AbstractsBiology & Animal Science

Biliary epithelial cells, the immune system and PSC pathogenesis

by Lena Berglin

Institution: Karolinska Institute
Year: 2015
Record ID: 1357279
Full text PDF: http://hdl.handle.net/10616/44487


Primary sclerosing cholangitis (PSC) is a chronic, inflammatory liver disease that leads to destruction of the bile duct system. PSC is strongly associated with inflammatory bowel disease, and PSC patients have an increased risk of developing malignancies, especially cholangiocarcinoma (CCA). The pathogenesis of PSC is still insufficiently understood, although T cells have been suggested to play a major role. Little is known about the involvement of other immune cell populations. In addition to this, a better understanding is needed about the capacity of liver resident immune cells to prevent tumor development. In this thesis we have investigated cellular and humoral components of the immune system, in PSC and the PSC-associated malignancy CCA. In the first study, we examined the role of autoreactive antibodies in PSC patients. Flow cytometry was used to investigate the presence of IgA and IgG antibodies in PSC patient sera, and its reactivity against isolated human biliary epithelial cells. A majority of the patients had antibodies that bound to the cells, while only low levels could be detected in serum of healthy individuals. Moreover, IgA autoantibodies in PSC patients were associated with a reduced survival, and therefore their presence may be of importance in the pathogenesis of PSC. In the second and third study, immunohistochemistry and image analysis was used, to explore the cell compositions in PSC and CCA livers. Specific phenotypic patterns, associated with severity of disease, were revealed in PSC livers. T cells were enriched, mainly localizing to fibrotic fields, whereas MAIT cells were not equally increased. Furthermore, one group of PSC patients, characterized by a potential loss of smooth muscle cell function, was found to have increased numbers of T cells and a more extensive bile duct proliferation. The tumor microenvironment in CCA was characterized by a selective loss of Kupffer cells and MAIT cells, and contained high numbers of regulatory T cells. Moreover, the expression of IL-33 was significantly lower in tumors. This distinct intratumoral phenotype was unaffected by tumor location, tumor differentiation, or an underlying PSC. Altogether, our studies provide insights into the pathogenesis of PSC and CCA and opens up for further studies of disease mechanisms.