Abstract
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.
