LAUSR

BACKGROUND & AIMS Growing evidence suggests an important role of B cells in the development of non-alcoholic fatty liver disease (NAFLD). However, a detailed functional analysis of B cell subsets in NAFLD pathogenesis is lacking. APPROACH & RESULTS In wildtype mice, 21 weeks of high fat diet (HFD) feeding resulted in NAFLD with massive macrovesicular steatosis, modest hepatic and adipose tissue inflammation, insulin resistance and incipient fibrosis. Remarkably, Bnull (JHT) mice were partially protected whereas B cell harboring but antibody-deficient IgMi mice were completely protected from the development of hepatic steatosis, inflammation and fibrosis. The common feature of JHT and IgMi mice is that they do not secrete antibodies, while HFD feeding in wildtype mice led to increased levels of serum IgG2c. Whereas JHT mice have no B cells at all, regulatory B cells were found in the liver of both wildtype and IgMi mice. HFD reduced the number of regulatory B cells and interleukin 10 production in the liver of wildtype mice, while these increased in IgMi mice. Livers of patients with advanced liver fibrosis showed abundant deposition of IgG, stromal B cells and low numbers of interleukin 10 expressing cells, compatible with our experimental data. CONCLUSIONS B lymphocytes have both detrimental and protective effects in HFD-induced NAFLD. The lack of secreted pathogenic antibodies protects partially from NAFLD, whereas the presence of certain B cell subsets provides additional protection. Interleukin 10-producing regulatory B cells may represent such a protective B cell subset.