Contribution of Vα24⁺Vβ11⁺ natural killer T cells in Wilsonian hepatitis

Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. There is no evidence that the WD patient's immune system attacks copper accumulated hepatocytes. Here we describe that the frequency and absolute number of Vα24⁺Vβ11⁺ natural killer T (NKT) cells were significantly increased in 3 cases of WD, whereas those of CD3 ⁺CD161⁺ NKT cells were within the normal range. Patients no. 1 and 2 had a presymptomatic form of WD. Their tissue specimens showed pathological changes of mild degeneration of hepatocytes with a few infiltrating mononuclear cells and a low degree of fatty change. Patient no. 3 displayed fulminant hepatitis with Coombs-negative haemolytic anaemia. The tissue specimens of patient no. 3 showed macronodular cirrhosis with thick fibrosis, inflammatory infiltrates and spotty necrosis. Human Vα24 ⁺Vβ11⁺ NKT cells are almost equal to CD1d-restricted NKT cells. Therefore we investigated CD1d-restricted NKT cells in the LEC rat as an animal model of WD. In LEC rats before hepatitis onset, the number and phenotype of liver NKT cells were normal. At about 4 months of age all LEC rats developed acute hepatitis accompanied by acute jaundice, and CD161 ^high NKT cells developed in their livers. CD161^highα βTCR^bright NKT cells developed in some of them. Their hepatitis was severe. CD161^highαβTCR^bright NKT cells expressed an invariant rat Vα14-Jα281 chain, which is CD1d-restricted. Furthermore, liver lymphocytes in the acute jaundiced LEC rats with CD161^highαβTCR^bright NKT cells had significant and CD1d-specific cytotoxic activity.