Abstract
BACKGROUND AND AIMS: Recently, the number of follicular helper T (Tfh) cells expressing interleukin (IL)-21 was found to increase in peripheral blood of human and murine models of autoimmune hepatitis (AIH). IL-21, the most recently discovered member of the type-I cytokine family, exerts various effects on the immune system, including B cell activation, plasma cell differentiation, and immunoglobulin production. We aimed to assess the relationship of serum IL-21 levels in patients with type I AIH with clinical and laboratory parameters and histology. METHODS: Ninety-two Japanese patients with liver disease (22 AIH, 20 primary biliary cholangitis, 19 drug-induced liver injury, 8 acute hepatitis B, 8 chronic hepatitis C, 10 non-alcoholic steatohepatitis, 5 viral hepatitis) and 10 healthy volunteers were recruited. Serum IL-21 levels were detected by enzyme-linked immunosorbent assay. Real-time polymerase chain reaction measured mRNA levels of Bcl-6, IL-21, and CXCR5 (Tfh-related factors) in peripheral mononuclear cells. RESULTS: Mean age at diagnosis of AIH was 58.6 years, male-to-female ratio was 4:18, 18.2 % of participants had cirrhosis, and 22.7 % had severe disease. IL-21 levels were significantly increased in the serum of patients with AIH compared to those with other liver diseases and controls (p < 0.0001). Particularly, serum IL-21 levels were significantly increased in severe AIH cases compared to non-severe cases (p < 0.05). Serum IL-21 levels correlated positively with total serum bilirubin levels (r = 0.46, p < 0.05), grading of necroinflammatory activity (r = 0.68, p < 0.005) and negatively with serum albumin levels in patients with AIH (r = -0.49, p < 0.05). In patients with biochemical remission of AIH, serum IL-21 levels remained elevated and correlated positively with serum IgG levels (r = 0.84, p < 0.01). Expression of Tfh-related factors, such as Bcl-6 and IL-21, in peripheral blood mononuclear cells of patients with AIH was significantly higher than that in healthy volunteers. CONCLUSIONS: IL-21 may play an important role in the pathogenesis and severity of AIH, and may present a promising target for AIH therapy.