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

Published on Aug 1, 2018in Free Radical Biology and Medicine 5.66
· DOI :10.1016/j.freeradbiomed.2018.06.015
Stefania Bruzzì5
Estimated H-index: 5
Salvatore Sutti12
Estimated H-index: 12
+ 9 AuthorsEmanuele Albano42
Estimated H-index: 42
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 + 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.
  • References (45)
  • Citations (1)
Published on Sep 20, 2017in Nature Reviews Gastroenterology & Hepatology 23.57
Zobair M. Younossi76
Estimated H-index: 76
Quentin M. Anstee39
Estimated H-index: 39
+ 5 AuthorsElisabetta Bugianesi50
Estimated H-index: 50
NAFLD is growing in prevalence worldwide, and has emerged as a leading cause of end-stage liver disease in many countries. In this Review, the authors describe the global epidemiology of NAFLD, discuss associated risk factors and outline challenges for screening and management.
Published on Dec 1, 2017in Lipids in Health and Disease 2.65
Laura C. Echeverri Tirado1
Estimated H-index: 1
Lina M. Yassin4
Estimated H-index: 4
Atherosclerosis is considered as an inflammatory and chronic disorder with an important immunologic component, which underlies the majority of cardiovascular diseases; condition that belongs to a group of noncommunicable diseases that to date and despite of prevention and treatment approaches, they remain as the main cause of death worldwide, with 17.5 million of deaths every year. The impact of lipids in human health and disease is taking center stage in research, due to lipotoxicity explained ...
Published on Nov 1, 2017in Nature 43.07
Shabnam Shalapour18
Estimated H-index: 18
Xue-Jia Lin3
Estimated H-index: 3
+ 20 AuthorsTakaji Matsutani19
Estimated H-index: 19
IgA+ B cells expressing programmed death ligand 1 (PD-L1) and interleukin 10 accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease where they promote the progression to hepatocellular carcinoma by limiting the local activation of PD-1-expressing CD8+ T cells.
Published on Oct 1, 2017in Free Radical Biology and Medicine 5.66
Francesco Bellanti18
Estimated H-index: 18
(University of Foggia),
Rosanna Villani6
Estimated H-index: 6
(University of Foggia)
+ 2 AuthorsGaetano Serviddio30
Estimated H-index: 30
(University of Foggia)
Non-alcoholic fatty liver disease (NAFLD) is the major public health challenge for hepatologists in the twenty-first century. NAFLD comprises a histological spectrum ranging from simple steatosis or fatty liver, to steatohepatitis, fibrosis, and cirrhosis. It can be categorized into two principal phenotypes: (1) non-alcoholic fatty liver (NAFL), and (2) non-alcoholic steatohepatitis (NASH). The mechanisms of NAFLD progression consist of lipid homeostasis alterations, redox unbalance, insulin res...
Published on Mar 1, 2017in Journal of Clinical Investigation 12.28
Wei Ying12
Estimated H-index: 12
(UCSD: University of California, San Diego),
Joshua Wollam7
Estimated H-index: 7
(UCSD: University of California, San Diego)
+ 7 AuthorsJerrold M. Olefsky106
Estimated H-index: 106
(UCSD: University of California, San Diego)
Published on Jan 3, 2017in Journal of Clinical Investigation 12.28
Tracey McLaughlin40
Estimated H-index: 40
Shelley E. Ackerman1
Estimated H-index: 1
+ 1 AuthorsEdgar G. Engleman79
Estimated H-index: 79
Abstract Chronic inflammation in adipose tissue, possibly related to adipose cell hypertrophy, hypoxia, and/or intestinal leakage of bacteria and their metabolic products, likely plays a critical role in the development of obesity-associated insulin resistance (IR). Cells of both the innate and adaptive immune system residing in adipose tissues, as well as in the intestine, participate in this process. Thus, M1 macrophages, IFN-γ-secreting Th1 cells, CD8+ T cells, and B cells promote IR, in part...
Published on Jan 1, 2017in The Journal of Pathology 5.94
Jennie Ka Ching Lau1
Estimated H-index: 1
(CUHK: The Chinese University of Hong Kong),
Xiang Hua Zhang1
Estimated H-index: 1
(CUHK: The Chinese University of Hong Kong),
Jun Yu52
Estimated H-index: 52
(CUHK: The Chinese University of Hong Kong)
Non-alcoholic fatty liver disease (NAFLD) is a continuous spectrum of diseases characterized by excessive lipid accumulation in hepatocytes. NAFLD progresses from simple liver steatosis to non-alcoholic steatohepatitis and, in more severe cases, to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Because of its growing worldwide prevalence, various animal models that mirror both the histopathology and the pathophysiology of each stage of human NAFLD have been developed. The selecti...
Published on Sep 16, 2016in Journal of Biological Chemistry
Christine Kowalczyk-Quintas5
Estimated H-index: 5
(UNIL: University of Lausanne),
Sonia Schuepbach-Mallepell4
Estimated H-index: 4
(UNIL: University of Lausanne)
+ 10 AuthorsJacques Eric Gottenberg11
Estimated H-index: 11
(UDS: University of Strasbourg)
Abstract B cell activating factor of the TNF family (BAFF), also known as B lymphocyte stimulator, is a ligand required for the generation and maintenance of B lymphocytes. In this study, the ability of different monoclonal antibodies to recognize, inhibit, or activate mouse BAFF was investigated. One of them, a mouse IgG1 named Sandy-2, prevented the binding of BAFF to all of its receptors, BAFF receptor, transmembrane activator and calcium modulating ligand interactor, and B cell maturation an...
Published on Jul 1, 2016in Journal of Digestive Diseases 1.69
Feng Zhang4
Estimated H-index: 4
(PKU: Peking University),
Wei Wei Jiang1
Estimated H-index: 1
(PKU: Peking University)
+ 5 AuthorsYu Lan Liu2
Estimated H-index: 2
(PKU: Peking University)
To investigate the alterations and functions of intrahepatic B (IHB) cells in non-alcoholic fatty liver disease (NAFLD) model induced by high-fat diet (HFD).C57BL/6 J mice were fed with HFD for 16 weeks to induce NAFLD. Flow cytometry was used to analyze lymphocytes from liver, spleen and peripheral blood mononuclear cells (PBMC). Real-time polymerase chain reaction and immunofluorescence stain were applied to investigate cytokine expression in the intrahepatic lymphocytes and IHB cells. CD4(+) ...
Published on Apr 1, 2016in Arteriosclerosis, Thrombosis, and Vascular Biology 6.62
Daniel B. Harmon4
Estimated H-index: 4
(Carter Center),
Prasad Srikakulapu7
Estimated H-index: 7
(Carter Center)
+ 13 AuthorsAyelet Gonen18
Estimated H-index: 18
(Carter Center)
Objective—Little is known about the role(s) B cells play in obesity-induced metabolic dysfunction. This study used a mouse with B-cell–specific deletion of Id3 (Id3Bcell KO) to identify B-cell functions involved in the metabolic consequences of obesity. Approach and Results—Diet-induced obese Id3Bcell KO mice demonstrated attenuated inflammation and insulin resistance in visceral adipose tissue (VAT), and improved systemic glucose tolerance. VAT in Id3Bcell KO mice had increased B-1b B cells and...