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Acquired and innate immunity in decidua
Journal of Reproductive Immunology 118 (2016) 147–148
Contents lists available at ScienceDirect
Journal of Reproductive Immunology journal homepage: www.elsevier.com/locate/jreprimm
31th Annual Meeting of the Japan Society for Immunology of Reproduction – Symposium 3
Role of autoantibody in pathophysiology of preeclampsia Takayuki Iriyama Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan The relationship between pregnancy and autoimmunity is represented by a bidirectional model. Autoimmune disease can be affected by pregnancy, in turn, pregnancy can also be affected by autoimmune disease from the early stage of gestation, which leads to the development of obstetric complications including preeclampsia (PE). Numerous recent studies have demonstrated that PE patients develop the autoantibodies that can activate angiotensin II type1 receptor (termed AT1 -AA) and contribute to the disease pathophysiology. These studies suggest the possibility that PE is a pregnancy-induced autoimmune condition. In this symposium, we will present our recent studies and advances in the understanding of roles of pathogenic autoantibodies (AT1 -AA) in PE. Conflicts of interest: The authors have no conflict of interest to declare. http://dx.doi.org/10.1016/j.jri.2016.10.109 Paternal antigen specific immune-tolerance for implantation and maintenance of pregnancy Tomoko Shima ∗ , Akemi Ushijima, Sayaka Tsuda, Kumiko Inada, Akitoshi Nakashima, Osamu Yoshino, Shigeru Saito Department of Gynecology and Obstetrics, University of Toyama, Japan Background: Regulatory T cells (Tregs) induce feto-maternal tolerance. Tregs depletion in allogeneic mating causes implantation failure and abortion. It is suggested that Tregs have a paternal antigen specific function. We have focused paternal antigen specific Tregs (PA-Tregs) in allogeneic pregnancy. Method: (1) The kinetics of PA-Tregs in allogeneic mating mice (BALB/c♀ × DBA/2♂) were analyzed by the flow cytometry. (2) To analyze the role of seminal fluid in Treg expansion, we resected the seminal vesicle of male DBA/2 (SVX). (3) Antigen specific Tregs 0165-0378/
are increased after antigen presentation by dendritic cell (DCs). The character of DCs in allogeneic mating was analyzed. Result: (1) The frequency of PA-Tregs increased in draining lymphnodes on day 3.5 pc and day 5.5 pc in allogeneic mating. (2) The frequency of PA-Tregs did not increase in SVX allogeneic mating. (3) CD86 and MHC class II expressions on DCs were decreased in uterus on day 3.5 pc and day 5.5 pc in allogeneic mating. On the other hand, B7-DC expression on DCs was increased. These molecules on DCs did not change in SVX allogeneic mating. DCs derived from uterus in allogeneic mating suppressed the proliferation of female spelenocytes. Conclusion: In allogeneic mating, seminal fluid priming induce tolerogenic DC resulting in expansion the PA-Tregs for the success of the implantation and pregnancy maintenance. Conflicts of interest: The authors have no conflict of interest to declare. http://dx.doi.org/10.1016/j.jri.2016.10.110 Acquired and innate immunity in decidua Shigeki Shimada Mommy’s Clinic Chitose, Japan Comparative study was carried out concerning immune abnormalities in the uterine endometrium and decidua (feto-maternal interface) on both sides of acquired and innate immunity or their mutual relationship. Th1/Th2 balance in miscarriages: Reduced number of CD3+ T cells, increased number of CD4+ helper T (Th) cells who do not express neither IFN-␥ nor IL-4, and decreased cell ratio of Th1 cells were observed in the endometriums of recurrent miscarriages (RM). In decidua of miscarriages, Th2 balance was observed compared with induced abortion (IA), but no difference was observed between miscarriage with normal chromosome (MN) and with abnormal chromosome (MA). CD4+IL−17+ (Th17) cells in miscarriages: Although Th17 cells were decreased in deciduae as compared with in endometrium in luteal phase (EM), no difference was observed among IA, MN and MA. Cytotoxicity T(Tc) cell balance in miscarriages: Tc1 cell ratio was increased in MN than in MA or IA.
