The association between the CB2-63 QQ variant and the status of HCV carrier with PNALT may be the result of a prolonged strong inhibition of the T cells with QQ variants,Landiolol hydrochloride with a consequently less vigorous immune response against infected hepatic cells. Support for this hypothesis comes from an in-vitro study on the CB2-mediated inhibition of T-cell proliferation, normal with T cells deriving from CB2-63 QQ subjects and reduced two-fold with T cells from subjects with the RR homozygous variant. In fact, aggressive autoimmune pathologies such as celiac disease and childhood immune thrombocytopenic purpura have been found to be associated with the CB2-63 RR variant. It has been recently suggested that HCV-related proteins induce prolonged activation of liver Kupffer cells, leading to the accumulation of inflammatory cytokines that contributes to liver damage. These cells, however, may also express a range of polarized phenotypes, including the M1proinflammatory phenotype and the M2 alternative phenotype involved in the resolution of inflammation and wound healing. It has been demonstrated CB2 stimulation inhibits pro-inflammatory M1 polarization and favors the transition to the anti-inflammatory M2phenotype. This transition might be more frequently expressed in CB2-63 QQ than in RR Kupffer cells due to the above-mentioned reduced inhibition of T-cell proliferation in subjects with CB2-63 RR. This transition may favor the progression from CHC to the PNALT status and explain, at least in part,Urolithin A the association observed between the QQ homozygous variant and the PNALT status. The mean age of the PNALT subjects in the present study was 8 years older than that in the abnormal ALT group, suggesting that a substantial percentage of them may have reached the PNALT status through a variety of immunological conditions, from an active cellular immune response at the time of acute hepatitis C and in the initial stage of HCV carriage to a subsequent inhibition/failure of the cellular immune response favoring the progressionto the clinical and histological profile characteristic of PNALT.