Omenetti Sara, Brogi Marco, Goodman Wendy A, Croniger Colleen M, Eid Saada, Huang Alex Y, Laffi Giacomo, Roskams Tania, Cominelli Fabio, Pinzani Massimo, Pizarro Theresa T
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA ; "DENOThe" Center, University of Florence, Florence, Italy.
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Cell Mol Gastroenterol Hepatol. 2015 Jul 1;1(4):406-419. doi: 10.1016/j.jcmgh.2015.05.007.
Liver inflammation is a common extraintestinal manifestation of inflammatory bowel disease (IBD); however, whether liver involvement is a consequence of a primary intestinal defect or results from alternative pathogenic processes remains unclear. Therefore, we sought to determine the potential pathogenic mechanism(s) of concomitant liver inflammation in an established murine model of IBD.
Liver inflammation and immune cell subsets were characterized in ileitis-prone SAMP1/YitFc (SAMP) and AKR/J (AKR) control mice, lymphocyte-depleted SAMP (SAMPx), and immunodeficient SCID recipient mice receiving SAMP or AKR donor CD4 T-cells. Proliferation and suppressive capacity of CD4 T-effector (Teff) and T-regulatory (Treg) cells from gut-associated lymphoid tissue (GALT) and livers of SAMP and AKR mice were measured.
Surprisingly, prominent inflammation was detected in 4-wk-old SAMP livers, prior to histologic evidence of ileitis, while both disease phenotypes were absent in age-matched AKRs. SAMP liver disease was characterized by abundant infiltration of lymphocytes, required for hepatic inflammation to occur, a Th1-skewed environment, and phenotypically-activated CD4 T-cells. SAMP intrahepatic CD4 T-cells also had the ability to induce liver and ileal inflammation when adoptively transferred into SCID recipients, whereas GALT-derived CD4 T-cells produced milder ileitis, but not liver inflammation. Interestingly, SAMP intrahepatic CD4 Teff cells showed increased proliferation compared to both SAMP GALT- and AKR liver-derived CD4 Teff cells, while SAMP intrahepatic Tregs were decreased among CD4 T-cells and impaired in suppressive function compared to AKR.
Activated intrahepatic CD4 T-cells induce liver inflammation and contribute to experimental ileitis via locally-impaired hepatic immunosuppressive function.
肝脏炎症是炎症性肠病（IBD）常见的肠外表现；然而，肝脏受累是原发性肠道缺陷的结果还是由其他致病过程引起仍不清楚。因此，我们试图在已建立的IBD小鼠模型中确定伴随肝脏炎症的潜在致病机制。
在易患回肠炎的SAMP1/YitFc（SAMP）和AKR/J（AKR）对照小鼠、淋巴细胞耗竭的SAMP（SAMPx）以及接受SAMP或AKR供体CD4 T细胞的免疫缺陷SCID受体小鼠中，对肝脏炎症和免疫细胞亚群进行了表征。测量了来自SAMP和AKR小鼠的肠道相关淋巴组织（GALT）和肝脏的CD4效应T细胞（Teff）和调节性T细胞（Treg）的增殖和抑制能力。
令人惊讶的是，在4周龄的SAMP肝脏中检测到明显炎症，早于回肠炎的组织学证据，而年龄匹配的AKR小鼠中两种疾病表型均不存在。SAMP肝脏疾病的特征是淋巴细胞大量浸润，这是肝脏炎症发生所必需的，存在Th1偏向的环境以及表型活化的CD4 T细胞。当将SAMP肝内CD4 T细胞过继转移到SCID受体小鼠中时，它们也有能力诱导肝脏和回肠炎症，而GALT来源的CD4 T细胞引起的回肠炎较轻，但不会引起肝脏炎症。有趣的是，与SAMP GALT来源和AKR肝脏来源的CD4 Teff细胞相比，SAMP肝内CD4 Teff细胞显示出增殖增加，而SAMP肝内Tregs在CD4 T细胞中减少，并且与AKR相比抑制功能受损。
活化的肝内CD4 T细胞通过局部受损的肝脏免疫抑制功能诱导肝脏炎症并导致实验性回肠炎。