148
Abstracts / Journal of Reproductive Immunology 118 (2016) 147–148
Regulatory T (Treg) cells in miscarriages: When CD4+CD25highFoxp3+ cells were defined as Treg cells, in MN, the Treg cells were rather increased compared with in MA. Natural killer (NK) cell ratio in miscarriages: In the endometriums of RM women and control women, there was no difference in CD56+NK cell ratio. In deciduae, there was no difference in NK cell ratio among IA, MN and MA. NK cell receptors in miscarriages: In the deciduae of MN, compared with MA or IA, an expression of inhibitory receptors CD158a and CD94 in NK cells was decreased, on the other hand, the perforin expressions in NK cells and cytotoxicity T (Tc) cells were increased. Moreover, in deciduae in MN, negative correlation was observed between the expressions of CD94 or CD158a in NK cells and the perforin expression in Tc cells. Therefore, it was suggested that such immune cells maintain pregnancy in cooperation, otherwise cause miscarriages. Macrophages (Mac) in miscarriages: Expressions of activation marker HLA-DR and maturation marker CD206 in CD68+CD163+Mac were decreased in IA as compared with in EM, but these reductions were not observed in miscarriage group. Conflicts of interest: The authors have no conflict of interest to declare. http://dx.doi.org/10.1016/j.jri.2016.10.111 NK cell abnormality and its treatment in women with reproductive failures such as implantation failure and recurrent pregnancy loss
cells dramatically increase at the secretory phase and early pregnancy. Appropriate regulation of the NK cells lead to reproductive success. We have reported that higher percentage of midsecretory endometrial CD16+ /CD56dim NK cells causes abortion or light for gestational age baby for subsequent pregnancies in IVF. NKp46 is a unique marker that functions in NK cell cytotoxicity and cytokine production. We have shown that expression of NKp46 on NK cells is lower in women with implantation failure and RPL. Some medicine has been applied for the treatment of women with RPL with abnormal NK cell, although their effects are still controversial. We have developed some treatments using IVIG, intralipid or GM-CSF added IVF medium. It is reported that IVIG therapy suppresses the NK cell cytotoxicity and similar effect is also reported by intralipid therapy for women with IF or RPL. Using these medicine, live birth rate for women with RPL was 84.2% (16/19) in IVIG treatment and 85.7% (6/7) in intralipid treatment. Moreover, GM-CSF is produced by immune cells such as NK cell and is important for the embryo quality and growth, and uterine endometrial environment. We have compared the clinical pregnancy rate (CPR) in frozen-thawed embryo transfer. The CPR in GM-CSF added medium group was 47.6% (20/42) and in regular medium was 30.4% (14/46). In conclusion, modification of abnormal NK cells may have preferable effects in women with NK cell abnormality and reproductive failure. Conflicts of interest: The authors have no conflict of interest to declare.
Atsushi Fukui 1,2 1
Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan 2 Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Japan The regulation of natural killer (NK) cells has been associated with problems related to reproductive failures. Uterine NK
http://dx.doi.org/10.1016/j.jri.2016.10.112
Contents lists available at ScienceDirect
Journal of Reproductive Immunology journal homepage: www.elsevier.com/locate/jreprimm
31th Annual Meeting of the Japan Society for Immunology of Reproduction – Symposium 3
Role of autoantibody in pathophysiology of preeclampsia Takayuki Iriyama Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Japan The relationship between pregnancy and autoimmunity is represented by a bidirectional model. Autoimmune disease can be affected by pregnancy, in turn, pregnancy can also be affected by autoimmune disease from the early stage of gestation, which leads to the development of obstetric complications including preeclampsia (PE). Numerous recent studies have demonstrated that PE patients develop the autoantibodies that can activate angiotensin II type1 receptor (termed AT1 -AA) and contribute to the disease pathophysiology. These studies suggest the possibility that PE is a pregnancy-induced autoimmune condition. In this symposium, we will present our recent studies and advances in the understanding of roles of pathogenic autoantibodies (AT1 -AA) in PE. Conflicts of interest: The authors have no conflict of interest to declare. http://dx.doi.org/10.1016/j.jri.2016.10.109 Paternal antigen specific immune-tolerance for implantation and maintenance of pregnancy Tomoko Shima ∗ , Akemi Ushijima, Sayaka Tsuda, Kumiko Inada, Akitoshi Nakashima, Osamu Yoshino, Shigeru Saito Department of Gynecology and Obstetrics, University of Toyama, Japan Background: Regulatory T cells (Tregs) induce feto-maternal tolerance. Tregs depletion in allogeneic mating causes implantation failure and abortion. It is suggested that Tregs have a paternal antigen specific function. We have focused paternal antigen specific Tregs (PA-Tregs) in allogeneic pregnancy. Method: (1) The kinetics of PA-Tregs in allogeneic mating mice (BALB/c♀ × DBA/2♂) were analyzed by the flow cytometry. (2) To analyze the role of seminal fluid in Treg expansion, we resected the seminal vesicle of male DBA/2 (SVX). (3) Antigen specific Tregs 0165-0378/
are increased after antigen presentation by dendritic cell (DCs). The character of DCs in allogeneic mating was analyzed. Result: (1) The frequency of PA-Tregs increased in draining lymphnodes on day 3.5 pc and day 5.5 pc in allogeneic mating. (2) The frequency of PA-Tregs did not increase in SVX allogeneic mating. (3) CD86 and MHC class II expressions on DCs were decreased in uterus on day 3.5 pc and day 5.5 pc in allogeneic mating. On the other hand, B7-DC expression on DCs was increased. These molecules on DCs did not change in SVX allogeneic mating. DCs derived from uterus in allogeneic mating suppressed the proliferation of female spelenocytes. Conclusion: In allogeneic mating, seminal fluid priming induce tolerogenic DC resulting in expansion the PA-Tregs for the success of the implantation and pregnancy maintenance. Conflicts of interest: The authors have no conflict of interest to declare. http://dx.doi.org/10.1016/j.jri.2016.10.110 Acquired and innate immunity in decidua Shigeki Shimada Mommy’s Clinic Chitose, Japan Comparative study was carried out concerning immune abnormalities in the uterine endometrium and decidua (feto-maternal interface) on both sides of acquired and innate immunity or their mutual relationship. Th1/Th2 balance in miscarriages: Reduced number of CD3+ T cells, increased number of CD4+ helper T (Th) cells who do not express neither IFN-␥ nor IL-4, and decreased cell ratio of Th1 cells were observed in the endometriums of recurrent miscarriages (RM). In decidua of miscarriages, Th2 balance was observed compared with induced abortion (IA), but no difference was observed between miscarriage with normal chromosome (MN) and with abnormal chromosome (MA). CD4+IL−17+ (Th17) cells in miscarriages: Although Th17 cells were decreased in deciduae as compared with in endometrium in luteal phase (EM), no difference was observed among IA, MN and MA. Cytotoxicity T(Tc) cell balance in miscarriages: Tc1 cell ratio was increased in MN than in MA or IA.
148
Abstracts / Journal of Reproductive Immunology 118 (2016) 147–148
Regulatory T (Treg) cells in miscarriages: When CD4+CD25highFoxp3+ cells were defined as Treg cells, in MN, the Treg cells were rather increased compared with in MA. Natural killer (NK) cell ratio in miscarriages: In the endometriums of RM women and control women, there was no difference in CD56+NK cell ratio. In deciduae, there was no difference in NK cell ratio among IA, MN and MA. NK cell receptors in miscarriages: In the deciduae of MN, compared with MA or IA, an expression of inhibitory receptors CD158a and CD94 in NK cells was decreased, on the other hand, the perforin expressions in NK cells and cytotoxicity T (Tc) cells were increased. Moreover, in deciduae in MN, negative correlation was observed between the expressions of CD94 or CD158a in NK cells and the perforin expression in Tc cells. Therefore, it was suggested that such immune cells maintain pregnancy in cooperation, otherwise cause miscarriages. Macrophages (Mac) in miscarriages: Expressions of activation marker HLA-DR and maturation marker CD206 in CD68+CD163+Mac were decreased in IA as compared with in EM, but these reductions were not observed in miscarriage group. Conflicts of interest: The authors have no conflict of interest to declare. http://dx.doi.org/10.1016/j.jri.2016.10.111 NK cell abnormality and its treatment in women with reproductive failures such as implantation failure and recurrent pregnancy loss
cells dramatically increase at the secretory phase and early pregnancy. Appropriate regulation of the NK cells lead to reproductive success. We have reported that higher percentage of midsecretory endometrial CD16+ /CD56dim NK cells causes abortion or light for gestational age baby for subsequent pregnancies in IVF. NKp46 is a unique marker that functions in NK cell cytotoxicity and cytokine production. We have shown that expression of NKp46 on NK cells is lower in women with implantation failure and RPL. Some medicine has been applied for the treatment of women with RPL with abnormal NK cell, although their effects are still controversial. We have developed some treatments using IVIG, intralipid or GM-CSF added IVF medium. It is reported that IVIG therapy suppresses the NK cell cytotoxicity and similar effect is also reported by intralipid therapy for women with IF or RPL. Using these medicine, live birth rate for women with RPL was 84.2% (16/19) in IVIG treatment and 85.7% (6/7) in intralipid treatment. Moreover, GM-CSF is produced by immune cells such as NK cell and is important for the embryo quality and growth, and uterine endometrial environment. We have compared the clinical pregnancy rate (CPR) in frozen-thawed embryo transfer. The CPR in GM-CSF added medium group was 47.6% (20/42) and in regular medium was 30.4% (14/46). In conclusion, modification of abnormal NK cells may have preferable effects in women with NK cell abnormality and reproductive failure. Conflicts of interest: The authors have no conflict of interest to declare.
Atsushi Fukui 1,2 1
Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan 2 Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, Japan The regulation of natural killer (NK) cells has been associated with problems related to reproductive failures. Uterine NK
http://dx.doi.org/10.1016/j.jri.2016.10.112