免疫学的異常による流産原因の解明 [in Japanese] The Approaches to Clarify Spontaneous Abortion Based on Immunological Aspects [in Japanese]
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Introduction: The process of pregnancy must include mechanisms to prevent allograft rejection, because a fetus is a semiallograft. Some mechanisms for the maintenance of pregnancy have been proposed. For example, villous trophoblasts do not express classical major histocompatibility complex (MHC) class I and class II molecules in humans, and human extravillous trophoblasts express only MHC-class I molecules such as human histocompatibility leukocyte antigen (HLA)-C, HLA-E, and HLA-G, which are specific ligands for uterine natural killer (NK) cells. Additionally, decidual NK cells produce a number of cytokines that promote trophoblast proliferation and differentiation, as well as angiogenesis factors. NK cells, however, sometimes have cytotoxic activity against fetal cells. Cytokines play an important role for the maintenance of pregnancy, and dysregulation of the cytokine profile induces abortion in mice. The old Th1/Th2 paradigm has developed into the new Th1/Th2/Th17 and regulatory T (Treg) paradigm. Previous data showed that regulatory T cells play an essential role in the induction of tolerance to paternal antigens during pregnancy. And, a reciprocal development pathway between Th17 cells, which are involved in inducting inflammation, and regulatory T cells was also reported. In unexplained recurrent spontaneous abortion cases, the proportion of decidual Th17 cells was significantly higher and the proportion of decidual regulatory T cells was significantly lower compared with that in normal pregnancy. Therefore, the balance between the activation system and regulation system in maternal immune cells is important to maintain successful pregnancy. Results: First topic is the cytokines expression profiles of CD16^-CD56^<bright> NK cells. Normal pregnant women had the significant high numbers of TGF-β positive NK cells, NK3, in decidual lymphocytes, compared with that of spontaneous abortion. Additionally, the significant high numbers of IL-10 positive NK cells, NKr1, was also obtained in peripheral blood lymphocytes of normal pregnant women. NK3 cells were induced by prolactin and soluble HLA-G1, and NKr1 cells were induced by human gonadotropin and progesterone in vitro. Second is the direct correlation between extravillous trophoblasts (EVTs) and CD16^-CD56^<bright> NK cells. The number of granulysin-positive CD56^<bright> NK cells significantly increased in the decidua basalis in spontaneous abortion, compared with normal pregnancy. In vitro study showed that granulysin-positive decidual NK cells attack EVTs; subsequently, the decidual NK-derived granulysin actively accumulates in the nuclei of EVTs, causing the death of EVTs due to apoptosis. This is the first report that maternal decidual NK cells directly attack fetusderived EVTs in human. Third topic is about the role of Th17 cells in spontaneous abortion. Th17 cells are involved in the chronic inflammation and infection. IL-17^+ cells were accumulated in decidua and were detected in decidual CD4^+ T cells in spontaneous abortion cases. The number of decidual IL-17^+ cells in inevitable abortion cases involving active genital bleeding was significantly higher than that in normal pregnancy cases. IL-17^+ cells might be involved in the induction of inflammation in the late stage of abortion, but not in the early stage of abortion. Last topic is the roles of regulatory T cells in pregnancy. We have reported that CD4^+CD25^<high> regulatory T cells increased in the peripheral blood, and these regulatory T cells in early pregnant decidua further increased to three times the level found in the peripheral blood in humans. In this study, we constructed a pregnant mice model with lower number of regulatory T cell by an administration of anti-CD25 monoclonal antibodies at days 4.5 and 7.5 of gestation. The ratio of regulatory T cells in CD4^+ regulatory T cells was decreased in proportion to the dosage of anti-CD25 monoclonal antibody. On the other hand, the abortion ratio was significantly increased in inverse proportion to the ratio of regulatory T cells in allogeneic pregnancy, but not in syngeneic pregnancy. Thus, regulatory T cells prevent fetal rejection at the implantation phase in an allogeneic pregnancy. Paternal antigen-reactive regulatory T cells increased in regional lymph nodes of the uterus such as para-aortic lymph nodes and pelvic lymph nodes at day 3.5 and increased in uterus since at day 5.5 in allogeneic pregnancy. Implantation occurs on day 4.5 in mice, so increased regulatory T cells in regional lymph nodes occurred before implantation. Additionally, seminal fluid contributed to the priming the paternal antigen by maternal immune cells. In human pregnancy, the ratio of regulatory T cells in decidual lymphocytes was significantly decreased in spontaneous abortion with normal karyotype, but not with karyotype abnormality, compared with that with normal pregnancy. Furthermore, immunohistochemical analysis showed the significant decreased number of regulatory T cells in decidua basalis in spontaneous abortion with normal karyotype. Conculsions: Maternal immune cells recognize the paternal antigen in seminal fluid. Subsequently, paternal antigen-reactive regulatory T cells increase in regional lymph nodes before implantation and these cells support to accept fetus in uterus. On the other hand, dysfunction of maternal regulatory T cells may cause to reject fetus. A decrease of maternal regulatory T cells might induce immunological response to fetus, and then activated NK cells directly attack EVT cells via granulysin. Finally excessive inflammation might accumulate Th17 cells and neutrophils, resulting in spontaneous abortion.
日本産科婦人科學會雜誌 63(12), 2185-2197, 2011-12-01