current understanding of the immunological changes and adaptations that occur in pregnancy enabling tolerance to the foreign paternal fetal antigens in the maternal uterus

1. Immunology Of Pregnancy
Residents-Obgyn
Dr Bwire Innocent 2022-08-11549
Dr Fahma Ibrahim Ali 2022-08-11840
Dr Hamdi Ahmed Jama 2022-08-12020
Lecturer : Dr Vidya S

2. Outline
 Introduction
 Immuno-protective mechanisms of placenta and its membranes
 Maternal immune adaptations

3. Dr Bwire Innocent
2022-08-11549

4. Introduction
 Pregnancy is an immunological balancing act in which the mother's immune
system has to remain tolerant of paternal MHC antigens and yet maintain
normal immune competence for defense against microorganisms
 Cytotoxic adaptive immune responses are diminished, bypassed, or even
abrogated, while regulatory adaptive immunity is enhanced.
 Innate (natural) immunity remains intact, serving two purposes: one, to
continue to provide host defense against infection, and two, to interact with
fetal tissues to promote successful placentation and pregnancy

7. 7

9. Endocrine Regulation
 Hormones such as Progesterone, Estrogen, and Human chorionic
gonadotropin (hCG)
 The effects of estrogen are predominantly mediated by 3 active forms:
estrone (E1), estradiol (E2), and estriol (E3)—the latter of which is
produced exclusively by the placenta
 E2 inhibits the proliferation and cytotoxicity of NK cells, inhibits Th17
differentiation, promotes the differentiation of peripheral Tregs, E3 is
capable of inhibiting activated B cells (NF-κB)-mediated transcription,

10. Human chorionic gonadotropin (hCG),
 Although its immunomodulatory role is less well studied than that of
progesterone or estrogen, evidence suggests that hCG may interact with
immune cells in order to foster placentation
 stimulates proliferation of dNK cells , key to establishing a local immune
tolerant state , also through the cellular system of apoptosis via Fas/Fas-Ligand,
modulates the Th1/Th2 balance , acts on complement C3 and C4A/B factors
modulating decidual immunity. Regulatory T cells are also attracted by hCG
 hCG results in telogenic dendritic cells results in an up-regulation of MHC
class II, IL-10 and IDO expression, reducing the ability to stimulate T cell
proliferation.

11. Progesterone
 Nuclear progesterone receptors (PR-B or PR-A) are found in decidual cells,
myometrial cells, and a subset of immune cells (e.g., CD4 and CD8 T cells)
 Progesterone binding to PR-B induces transcription of PIBF. In humans,
progesterone (either directly or via PIBF) contributes to the arrest of dDC
maturation in vitro, which fosters a Th2 environment and encourages
differentiation and expansion of Tregs
 PR-B inhibits the transcription factor NF-κB in human myometrial cells
decreasing prodn of cytokines such as IL-1β and IL-8,(implicated on the onset
of labor). PR-A is a/w production of IL-1β and IL-8 by myometrial cells

13. Maternal Systemic Immune Responses
 there are 2 mechanisms for overcoming immune reactions: One is active
suppression, and the other is enhanced tolerance.
 Regulatory T cells (Tregs), which are critical mediators of tolerance,
become more numerous in pregnancy in response to the introduction of
fetal (paternal) antigens . These Tregs produce IL-10, which appears to play
a role in maintaining pregnancy
 IL-10 producing CD19+CD24hi CD27+ regulatory B cells expands during
normal pregnancy, and their role may be to suppress undesired immune
responses from maternal T cells.

14.  During the first trimester, NK cells, dendritic cells and macrophages infiltrate
the decidua and accumulate around the invading trophoblast cells.
 Studies have shown that in the absence of NK cells, trophoblast cells are not
able to reach the endometrial vascularity leading to termination of the
pregnancy, Similarly, depletion of DCs prevented blastocyst implantation and
decidual formation.
 it is appropriate to refer to pregnancy as a unique immune condition that is
modulated, rather than suppressed ---Transplantation Versus Implantation

15. Fetus as an Allograft
 Allograft is a tissue or organ obtained from one member of a species and
grafted to a genetically dissimilar member of the same species.
 the fetus is an allograft and the mother should normally recognize the fetus as
foreign and reject the fetus, but such rejection seldom occur.
 the fetal–maternal immune interaction is more complex than the comparison
to transplant allograft
 Immune tolerance in pregnancy is defined as the absence of a maternal
immune response against the fetus and placenta.

16. Fetal Immune System
 Contributions of the fetus to maternal-fetal immunologic interactions are not
well understood
 Some evidence suggests that the fetus is unable to mount an anti-maternal
immune response until mid- to late pregnancy
 astudy showed that fetal T cells were highly responsive but were biased towards
developing into regulatory T cells (Tregs), which are important in tolerance.
 However, if fetal T cells are able to mount a response to maternal antigens,
these fetal T cells may play a role in preterm labor

17. Placenta
 placenta functions as an anatomical
immunological barrier between the
mother and the fetus
 creates an immunologically privileged
site
 the placenta does not block maternal
IgG antibodies, provide immune
protection to the fetus.

