Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Department of Microbiology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan.
Int Immunol. 2019 Nov 8;31(12):795-809. doi: 10.1093/intimm/dxz050.
Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a newly proposed disease entity, IgG4-related disease (IgG4-RD), characterized by enhanced IgG4 antibody responses and involvement of multiple organs. We have previously reported that innate immune activation contributes to the development of AIP and IgG4-RD, as these diseases are characterized by the production of IFN-α and IL-33 by plasmacytoid dendritic cells (pDCs) that mediate chronic fibroinflammatory responses. In this study, we investigated the roles played by innate immunity against intestinal microflora in experimental AIP induced in MRL/MpJ mice by repeated administrations of 100 µg of polyinosinic-polycytidylic acid [poly (I:C)]. Bowel sterilization with a broad spectrum of antibiotics inhibited pancreatic accumulation of pDCs producing IFN-α and IL-33, and thereby suppressed the development of AIP. Mice treated with 10 µg of poly (I:C) developed severe AIP equivalent to that induced by 100 µg of poly (I:C) upon co-housing with mice treated with 100 µg of poly (I:C). Fecal microbiota transplantation (FMT) from donor mice treated with 100 µg of poly (I:C) led to the development of severe AIP in the recipient mice upon injection with 10 µg of poly (I:C). Induction of severe AIP in mice with 10 µg of poly (I:C) was associated with pancreatic accumulation of pDCs producing IFN-α and IL-33 in the co-housing and FMT experiments. These data collectively suggest that innate immune responses against intestinal microflora are involved in the development of experimental AIP, and that intestinal dysbiosis increases sensitivity to experimental AIP via activation of pDCs.
自身免疫性胰腺炎（AIP）是一种新提出的疾病实体，即 IgG4 相关疾病（IgG4-RD）的胰腺表现，其特征为增强的 IgG4 抗体反应和多个器官受累。我们之前曾报道固有免疫激活有助于 AIP 和 IgG4-RD 的发展，因为这些疾病的特征是浆细胞样树突状细胞（pDC）产生 IFN-α和 IL-33，这些细胞介导慢性纤维炎症反应。在这项研究中，我们研究了固有免疫对肠道微生物群的作用在重复给予 100μg多聚肌苷酸-多聚胞苷酸[多聚（I：C）]诱导的 MRL/MpJ 小鼠实验性 AIP 中的作用。广谱抗生素对肠道进行消毒可抑制产生 IFN-α和 IL-33 的 pDC 向胰腺的积聚，并由此抑制 AIP 的发展。用 10μg多聚（I：C）处理的小鼠与用 100μg多聚（I：C）处理的小鼠共同饲养时，会发展为相当于用 100μg多聚（I：C）诱导的严重 AIP。来自用 100μg多聚（I：C）处理的供体小鼠的粪便微生物群移植（FMT）在注射 10μg多聚（I：C）后导致接受小鼠发生严重 AIP。在共饲养和 FMT 实验中，用 10μg多聚（I：C）诱导的严重 AIP与胰腺中产生 IFN-α和 IL-33 的 pDC 的积聚有关。这些数据共同表明，针对肠道微生物群的固有免疫反应参与了实验性 AIP 的发展，而肠道菌群失调通过激活 pDC 增加了对实验性 AIP 的敏感性。
