Adaptive immunity: an emerging player in the progression of NAFLD

Abstract

In the past decade, nonalcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease and cirrhosis, as well as an important risk factor for hepatocellular carcinoma (HCC). NAFLD encompasses a spectrum of liver lesions, including simple steatosis, steatohepatitis and fibrosis. Although steatosis is often harmless, the lobular inflammation that characterizes nonalcoholic steatohepatitis (NASH) is considered a driving force in the progression of NAFLD. The current view is that innate immune mechanisms represent a key element in supporting hepatic inflammation in NASH. However, increasing evidence points to the role of adaptive immunity as an additional factor promoting liver inflammation. This Review discusses data regarding the role of B cells and T cells in sustaining the progression of NASH to fibrosis and HCC, along with the findings that antigens originating from oxidative stress act as a trigger for immune responses. We also highlight the mechanisms affecting liver immune tolerance in the setting of steatohepatitis that favour lymphocyte activation. Finally, we analyse emerging evidence concerning the possible application of immune modulating treatments in NASH therapy.

Fig. 1. Lymphocyte aggregates.

Immunohistochemical detection of lymphocyte aggregates containing CD3⁺ T cells and CD20⁺ B cells in serial sections of liver biopsy samples from patients with nonalcoholic steatohepatitis (magnification ×10 and ×40).

Fig. 2. Role of oxidative stress in hepatic inflammation and parenchymal injury in nonalcoholic steatohepatitis.

Liver dendritic cells and other antigen-presenting cells (APCs) present oxidative stress-derived epitopes (OSE) to CD4⁺ T helper (T_H) cells in the context of major histocompatibility complex class II (MHC II) molecules. This signal, together with enhanced expression of costimulatory molecules such as OX40, leads to the activation of CD4⁺ T cells and their T_H1 cell or T_H17 cell polarization. CD4⁺ T_H cells also support both cytotoxic CD8⁺ T cell responses and B cell maturation of plasma cells secreting anti-OSE IgG. In turn, B cells can promote immune-inflammatory processes by antigen presentation to CD4⁺ T cells and by producing inflammatory cytokines. IFNγ and T_H1 cell cytokines also stimulate liver macrophages to release M1 pro-inflammatory cytokines and chemokines (IL-12, CC-chemokine ligand 2 (CCL2) and CXC-chemokine ligand 9 (CXCL9)) that further contribute to recruiting monocytes and lymphocytes. Macrophages and dendritic cells also release B cell stimulating cytokines such as B cell-activating factor (BAFF), which are critical for B cell maturation to plasma cells. IL-15 produced by both hepatocytes and liver macrophages favours the survival of CD8⁺ T cells and, together with CXCL16, is implicated in promoting liver natural killer T (NKT) cell differentiation and survival. NKT cells and CD8⁺ T cells can further contribute to steatohepatitis through the secretion of LIGHT and IFNγ. TCR, T cell receptor.

Fig. 3. Factors involved in stimulating the onset of adaptive immune responses during the evolution of nonalcoholic steatohepatitis.

During the development of nonalcoholic steatohepatitis, the combined action of damage-associated molecular patterns (DAMPs) released by damaged hepatocytes, oxidative stress-derived epitopes (OSEs) and pro-inflammatory mediators affects the tolerogenic action of liver dendritic cells, Kupffer cells and sinusoidal endothelial cells. These changes contribute to a reduction in liver regulatory T (T_reg) cells and favours the expansion and activation of dendritic cells. Alterations in the gut–liver axis due to dysbiosis and obesity-related changes in the adipokine network are additional factors that affect liver immune tolerance. As a result, enhanced antigen presentation to lymphocytes associated with increased expression of costimulatory molecules leads to the development of both cellular and humoral immune responses. APC, antigen presenting cell; SCFA, short-chain fatty acid; T_H cell, T helper cell.