The Intrahepatic Expression and Distribution of BTLA and its Ligand HVEM in patients with HBV-related acute-on-chronic liver failure

OBJECTIVE: It has been demonstrated that signals from the inhibitory receptor B and T lymphocyte attenuator (BTLA) are involved in regulating the pathogenesis of infectious diseases. However, the expression and anatomical distribution of BTLA and its ligand, the herpes virus entry mediator (HVEM), have not yet been determined in cases of HBV-related acute-on-chronic liver failure (HBV-ACLF) patients. METHODS: In this study, the expression of BTLA and HVEM in liver tissues from HBV-ACLF, chronic hepatitis B (CHB) patients and healthy individuals was analyzed by immunohistochemistry. RESULTS: The results of this analysis demonstrated that both molecules were observed in the HBV-ACLF samples and that their expression was chiefly in the infiltrating inflammatory cells and the damaged bile ducts. However, they were absent in liver sections from CHB patients and healthy controls. Immunofluorescence double-staining indicated that BTLA was found on CK-18(+) epithelial cells, CD31(+) endothelial cells, CD68(+) macrophages, CD56(+) NK cells, CD16(+) monocytes, CD3(+) , CD8(+) T cells, and Foxp3(+) regulatory T cells (Treg). By contrast, HVEM expression was restricted to CK18(+) epithelial cells and CD68(+) macrophages. Moreover, the expression of several members of the B7 superfamily, including PD-L1, PD-L2, B7-H3 and B7-H4, was also detected in these liver tissues, and these proteins were co-expressed with HVEM. Interestingly, the expression of fibrinogen-like protein 2 (FGL2), a virus-induced procoagulant molecule, was also found in liver sections from HBV-ACLF, this molecule also co-expresses with BTLA and HVEM. CONCLUSIONS: These results suggest that BTLA-HVEM signaling is likely to affect the pathogenesis of HBV-ACLF, a clear understanding of the functional roles of these proteins should further elucidate the disease process. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8080806838149123