Braley-Mullen H, Sharp G C, Tang H, Chen K, Kyriakos M, Bickel J T
Department of Internal Medicine, University of Missouri-Columbia School of Medicine, 65212, USA.
Am J Pathol. 1998 May;152(5):1347-58.
Granulomatous inflammatory lesions are a major histopathological feature of a wide spectrum of human infectious and autoimmune diseases. Experimental autoimmune thyroiditis (EAT) with granulomatous histopathological features can be induced by mouse thyroglobulin (MTg)-sensitized spleen cells activated in vitro with MTg and anti-interleukin-2 receptor (anti-IL-2R), anti-IL-2, or anti-interferon-gamma (anti-IFN-gamma) monoclonal antibody (MAb). These studies suggested that IFN-gamma-producing T cells requiring IL-2 for growth may negatively regulate activation of granulomatous EAT effector cells. As IL-12 promotes activation of IFN-gamma-producing Th1 cells, the present study was undertaken to determine the role of IL-12 in activation of effector cells for granulomatous EAT. MTg-sensitized cells activated in vitro with MTg, anti-IL2R MAb, and IL-12 induced severe, destructive granulomatous thyroiditis with neutrophil inflammation, fibrin deposition, and necrosis. Many glands ultimately underwent atrophy and became fibrotic; some also showed fibrinoid necrosis and a mixed inflammatory cell infiltration of blood vessel walls indicative of a necrotizing vasculitis. Induction of severe granulomatous EAT by IL-12 required MTg in vitro and was unrelated to the IL-12-induced increase in IFN-gamma production. IL-12 markedly increased IFN-gamma production but did not induce a shift to a Th1-dominant phenotype, as other Th1 and Th2 cytokines were generally unaffected and both Th1 and Th2 cytokines were expressed in recipient thyroids. Addition of IL-12 or neutralization by anti-IL-12 at various times indicated that IL-12 exerted its primary effects in the final 24 hours of the 72-hour culture and was not required in recipient mice. Cells cultured with anti-IL-12, MTg, and anti-IL2R MAb transferred mild lymphocytic EAT but little or no granulomatous EAT. Thus, IL-12 profoundly regulates the in vitro activation of effector cells that induce histologically distinct autoimmune inflammatory lesions in the thyroid.
肉芽肿性炎性病变是多种人类感染性疾病和自身免疫性疾病的主要组织病理学特征。具有肉芽肿组织病理学特征的实验性自身免疫性甲状腺炎（EAT）可由用小鼠甲状腺球蛋白（MTg）和抗白细胞介素-2受体（抗IL-2R）、抗IL-2或抗干扰素-γ（抗IFN-γ）单克隆抗体（MAb）体外激活的MTg致敏脾细胞诱导产生。这些研究表明，需要IL-2来生长的产生IFN-γ的T细胞可能对肉芽肿性EAT效应细胞的激活起负调节作用。由于IL-12促进产生IFN-γ的Th1细胞的激活，因此进行本研究以确定IL-12在肉芽肿性EAT效应细胞激活中的作用。用MTg、抗IL2R MAb和IL-12体外激活的MTg致敏细胞诱导出严重的、破坏性的肉芽肿性甲状腺炎，伴有中性粒细胞炎症、纤维蛋白沉积和坏死。许多腺体最终发生萎缩并纤维化；一些还表现出纤维蛋白样坏死和血管壁混合性炎性细胞浸润，提示坏死性血管炎。IL-12在体外诱导严重的肉芽肿性EAT需要MTg，且与IL-12诱导的IFN-γ产生增加无关。IL-12显著增加IFN-γ的产生，但未诱导向Th1主导表型的转变，因为其他Th1和Th2细胞因子通常未受影响，且Th1和Th2细胞因子均在受体甲状腺中表达。在不同时间添加IL-12或用抗IL-12中和表明，IL-12在72小时培养的最后24小时发挥其主要作用，且受体小鼠中不需要。用抗IL-12、MTg和抗IL2R MAb培养的细胞转移了轻度淋巴细胞性EAT，但很少或没有肉芽肿性EAT。因此，IL-12深刻调节效应细胞的体外激活，这些效应细胞在甲状腺中诱导出组织学上不同的自身免疫性炎性病变。
