Immune interactions with the liver

• The liver has an important role in the induction of immune tolerance and can be a target for immune mediated damage. The following studies are performed to address the role of liver sinusoidal endothelial cells (LSEC) in tolerance induction and to understand some of the mechanisms involved in the pathogenesis of primary sclerosing cholangitis (PSC). We performed study I and II to investigate the role of LSEC in liver immunity. We hypothesized that LSEC would be the ideal cells responsible for tolerance induction and may also play a role in liver allograft rejections. We were interested in studying if antibodies to LSEC (LSEC Ab) may alter LSEC function, leading to liver allograft rejection. Study III and IV address the role of biliary epithelial cell antibodies (BEC Ab) in the immunopathogenesis of PSC. BEC are the targeted cells that are damaged in PSC. Earlier we reported that PSC patients have high frequency of BEC Ab. We hypothesized that BEC Ab may play a role in the inflammatory process during PSC. We therefore investigated the correlation between the chronic inflammation and the high frequency of BEC Ab. We studied the functional role of BEC Ab and innate immunity, Toll like receptors (TLR). The male predominance in PSC and the high levels of BEC Ab prompted us to investigate the functional relationship between the sex hormones (estradiol) and BEC Ab. In study I, we provide evidence that LSEC is one of the major cell types in the liver that contribute to peripheral tolerance through the induction of apoptosis of activated T cells. The apoptosis is mediated via the production of the immunosuppressive cytokine transforming growth factor beta (TGF-beta) and needed caspase 3 and 8 activity. In study II, we showed that the presence and binding of antibodies to LSEC are associated with acute liver allograft rejections. Antibodies to LSEC may facilitate acute liver allograft rejections by inducing CD86 expression and downregulating the production of TGF-beta and therefore upregulating alloreactive T cell proliferation. In study III, we found that PSC BEC Ab upregulate TLR-4 and -9 on BEC which in turn induced the production of interleukin-1beta (IL-1beta), interleukin-8 (IL-8) andgranulocyte-macrophage colony stimulating factor (GM-CSF). TLR upregulation specifically phosporylated ERK1/2 and the transcription factors ELK-1 and NF-kappaB. TLR-4 and -9 ligation induced the production of TNF-alpha and IFN-gamma. The adaptive immune response (BEC Ab) may facilitate the innate immune responses by induction of TLR on the bile duct epithelium in PSC patients. In study IV, we demonstrate that PSC patients have significantly high levels of estradiol which correlates with presence of BEC Ab. Our in vitro results show that estradiol binds to estrogen receptor beta ERbeta (upregulated by BEC Ab), which then decreases BEC proliferation and induces BEC apoptosis. Immunohistochemical staining of diminishing ducts in livers from PSC patients expresses ERbeta. This is one mechanism by which increased levels of estradiol and BEC Ab play a role in the pathogenesis of PSC. In summary, our findings indicate that LSEC play a role in peripheral tolerance by inducing apoptosis of activated T cells. Antibodies to LSEC may contribute to liver allograft rejections by modulating cellular immune responses. Antibodies to BEC and the high estradiol levels play a major role in PSC pathogenesis.

Nyckelord

Liver sinusoid, endothelial cells, apoptosis, antibodies, liver immunity, biliary cells, autoimmune liver diseases, estrogen

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