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Abstract Details
Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways
J Infect Dis. 2022 Dec 28;227(1):123-132. doi: 10.1093/infdis/jiac375.
1Gastroenterology Department of St Vincent's Hospital Melbourne, Melbourne, Australia.
2Department of Infectious Disease and Immunology Research Centre, St Vincent's Hospital, Melbourne, Australia.
3The Department of Public Health, La Trobe University, Melbourne, Australia.
4Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Australia.
5Gastroenterology Department of Liverpool Hospital, Sydney, Australia.
6Department of Gastroenterology, Alfred Health, Melbourne, Australia.
7Central Clinical School, Monash University, The Alfred Centre, Melbourne, Australia.
8Gastroenterology Department of Eastern Health, Melbourne, Australia.
9AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.
10Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
11Department of Medicine, Monash University, Melbourne, Australia.
12Gastroenterology Department of Concord Repatriation General Hospital, Sydney, Australia.
13Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Australia.
14Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia.
15Gastroenterology Department of Bankstown-Lidcombe Hospital, Sydney, Australia.
16Department of infectious Disease, St Vincent's Hospital Sydney, SydneyAustralia.
17Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, The Doherty Institute, Melbourne, Australia.
Abstract
Background: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy.
Methods: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured.
Results: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients.
Conclusions: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.
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