B cells: no longer bystanders in liver fibrosis

Abstract

Cytokines secreted by cells that mediate the innate and adaptive immune responses play a critical role in regulating the synthesis of ECM components by fibroblasts. Overexpression and deposition of ECM components are dominant features of fibrotic diseases, including hepatic fibrosis. The contribution of CD4 + Th2 cells to hepatic fibrosis has been well described. Now, in this issue of the JCI, Novobrantseva et al. provide data to suggest that hepatic B cells also play a role in liver injury (see the related article beginning on page 3072). In a carbon tetrachloride-induced mouse model of hepatic fibrosis, T cell-deficient mice developed severe liver fibrosis; however, in B cell-deficient animals, hepatic fibrosis was attenuated. This study provides new insight into our understanding of the cells involved in mediating the adaptive immune response that leads to hepatic fibrosis.The ECM is composed of a variety of molecules including the fibrous proteins collagen and fibrillin, adhesion molecules, glycoproteins, proteoglycans, and metalloproteinases, which together form a scaffold on which cells adhere, grow, and differentiate. The most abundant proteins in the ECM belong to the collagen family. In general, ECM molecules are synthesized by fibroblasts; in the liver, they are synthesized by activated hepatic stellate cells (HSCs), portal fibroblasts, and myofibroblasts of bone marrow origin.Maintenance of the normal structure and function of the ECM involves constant remodeling, which results from regulated, low levels of ECM synthesis and degradation. During wound healing, there is a short-lived shift in the balance of synthesis and degradation, which leads to a transient increase in collagen production and deposition. Chronic collagen production can result in keloid scars. A permanent imbalance resulting in major alterations in both the quantity and composition of the ECM causes fibrosis. Excessive accumulation of type I collagen is a major pathological feature in diseases such as scleroderma, osteogenesis imperfecta, and scurvy as well as other conditions of the lung, kidney, and liver characterized by tissue fibrosis (1). The main causes of liver fibrosis include chronic HCV infection, alcohol abuse, and nonalcoholic steatohepatitis. We note that exposure to carbon tetrachloride (CCl 4 ), the most commonly used model of chemically induced hepatic fibrosis in rodents, is not considered to be a main cause of hepatic fibrosis in humans.The cellular and molecular mechanisms underlying fibrotic disorders are similar regardless of the tissue involved. First, excessive collagen production results from the increased expression of the collagen gene. Second, decreased activity of ECM-removing metalloproteinases, primarily due to the overexpression of tissue inhibitors of metalloproteinases (TIMPs), results in decreased ECM (including collagen) degradation. Third, acquisition of a novel phenotype by fibroblasts is related to abnormal activation of receptors and signaling pathways (2, 3), leading to autocrine synthesis of c...

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