Eosinophils and primary biliary cirrhosis—Stoking the fire?

Eosinophilic infiltration of the liver is seen in a wide spectrum of liver diseases, including viral liver diseases (hepatitis C), adverse drug reactions (such as in halothane hepatitis), liver allograft rejection, and graft-versus-host disease and primary biliary cirrhosis (PBC). Eosinophils are nondividing, granulated cells with characteristic, membranebound specific granules, eosinophil primary granules, and lipid bodies. The membrane-bound granules consist of a matrix and a core: the core of the granule consists of major basic protein and the matrix contains eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin. The primary granules contain Charcot-Leyden crystal protein. Lipid bodies are not membrane bound and are the main store of arachidonic acid. Eosinophils have the capacity to secrete many mediators, including the basic proteins, peroxidases, cytokines, superoxide, and hydrogen peroxide. Degranulation can be stimulated by many factors including cytokines such as RANTES (regulated upon activation, normal T cell expressed and presumably secreted), interleukin 5 (IL-5), and IL-3.1 These mediators released by degranulation, will stimulate many aspects of inflammation, including activation of basophils, neutrophils, and platelets; generation of cytokines; and stimulation of the cyclo-oxygenase pathway and they are toxic to a variety of cell types, including epithelial cells.2 Major basic protein is also an important regulator of fibroblast function by regulating fibroblastic production of cytokines.3 Eosinophil growth and differentiation is stimulated by T-cell–derived cytokines including IL-3, IL-5, and granulocyte macrophage colony stimulating factor and these cytokines are associated with Th2 responses. Tissue accumulation of eosinophils is dependent on a multi-stepped, tightly regulated process: tethering of the eosinophils to the endothelium is by binding of a selectin receptor to its ligand (eosinophils express L-selectin, p-selectin glycoprotein ligand-1, and E-selectin ligand-1); adhesion is mediated through a variety of integrins (including VLA-4, VLA-6, LFA-1, and Mac-1). There are several chemoattractants for eosinophils, including lipids such as platelet-activating factor and LTB4, growth factors such as IL-3 and IL-5, and chemokines. Those chemokines that are chemoattractant for eosinophils include RANTES, eotaxin, and monocyte chemotactic protein 3 (MCP-3) and macrophage inflammatory protein 1a (MIP1a). Eosinophils are capable of remaining in tissue for a prolonged period before undergoing apoptosis and phagocytosis by macrophages. The mediators secreted by eosinophils are capable of inducing cell damage: both eosinophil peroxidase and major basic protein are toxic to epithelial cells.2 The possible involvement of eosinophils in PBC has been suggested for many years. In patients with PBC, there is a peripheral eosinophilia that is more marked in those with earlier histological disease4-6; peripheral eosinophilia correlates not only with tissue eosinophilia and mast cells, but also basophil count and serum IgA.7,8 In the liver in patients with PBC, eosinophils containing eosinophil cationic protein are found in the portal tracts, especially where there is lymphocytic activity, with infiltrates, granulomas, and the florid duct lesions; eosinophilic infiltration is less where bile ducts have disappeared. The association between eosinophilia and PBC is intriguing and raises a number of issues: Why are eosinophils activated in PBC? Why are they attracted to the liver? Are they toxic to biliary epithelial cells and other liver cell types? Why is ursodeoxycholic acid (UDCA) associated with a decrease in eosinophil count and activity? Can answers to any of these questions help in elucidating the cause or treatment of PBC? In the serum of patients with PBC, levels of IL-5 and interferon-g are increased.9 Although both Th1 and Th2 cells are found in the liver of patients with PBC,10 assessment of the cytokine profile in the liver of patients with PBC gives conflicting results: Martinez et al.11 found evidence of Th2type cytokines with increased messenger RNA for IL-5 when compared with livers from patients with autoimmune hepatitis, whereas Harada et al.12 found evidence to support a Th1 profile, with increased messenger RNA for IL-4, although interferon-g was seen around damaged portal tracks. Shindo et al.13 were able to detect in the liver of PBC patients messenger RNA for interferon-g but not for IL-1, 2, 4, 5, or 6. Dienes et al.14 also found evidence for a Th1 predominance. Given that eosinophils are associated with IL-5 and that these cells are found in early disease, it may be that during the progression of PBC, there is a switch from Th2 to Th1.15 The particular involvement of eosinophils with biliary epithelial cells is suggested by several pointers: biliary epithelial cells can secrete RANTES (Moreland and Adams, personal communication); secretory IgA and secretory component play an important role in regulating eosinophil function.16,17 It is possible that degranulation of eosinophils around the bile ducts, will lead to lipid peroxidation, granuloma formation and inflammation as has been suggested for Schistosomal liver infestation.18 UDCA has become the accepted treatment for patients with PBC. Although there is some controversy about whether UDCA is associated with a significant improvement in survival,19,20 many serological changes are associated with its use: liver tests improve and there is a reduction in serum immunoglobulins and the titer of antimitochondrial antibody, a fall in serological markers of inflammation, such as Abbreviations: PBC, primary biliary cirrhosis; IL, interleukin; UDCA, ursodeoxycholic acid. From the Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. Received May 3, 1999; accepted May 14, 1999 Address reprint requests to: James Neuberger, M.D., The Liver and Hepatobiliary Unit, 3rd Floor, Nuffield House, The Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK. E-mail: J.M. Neuberger@bham.ac. uk; fax: (44) 121 627 2449. Copyright r 1999 by the American Association for the Study of Liver Diseases. 0270-9139/99/3001-0046$3.00/0