B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD).

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Version: Author's accepted manuscript
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Serval ID
serval:BIB_157A3B39B831
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
B2-Lymphocyte responses to oxidative stress-derived antigens contribute to the evolution of nonalcoholic fatty liver disease (NAFLD).
Journal
Free radical biology & medicine
Author(s)
Bruzzì S., Sutti S., Giudici G., Burlone M.E., Ramavath N.N., Toscani A., Bozzola C., Schneider P., Morello E., Parola M., Pirisi M., Albano E.
ISSN
1873-4596 (Electronic)
ISSN-L
0891-5849
Publication state
Published
Issued date
20/08/2018
Peer-reviewed
Oui
Volume
124
Pages
249-259
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Recent evidence implicates adaptive immunity as a key player in the mechanisms supporting hepatic inflammation during the progression of nonalcoholic fatty liver disease (NAFLD). In these settings, patients with NAFLD often show an increase in the circulating levels of antibodies against oxidative stress-derived epitopes (OSE). Nonetheless, the actual role of humoral immunity in NAFLD is still unclear. This study investigates the contribution of B-lymphocytes to NAFLD evolution. B-lymphocyte immunostaining of liver biopsies from NAFLD patients showed that B-cells were evident within cell aggregates rich in T-lymphocytes. In these subjects, B/T-lymphocyte infiltration positively correlated with both circulating IgG targeting oxidative stress-derived epitopes (OSE) and interferon-γ (IFN-γ) levels. Furthermore, high prevalence of lymphocyte aggregates identified patients with more severe lobular inflammation and fibrosis. In mouse models of NAFLD, the onset of steatohepatitis was characterized by hepatic B2-lymphocytes maturation to plasma cells and by an elevation in circulating anti-OSE IgG titers. B-cell responses preceded T-cell activation and were accompanied by the up-regulation in the hepatic expression of B-cell Activating Factor (BAFF). Selective B2-cell depletion in mice over-expressing a soluble form of the BAFF/APRIL receptor Transmembrane Activator and Cyclophilin Ligand Interactor (TACI-Ig) prevented plasma cell maturation and Th-1 activation of liver CD4 <sup>+</sup> T-lymphocytes. Furthermore, TACI-Ig mice showed milder steatohepatitis and a decreased progression to fibrosis. Similarly, mice treatment with the BAFF-neutralizing monoclonal antibody Sandy-2 prevented hepatic B2-cell responses and ameliorated steatohepatitis. From these data we conclude that B2-lymphocyte activation is an early event in NAFLD evolution and contributes to the disease progression through the interaction with T-cells. Furthermore, combined clinical and experimental data suggest that elevated circulating anti-OSE IgG can identify a subset of NAFLD patients in whom adaptive immunity has a relevant role in the disease evolution toward fibrosis.
Keywords
Animals, Antigens/immunology, B-Lymphocyte Subsets/immunology, B-Lymphocytes/immunology, Disease Progression, Female, Humans, Lymphocyte Activation/immunology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Non-alcoholic Fatty Liver Disease/immunology, Non-alcoholic Fatty Liver Disease/pathology, Oxidative Stress/immunology, T-Lymphocytes/immunology, Immune responses, Lipid peroxidation, Liver fibrosis, Liver inflammation, Nonalcoholic steatohepatitis
Pubmed
Web of science
Open Access
Yes
Create date
25/06/2018 14:33
Last modification date
18/09/2019 6:10
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