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.
- Fulminant viral hepatitis
- acute liver failure
- hepatobiliary pathology
- infectious disease
- immune-mediated liver damage
- immunology in hepatology
- inflammatory mechanisms
- cell biology
- cellular immunity
- cellular immunology
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Funding This work was supported by grants from The Major Program of National Natural Science Foundation of China (30930086 and 2007CB512805) and the General Program of National Natural Science Foundation of China (NSFC No 81171585, 30971099, 30901347 and 61141012) and Natural Science Foundation of Chongqing (No CSTC2011BB5037).
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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