Interleukin-32 production associated with biliary innate immunity and proinflammatory cytokines contributes to the pathogenesis of cholangitis in biliary atresia

Biliary atresia (BA) is thought to be associated with infections by viruses such as Reoviridae and is characterized histologically by fibrosclerosing cholangitis with proinflammatory cytokine-mediated inflammation. Interleukin (IL)-32 affects the continuous inflammation by increasing the production of proinflammatory cytokines. In this study, the role of IL-32 in the cholangitis of BA was examined. Immunohistochemistry for IL-32 and caspase 1 was performed using 21 samples of extrahepatic bile ducts resected from BA patients. Moreover, using cultured human biliary epithelial cells (BECs), the expression of IL-32 and its induction on stimulation with a Toll-like receptor [(TLR)-3 ligand (poly(I:C)] and proinflammatory cytokines was examined. BECs composing extrahepatic bile ducts showing cholangitis expressed IL-32 in BA, but not in controls. Caspase 1 was expressed constantly on BECs of both BA and control subjects. Furthermore, poly(I:C) and proinflammatory cytokines [(IL-1β, interferon (IFN)-γ and tumour necrosis factor (TNF)-α] induced IL-32 expression strongly in cultured BECs, accompanying the constant expression of TLR-3 and caspase 1. Our results imply that the expression of IL-32 in BECs was found in the damaged bile ducts of BA and induced by biliary innate immunity via TLR-3 and proinflammatory cytokines. These findings suggest that IL-32 is involved initially in the pathogenic mechanisms of cholangitis in BA and also plays an important role in the amplification and continuance of periductal inflammatory reactions. It is therefore tempting to speculate that inhibitors of IL-32 could be useful for attenuating cholangitis in BA. © 2013 British Society for Immunology

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

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

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD