J Clin Pathol 66:99-108 doi:10.1136/jclinpath-2012-201097
  • Original articles

Participation of natural killer cells in the pathogenesis of bile duct lesions in biliary atresia

  1. Yasuni Nakanuma1
  1. 1Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa
  2. 2Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
  1. Correspondence to Professor Yasuni Nakanuma, Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 920-8640, Japan; nakanuma{at}
  • Received 24 July 2012
  • Revised 19 September 2012
  • Accepted 23 September 2012
  • Published Online First 16 November 2012


Aims Immunological disturbances including innate immunity after a suspected viral infection are considered important to the pathogenesis of bile duct lesions in cases of biliary atresia (BA). In this study, we tried to evaluate whether natural killer (NK) cells and CX3CL1 (Fractalkine) and its receptor (CX3CR1) are involved in the bile duct injury.

Methods Using the section of BA (22 cases) and controls, immunohistochemistry for CD56, CD16, CD68, CX3CL1 and CX3CR1 was performed. Moreover, using cultured biliary epithelial cells (BECs) and NK cells, the production of CX3CL1 in BECs and the migration of NK cells were evaluated.

Results It was found that CD56(−)CD16(+)CD68(−) NK cells were increased around the damaged small and large bile ducts in BA and hepatitis C virus-related chronic hepatitis in comparison with other controls. CX3CL1 was strongly expressed on the damaged bile ducts in BA, while this expression was relatively weak or absent in the bile ducts of normal liver. The results suggest the CD56(−)CD16(+) NK cells to be involved in the development of bile duct injuries in BA. These CD16(+) NK cells were positive for CX3CR1, and attracted by CX3CL1 expressed on bile ducts. Further study revealed that stimulation with poly(I:C) (a synthetic analogue of viral dsRNA) increased the expression of CX3CL1 on cultured BECs followed by increased migrational activity of cultured NK cells.

Conclusions CD56(−)CD16(+) NK cells with reduced NK activity may be involved in the bile duct damage in BA, and CD16(+) NK cells expressing CX3CR1 may be attracted by and interact with bile ducts expressing CX3CL1.