了EAT中的第一个证据，即可变的免疫优势可能部分解释了为何各种物种/ Tg组合中的单克隆抗体都可以识别出不同的Tg表位，并且可能对致病性Tg表位的血清学筛查产生影响。

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    Balasa Balaji;

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  • 年度 1995
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  • 原文格式 PDF
  • 正文语种 {"code":"en","name":"English","id":9}
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