Abstract
In this thesis we address the immunomodulatory role of human leukocyte antigen G (HLA-G). The placental trophoblast cells express HLA-G as membrane bound and soluble form (due to alternative splicing) at the fetomaternal interface. HLA-G putatively interacts with the maternal endometrial (decidual) immunocompetent cells. We have studied the expression of HLA-G protein and RNA spliceforms in normal and pathological pregnancies. Although HLA-G protein is evidently expressed in recurrent miscarriage (RM) as well as ectopic pregnancy, in (RM) a decrease in HLA-G as compared to normal pregnancies was observed. In addition, placental biopsies of pregnancies affected by preeclampsia show a shift in spliceform expression. In midtrimester amnioticfluid from offspring affected by neuraltube defects, we show decreased levels of soluble-HLA-G as compared to normal pregnancies. Interestingly, in normal pregnancies amnioticfluid soluble-HLA-G was decreased for female as compared to male offspring. Peripheral NK cell parameters were linked to RM. Furthermore, normal decidual NK cells seem to change upon contact with HLA-G expressing trophoblasts, entering a blast like state that seems to be followed by the formation of apoptotic bodies and cell death. Whereas, in RM tissue an altered NK cell phenotype was paralleled by a decreased expression of HLA-G. In an in vitro model we show that a high dose of membrane-HLA-G inhibited the T cell proliferation as well as cytokine production by T cells (these effects were inverted at low dose). In contrast, at high dose of membrane-HLA-G both NK cell proliferation and cytokine production were stimulated. Our findings imply a finely tuned modulatory effect of membrane-HLA-G on both T and NK cell function. In conclusion, understanding the expression of HLA-G has deepened insight in and etiology of pregnancy disorders. Furthermore, the immuno-modulatory properties of HLA-G might be applicable in the transplantation immunology and autoimmune disease
