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

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.

Adaptive immunity: an emerging player in the progression of NAFLD

“…These findings are supported by clinical observations that both paediatric and adult patients with NASH are characterized by an increase in levels of liver and circulating IFNγ-producing CD4 + T cells 36,37 . Moreover, in adult patients with NASH, plasma IFNγ levels positively correlate with the number and size of hepatic lymphocyte aggregates as well as with the severity of fibrosis 27 . In response to inflammatory stimuli, CD4 + T cells can also differentiate to type 17 T helper (T H 17) cells, which are characterized by the expression of the nuclear receptor retinoic acid-related orphan receptor-γt and by the production of IL-17 and, to a lesser extent, IL-21, IL-22, IFNγ and TNF 38 .…”

“…1). Interestingly, the size and prevalence of these aggregates positively correlate with lobular inflammation and fibrosis scores 27 . Hepatic infiltration by B cells and CD4 + and CD8 + T cells is also evident in different experimental models of NASH, in which it parallels with worsening parenchymal injury and lobular inflammation 29-33 . These T cells express the memory or effector markers CD25, CD44 and CD69, along with enhanced production of the cytokine LIGHT (also known as TNFSF14), indicating their functional activation 29,30,33 .…”

“…These cells are also an important component of periportal infiltrates associated with NASH ductular reactions 26 . In ~60% of patients with NASH, B cells and T cells form focal aggregates 27 , resembling ectopic lymphoid structures 28 (Fig. 1).…”

Mesenteric adipose tissue B lymphocytes promote local and hepatic inflammation in non‐alcoholic fatty liver disease mice

“…13 In recent years, increasing studies have suggested that B lymphocytes are also involved in adipose tissue inflammation. 16 However, the role of B lymphocytes in the inflammation of MAT is poorly understood. 14 Transferred B2 cells in EAT of HFD-fed mice to HFD-fed B null recipient mice result in increased adipose tissue inflammation.…”

“…15 B null mice show improved insulin resistance and glucose metabolism compared to control mice under the stimulation of HFD, 14,15 and B2 cell depletion in mice resulted in alleviated NAFLD. 16 However, the role of B lymphocytes in the inflammation of MAT is poorly understood. Here, we aimed to explore the role of MAT B cells in MAT inflammation.…”