18. Specific immune-protective mechanisms
 Altered expression of HLA and related molecules
 The primary cellular immune response that develops against transplanted tissue
is directed against the MHC proteins on donor tissue.
 Placental trophoblast cells do not express the classical MHC class Ia isotypes
HLA-A and HLA-B, unlike most other cells in the body but they do express
the atypical MHC class Ib isotypes HLA-E and HLA-G, which is assumed to
prevent destruction by maternal NK cells, which otherwise destroy cells that do
not express any MHC class I.

20.  The extravillous trophoblasts migrating into the decidua lack expression of
HLA-A or HLA-B class Ia antigens that are primary stimulators of classical
graft rejection and instead display a unique pattern of class Ia HLA-C and the
non-classical HLA class Ib molecules, HLA-E, HLA-F, and HLA–G.
 The genes encoding HLA-E, HLA-F, and HLA–G antigens have few alleles in
comparison with HLA-A and HLA-B.
 HLA-G, HLA-C, and HLA-F are expressed by first trimester by extravillous
trophoblast, and, as gestation proceeds, their expression weakens and becomes
intracellular.
 HLA-E is expressed by the extravillous trophoblast only in the first trimester.

21.  HLA-C, HLA-E, HLA-G, and HLA-F may act to dampen or modulate maternal
immune responses by interacting with killer immunoglobulin-like receptors
(KIRs) on decidual NK (dNK) cells, macrophages, and a subset of T cells and
with the T cell receptor on CD8+ T cells
 The consequences of these interactions include activation of pathways in NK
cells and macrophages that interfere with the killer functions of these cells.
 At the same time, HLA-E and HLA-G may activate pathways in dNK cells,
macrophages, and T cells that promote trophoblast migration and placentation

22. 22

24.  One mechanism by which HLA-G influences dNK cell and T cell function is
through a process of trogocytosis, in which a lymphocyte transfers plasma
membrane fragments containing cell surface molecules from an antigen-
presenting cell to its own surface via the immunologic synapse.
 These acquired HLA-G+ NK and T cells are immunosuppressive
 Trogocytosis is an active process whereby plasma membrane proteins are
transferred from one cell to the other cell in a cell-cell contact-dependent
manner.

25. HLA class II
 The genes that encode potentially dangerous paternally derived foreign HLA
class II HLA-D region molecules are entirely repressed in trophoblast cells.
 None of the trophoblast subpopulations express HLA class II antigens either in
vivo or in vitro.
 Control over transcription of class II genes may be exerted by silencing of
expression of the class II transactivator (CIITA), a transacting factor that is
essential for constitutive and interferon (IFN) gamma-inducible MHC class II
gene transcription

26. Dr Fahma Ibrahim
2022-08-11840

27. B7 family
 B7 family of costimulatory molecules that have both lymphocyte stimulatory and
inhibitory functions are expressed on trophoblast cells in human placentas and may
play a role in maintaining tolerance to the fetus
 The B7H1 protein (Programmed Death ligand 1 [PD-L1]; CD274), which has
lymphocyte inhibitory properties, is expressed on syncytiotrophoblast and, therefore,
positioned to interfere with activation of lymphocytes circulating in maternal blood.
 Interactions between villous and extravillous trophoblast PD-L1 (B7H1) and
Programmed cell death protein 1 (PD-1; CD279) expressed by maternal lymphocytes
promote T regulatory (Treg) cell development and function and inhibit activated T
cells (T helper cell type 17 -Th17 cells)

28. Indoleamine 2,3-dioxygenase (IDO)
 Trophoblast cells produce indoleamine 2,3-dioxygenase (IDO), which depletes
tryptophan by promoting its catabolism.
 This is believed to inactivate T cells since they require tryptophan.
 Although IDO is clearly important to survival of the mouse embryo, studies in
IDO-/- knockout mice have failed to reveal any impact on pregnancy.
 Evidence is beginning to emerge in support of this potential mechanism in
humans

29. TNF superfamily
 Apoptosis-inducing members of the TNF supergene family may also have roles in
protecting the placenta by inducing apoptosis in potentially cytotoxic T cells.
 Include TNF-alpha, FasL, and TRAIL (tumor necrosis factor–related apoptosis–
inducing ligand) , B-cell activating factor (BAFF)
 All of these molecules, which are expressed as both membrane and soluble forms, can
kill activated immune cells targeting the trophoblast by transducing an apoptotic
signal via specific receptors on activated leukocytes.
 FasL may be of particular importance since FasL prevents immune cell attack by
interacting with leukocyte receptors (eg, Fas) in other organs such as the eye and the
testis.

