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Elucidation of the role of invariant NKT cells in the pathological evolution toward fibrosis in the liver of subjects affected by hepatitis

Invariant (inv)NKT cells are autoreactive lymphocytes recognizing endogenous lipid ligands presented by CD1d, and are suspected to regulate the host response to cell stress and tissue damage via the prompt production of cytokines.

We investigated invNKT cell response during the progression of chronic viral hepatitis caused by hepatitis B or C virus infection, a major human disease characterized by a diffused hepatic necroinflammation with scarring fibrotic reaction, which can progress toward cirrhosis and cancer. Ex vivo frequency and cytokine production were determined in circulating and intrahepatic invNKT cells from controls or chronic viral hepatitis patients without cirrhosis, with cirrhosis, or with cirrhosis and hepatocellular carcinoma. invNKT cells increase in chronically infected livers and showed modified effector functions, consisting in the production of the type 2 profibrotic IL-4 and IL-13 cytokines, which characterizes the progression of hepatic fibrosis to cirrhosis. CD1d, nearly undetectable in noncirrhotic and control livers, is strongly expressed by APCs in cirrhotic ones. Furthermore, in vitro CD1d-dependent activation of invNKT cells from healthy donors elicits IL-4 and IL-13.

Together, these findings show that invNKT cells respond to the progressive liver damage caused by chronic viral hepatitis, and suggest that these cells contribute to the pathogenesis of cirrhosis by expressing a set of cytokines involved in the progression of fibrosis.

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Experimental Immunology Unit
H. San Raffaele Scientific Institute via Olgettina 58
I-20132 MILANO
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