congresos y reuniones científicas
KIR-mediated cytotoxic activity in NK cells are associated with liver injury in chronic HCV patients
N PALADINO, AC FLORES, L ARRUVITO, H FAINBOIM, T SCHRODER, AE MUÑOZ, O GALDAME, D MIDDLETON AND L FAINBOIM
Rio de Janeiro, Brasil
Congreso; 15th Histocompatibility and Immunogenetics Conference; 2008
A strong NK and Th1 cells mediated immune response in the acute state is a key factor in the protection against hepatitis C virus (HCV) infection. Their failure generates a persistent cellular immunity responsible for chronic liver injury. The cytotoxic activity of NK cells is partially regulated by inhibitory (2DL1-5, 3DL1-3) and stimulatory (2DS1-5, 3DS1) Killer Immunoglobulin-like Receptor (KIR). We previously identified the KIR2DS3 and 3DS1 associated with chronic evolution and cirrhosis of HCV patients, but decreased frequency of KIR2DS4. In order to confirm the diminution of this activating receptor we performed the allelic typing of deleted (003, 005, 006: soluble secreted receptor) and no deleted (00101, 00102, 002: functional membrane receptor) forms of KIR2DS4 by PCR-SSOP technique. The comparison of 257 HCV patients with 420 healthy controls (HC) showed a decreased frequency of the deleted forms of KIR2DS4 (P=0.006) in the patients, particularly in cirrhotic individuals (p=0.0006). The diminution of 003 was mainly detected in cirrhotic individuals (p=0.003), meanwhile the decrease of 005 and 006 allele frequencies was observed in chronically infected individuals (p=0.004 and p=0.01, respectively). Thus, in HCV patients,decreased frequency of the deleted forms represent a relative increase of the functional KIR2DS4 gene. The flow cytometry analysis of the membrane expression of KIR genes, demonstrated an increased proportion of KIR2DS4 positive cells within the NK CD56dim subpopulation (p=0.025). Additionally, we also observed, mainly in CD56bright an increased frequency of NK expressing KIR2DL1/2DS1, 3DL1 and 2DL4 (p=0.0008, p=0.0007, p=0.015, respectively). This last finding might be associated with the maturation state of the NK cells, probable induced by the virus infection. In conclusion, our results indicate that NK cell mediated cytotoxicity might be responsible for the liver injury observed in chronic HCV patients.