Expression of B and T lymphocyte attenuator (BTLA) in macrophages contributes to the fulminant hepatitis caused by murine hepatitis virus strain-3.
OBJECTIVE
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.


METHODS
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.
Deaprtment of Basic Medicine, Institute of Immunology, PLA, Third Military Medical University, Chongqing, China.
Chengying
C
Yang
Yongwen
Y
Chen
Guoning
G
Guo
Hong
H
Li
Dayan
D
Cao
Huan
H
Xu
Sheng
S
Guo
Lei
L
Fei
Weiming
W
Yan
Qing
Q
Ning
Lixin
L
Zheng
Yuzhang
Y
Wu
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D018352:Coronavirus Infections / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006524:Hepatitis, Viral, Animal / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D008264:Macrophages / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006517:Murine hepatitis virus; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C488868:BTLA protein, mouse; D011971:Receptors, Immunologic; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha