Fetomaternal Immunity (PDF)

Fetomaternal Immunity Shabani M, PhD Department of Immunology, School of Medicine, SBMU Early development of the embryo  After fertilization, the human blastocyst consists of:  The inner cell mass, which will give rise to the embryo  The external layer (known as the trophect...

Fetomaternal Immunity Shabani M, PhD Department of Immunology, School of Medicine, SBMU Early development of the embryo  After fertilization, the human blastocyst consists of:  The inner cell mass, which will give rise to the embryo  The external layer (known as the trophectoderm), which will give rise to the placenta. 0.1–0.2 mm 200–300 cells IVF A human blastocyst, Blastocyst just before implantation with inner cell mass at Shabani M, PhD, SBMU upper right Early development of the embryo  The decidua is the specialized layer of endometrium that forms the base of the placental bed.  The corpus luteum of the ovary (and later, the placenta itself) produces progesterone that induces endometrial stromal cells to undergo cellular modifications and vascular alterations termed the 'decidual reaction.  Implantation is initiated when the trophoblast cells breach the surface epithelial lining of the decidua to attach and invade, leading to the formation of the placenta. Shabani M, PhD, SBMU Human Endometrial Stromal Cell Decidualization Shabani M, PhD, SBMU Early development of the embryo Shabani M, PhD, SBMU  Implantation Implantation is made possible through structural changes in both the blastocyst and endometrial wall Shabani M, PhD, SBMU Attachment invasion Decidualization Implantation stages 6 Maria Ariadna Ochoa-Bernal et al. 2020 Shabani M, PhD, SBMU Immune Responses to Alleogenic Fetus In immunological terms, the fetus is called semiallogenic since is characterized by the presence of antigens of maternal and paternal origin. Shabani M, PhD, SBMU Materno-Fetal Immunity  During pregnancy, a delicate balance of innate and adaptive immune responses at the maternal–fetal interface promotes:  Survival of the semiallogeneic embryo  Allows effective immunity to protect the mother from environmental pathogens Shabani M, PhD, SBMU The host–graft model: an outdated concept.  Normal post-implantation decidua is rich in immune infiltrates.  The infiltrates observed comprise both innate and adaptive immune cells. Shabani M, PhD, SBMU The host–graft model: an outdated concept.  Approximately 70% of decidual leukocytes are NK cells, 20–25% are macrophages, 1.7% are DCs and approximately 3–10% are T cells.  The presence of these various immune cell types in the decidua early on in pregnancy has supported Sir Peter Medawar theory:  Implanting blastocyst is a semi-allograft and is capable of triggering a maternal immune response that is devoted to its rejection. Shabani M, PhD, SBMU The host–graft model: an outdated concept.  Maternal lymphocytes such as CD4+ T cells, CD8+ T cells, and CD16−CD56bright NK cells express activation markers on their surfaces, suggesting that maternal lymphocytes recognize trophoblasts or fetuses.  Interaction with maternal immune regulation and trophoblast-derived tolerogenic molecules induces a tolerogenic environment at the feto-maternal interface. Shabani M, PhD, SBMU The host–graft model: an outdated concept.  The immunological regulation which maintains pregnancy is reported to involve both cellular and humoral regulation.  Anti-paternal cytotoxic antibodies have been detected with high frequency in the sera of normal pregnant women.  Anti-T-cell receptor (TCR) idiotypic antibodies capable of specifically inhibiting maternal autologous immune responses have been demonstrated in normal pregnant women Shabani M, PhD, SBMU Immune Responses to Alleogenic Fetus ⚫ 1- the inhibition of T cells proliferation by tryptophan deprivation by indoleamine 2,3-dioxygenase (IDO),a tryptophan-catabolizing enzyme expressed by trophoblasts and MQ. ⚫ The IDO is an enzyme, which initiates the catabolism of tryptophan ⚫ A couple of hypotheses have been advanced to explain the mechanism of IDO-induced suppression  Tryptophan depletion hypothesis  Tryptophan metabolites hypothesis Shabani M, PhD, SBMU Tryptophan Depletion Hypothesis ⚫ According to this hypothesis, depletion of tryptophan deprives the lymphocytes of an essential amino acid, thus compromising their ability to proliferate ⚫ To suppress T cells the tryptophan concentration should decrease below 0.5–1 Micromol ⚫ Under cell culture conditions, i.e. in a limited volume, complete degradation of tryptophan by IDO is conceivable BUT: ⚫ In vivo we have an open system in which a local decrease of tryptophan is rapidly compensated by diffusion from surrounding tissues and from plasma where the concentration lies in the range of 50–100 Micromol Shabani M, PhD, SBMU Tryptophan Metabolites Hypothesis ⚫ Based on findings certain tryptophan metabolites inhibit T-cell proliferation in vitro ⚫ 3-OH-kynurenine , 3-OH-anthranilic acid and to a lesser extent kynurenine and picolinic acid are tryptophan metabolites which inhibit T-cell proliferation  3-OH-anthranilic and quinolinic acid, when injected into mice, cause a depletion of specific thymocyte subsets in a fashion similar to dexamethasone  These compounds suppress proliferation of myelin-specific T cells and skew the cytokine profile from Th1 to Th2 Shabani M, PhD, SBMU Immune Responses to Alleogenic Fetus ⚫ 2- the specialized fetal tissue (trophoblast) expresses Fas ligand and may cause apoptosis of activated maternal T cells that express Fas. ⚫ PD-L1 is expressed not only on some cancer cells, but also on the outer surface of placental syncytiotrophoblasts, which is assumed to induce maternal immune tolerance to fetal tissue via programmed death-1 (PD-1) receptors on T cells. ⚫ 3- Moreover it has been shown that trophoblast cells express, at the feto- maternal interface, human leukocyte antigen G, a non-classical major histocompatibility complex class I molecule, that play an important role in maternal tolerance of the fetus through the inhibition of fetal cells cytolysis by natural killer cells. Shabani M, PhD, SBMU MHC recognition by CTL and NK cells Shabani M, PhD, SBMU  Non-classic MHC class I expression by trophoblast cells Villous trophoblasts lack the surface expression of MHC class I and class II. EVTs do not express polymorphic HLA-A, B, whereas they express HLA-C and non- polymorphic HLA-E, G, and F Shabani M, PhD, SBMU Shabani M, PhD, SBMU Immunological balance at the feto-maternal interface during early pregnancy Shabani M, PhD, SBMU Immune Responses to Alleogenic Fetus ⚫ 3- It has also been shown that decidual natural killer cells (dNK), in contrast to peripheral NK cells, displayed very reduced lytic activity. ⚫ Indeed, although dNK cells express all the molecules required for lysis, they failed to polarize their micro-tubule organizing centers and perforin- containing granules to the synapse; this phenomenon results in lack of cytotoxicity versus fetal trophoblasts. ⚫ dNKs inhibit macrophage and T cell functions by producing inhibitory cytokines, such as TGF-β. ⚫ The absence of NK cells, trophoblast cells are not able to reach the endometrial vascularity leading to termination of the pregnancy Shabani M, PhD, SBMU Immune Responses to Alleogenic Fetus ⚫ 4- Treg cells display a pivotal role in maintaining tolerance to paternal alloantigens, critical step for successful of pregnancy. ⚫ Treg cells also increase systemically and locally during human pregnancies. ⚫ The key role of Treg cells in tolerization against fetal antigens is also con- firmed by studies in mice employing an adaptive transfer system and showing that depletion of CD25+Treg cells leads to gestation failure. Shabani M, PhD, SBMU ⚫ Paternal antigen-specific Treg cells accumulate during pregnancy, and seminal plasma priming plays an important role in expanding paternal antigen-specific Treg cells in mouse models and in human. ⚫ Reduction of decidual functional Treg cells occurs during miscarriage with normal fetal chromosomal content, whereas insufficient clonal expansion of decidual Treg cells is observed in preeclampsia. Shabani M, PhD, SBMU  Immune Responses to Alleogenic Fetus 1. Anatomic location: Uterine decidua may be an immunologically privileged site 2. Cellular content of Deciduas: inhibit macrophage and T cell functions by producing inhibitory cytokines, such as TGF-β. 3. Uterine cytokine and chemokine network (Th2 type and Treg). 4. Immunomodulatory hormones (prolactin, chorionic gonadotropin, progesterone) 5. Trophoblast cells fail to express paternal MHC molecules. These cells express HLA-G which protects them from NK cell lysis. 6. Low indolamine 2,3-dioxygenase (IDO) which catabolizes tryptophan. 7. Trophoblast and decidua may also be relatively resistant to complement-mediated damage because they express high levels of a C3 and C4 inhibitor called Crry. Shabani M, PhD, SBMU Shabani M, PhD, SBMU 27