Masunaga Atsuko, Ishibashi Fumihiro, Koh Eitetsu, Oide Takashi, Sekine Yasuo, Hiroshima Kenzo
Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, 477-96 Owada-Shinden, Yachiyo, Chiba, 276-8524, Japan.
Respiratory Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Kanagawa, Japan.
Diagn Pathol. 2018 Jan 17;13(1):6. doi: 10.1186/s13000-018-0684-1.
IgG4-related disease often forms a mass and the affected lesion is clinically removed because the mass cannot be differentiated from a neoplasm. Affected lesions commonly occur in the pancreas, hepatobiliary tract, kidney, and retroperitoneum. However, the lesion rarely occurs in the thymus. A histological worldwide consensus of IgG4-related disease proposed that pathological diagnosis of IgG4-related disease should meet more than two of three major features: 1) dense lymphoplasmacytic infiltration with greater than 40% IgG4+/IgG+ plasma cells, 2) storiform fibrosis; and 3) obliterative phlebitis. Currently, fibrosis of IgG4-related disease is thought to be induced by profibrotic cytokines such as transforming growth factor beta 1 (TGFB1), interleukin 1 beta (IL1B) and interferon gamma (IFNG), which are secreted by regulatory T cells (Tregs) and CD4-positive cytotoxic T cells. However, it is unclear whether profibrotic cytokines are associated with the fibrosis seen in IgG4-related thymitis. Here we examined whether cytokines in the mass were increased compared with those in the surrounding thymus, and whether Tregs were present in the mass, using reverse transcription absolute quantitative polymerase chain reaction (RT-ab-qPCR) and immunohistochemistry.
A 70-year-old Japanese man contracted IgG4-letated thymitis. Histological and immunohistochemical analyses demonstrated his mass had massive fibrosis with a focally storiform pattern and lymphoplasmacytic infiltration with 40% IgG4+/IgG+ plasma cells, but not obliterative phlebitis. The mass was surrounded by atrophic thymus. We diagnosed the mass as IgG4-related thymitis. Immunohistochemically, Tregs were scattered throughout the mass. RT-ab-qPCR showed that messenger RNA expressions of TGFB1, IL1B and IFNG in the mass were 270-, 158- and 5.5- fold higher than in the surrounding thymus. His serum IgG4 level after surgery was within the normal range (83.4 mg/dl soon after surgery, 89.3 mg/dl 2 weeks after surgery).
Our results suggested the profibrotic cytokines TGFB1, IL1B and IFNG induce fibrosis and that Tregs might produce some of these cytokines in IgG4-related thymitis as well as in the other affected lesions of IgG4-related disease.
IgG4相关疾病常形成肿块，由于该肿块无法与肿瘤相鉴别，临床上会将受影响的病变切除。受影响的病变常见于胰腺、肝胆管、肾脏和腹膜后。然而，该病变很少发生于胸腺。IgG4相关疾病的一项全球组织学共识提出，IgG4相关疾病的病理诊断应满足三大主要特征中的两项以上：1）密集的淋巴细胞和浆细胞浸润，IgG4+/IgG+浆细胞大于40%；2）席纹状纤维化；3）闭塞性静脉炎。目前，IgG4相关疾病的纤维化被认为是由调节性T细胞（Tregs）和CD4阳性细胞毒性T细胞分泌的促纤维化细胞因子如转化生长因子β1（TGFB1）、白细胞介素1β（IL1B）和干扰素γ（IFNG）诱导的。然而，尚不清楚促纤维化细胞因子是否与IgG4相关胸腺炎中所见的纤维化有关。在此，我们使用逆转录绝对定量聚合酶链反应（RT-ab-qPCR）和免疫组织化学检查了肿块中的细胞因子是否比周围胸腺中的细胞因子增加，以及肿块中是否存在Tregs。
一名70岁的日本男性患IgG4相关胸腺炎。组织学和免疫组织化学分析显示，他的肿块有大量纤维化，呈局灶性席纹状模式，淋巴细胞和浆细胞浸润，IgG4+/IgG+浆细胞占40%，但无闭塞性静脉炎。肿块被萎缩的胸腺包围。我们将该肿块诊断为IgG4相关胸腺炎。免疫组织化学显示，Tregs散在于整个肿块中。RT-ab-qPCR显示，肿块中TGFB1、IL1B和IFNG的信使核糖核酸表达分别比周围胸腺高270倍、158倍和5.5倍。他术后的血清IgG4水平在正常范围内（术后不久为83.4mg/dl，术后2周为89.3mg/dl）。
我们的结果表明，促纤维化细胞因子TGFB1、IL1B和IFNG可诱导纤维化，并且在IgG4相关胸腺炎以及IgG4相关疾病的其他受影响病变中，Tregs可能会产生其中一些细胞因子。
