Expression of B and T lymphocyte attenuator (BTLA) in macrophages contributes to the fulminant hepatitis caused by murine hepatitis virus strain-3. Issue 8 (25th May 2012)

• Record Type: Journal Article
• Authors: Yang, Chengying; Chen, Yongwen; Guo, Guoning; Li, Hong; Cao, Dayan; Xu, Huan; Guo, Sheng; Fei, Lei; Yan, Weiming; Ning, Qing; Zheng, Lixin; Wu, Yuzhang
• Is Part Of: Gut. Volume 62:Issue 8(2013)
• Page Start: 1204
• Page End: 1213
• Publication Date: 2012-05-25
• Subjects: BTLA -- Fulminant viral hepatitis -- FGL2 -- TNFα -- immune -- acute liver failure -- hepatobiliary pathology -- infectious disease -- inflammation -- immune-mediated liver damage -- immunology in hepatology -- vitamins -- immunology -- inflammatory mechanisms -- cell biology -- cellular immunity -- cellular immunology; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2012-302239
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Objectives: Fulminant viral hepatitis (FH) remains a serious clinical problem for which the underlying pathogenesis remains unclear. The B and T lymphocyte attenuator (BTLA) is an immunoglobulin-domain-containing protein that has the capacity to maintain peripheral tolerance and limit immunopathological damage during immune responses. However, its precise role in FH has yet to be investigated. Design: BTLA-deficient (BTLA −/− ) mice and their wild-type littermates were infected with murine hepatitis virus strain-3 (MHV-3), and the levels of tissue damage, cell apoptosis, serum liver enzymes, fibrinogen-like protein 2 (FGL2) and cytokine production were measured and compared. Survival rate was studied after MHV-3 infection with or without adoptive transferring macrophages. Results: FGL2 production, liver and spleen damage, and mortality were significantly reduced in BTLA −/− mice infected with MHV-3. This effect is due to rapid, TRAIL (TNF-related apoptosis-inducing ligand)-dependent apoptosis of MHV-3-infected macrophages in BTLA −/− mice. The early loss of macrophages resulted in reduced pathogenic tumour necrosis factor α (TNFα) and FGL2 levels and lower viral titres. The importance of TNFα in MHV-3-induced pathology was demonstrated by increased mortality in TNFα-treated MHV-3-infected BTLA −/− mice, whereas TNFα −/− mice were resistant to the infection. Moreover, adoptively transferring macrophages to BTLA −/− mice caused sensitisation, whereas blocking BTLA protected wild-type mice from virus-induced FH mortality. Conclusions: BTLA promotes the pathogenesis of virus-induced FH by enhancing macrophage viability and function. Targeting BTLA may be a novel strategy for the treatment of FH.