30. Complement proteins
 Trophoblast cells express high levels of the following complement regulatory
proteins: for protecting the extraembryonic tissues from maternal antipaternal
cytotoxic antibodies
 CD46 (membrane cofactor protein -MCP), CD55 (Decay Accelerating factor-
DAF), and CD59 (Membrane Inhibitor of Reactive lysis-MIRL).
 Mothers routinely produce high titers of Antibody to paternally derived HLA
and unique trophoblast antigens, such as the unique placental isoform of
alkaline phosphatase. Antibody induction of complement-mediated lysis is
prevented by high expression of CD46 and DAF in trophoblast cells

32. Microparticles
 Some B7 family members, as well as HLA-G, can also be released from the
placenta via exosomes
 Exosome-mediated transfer of placental-specific microRNAs regulates
trophoblast and maternal cell immunity to viral infections
 the release and content of these microparticles are increased and/or altered
under certain pathologic conditions, and, as such, they may be involved in the
pathogenesis of pregnancy complications such as preeclampsia

33. Soluble immunomodulators
 Maternal immune modulation during pregnancy may also be conferred by the
synthesis of immunosuppressive or immunoregulatory molecules.
 Placenta produces progesterone, prostaglandin E2 (PGE2), and anti-
inflammatory cytokines such as interleukin (IL) 10 and IL-4.
 Progesterone may drive placental production of these anti-inflammatory
cytokines. IL-10 appears to stimulate production of HLA-G, and dysfunction of
this pathway may be important in preeclampsia

34.  Soluble thymic stromal lymphopoietin (TSLP) secreted by trophoblast cells
stimulates decidual dendritic cells (dDCs) to produce IL-10 and chemokine (C-
C motif) ligand 17 (CCL17).
 These activated dDCs induce T helper cell type 2 (Th2) differentiation of
decidual T cells. Lower levels of TSLP are seen in miscarriage than in normal
pregnancy.
 Secretory leukocyte protease inhibitor (SLPI), which is a potent inhibitor of
HIV infection and inducer of bacterial lysis in placenta prevents transmission
of viral infection (e.g. HIV) to the fetus during pregnancy

35. Immune Adaptation In The Pregnant Uterus
Changes take place in the uterus during pregnancy
that also help contribute to immune acceptance of
and/or crosstalk with the fetus/placenta to promote a
successful pregnancy.

36. Differences in lymphocyte populations
 Invading fetal trophoblasts become admixed with dNK cells, macrophages, and
dendritic cells that account for ~70, 20, & 2% of all cells in the decidua.
 The endometrial natural killer (NK) cell population shifts from uterine NK
(uNK) cells to decidual NK (dNK) cells (CD56brightCD16-), and this phenotype
is distinct from both CD56bright and CD56dim peripheral blood NK (pNK)
cells. The origin of dNK cells remains controversial
 their function is thought to be distinct given that many genes, including some
with immunomodulatory properties, are overexpressed in dNK cells when
compared with their peripheral counterparts.

37.  the major roles of dNK cells may also be unique to pregnancy.
 Although dNK cells express a high level of cytotoxic factors, they are unable to
form cytotoxic synapses to deliver granule contents and instead appear to play a
role in trophoblast attraction and invasion, decidual and placental angiogenesis
and possibly fetal vasculogenesis, and vascular modifications in the uterus.
 A popn of uNK cells that are found in repeated pregnancies has been identified.
These "memory-like" uNK cells may be involved in promoting placentation.
 One study proposed that uNK cells maintain endometrial homeostasis by
clearing senescent decidual cells.

38.  In addition, the uterine T cell population during pregnancy expands across
gestation and is mostly regulatory in nature.
 Decidual macrophages exhibit phenotypic elasticity, adapting to the local
microenvironment. During the peri-implantation period, decidual macrophages
display an M1 (inflammatory) phenotype.
 During the period of placentation, there is a mixture of M1 (inflammatory) and
M2 (antiinflammatory) decidual macrophages, which shift to predominantly M2
after placentation.

39.  some studies suggest that trophoblast-macrophage crosstalk is more important
for promoting normal placentation by being involved in implantation, placental
development, immunoregulation, vascular remodeling, and tissue homeostasis.
 Aberrant macrophage numbers and activation may play a role in pregnancy
complications, such as preeclampsia, intrauterine growth restriction (IUGR), or
preterm birth
 Macrophages present throughout gestation in the placental villi and are known as
Hofbauer cells. These fetally derived immune cells also display a M2 phenotype,
although they can generate strong inflammatory responses to infectious triggers.
 Hofbauer cell numbers are also altered in pregnancy complications such as
preeclampsia and chorioamnionitis

40.  As with macrophages, alterations in dNK cell numbers and activation status may
play a role in pregnancy complications, such as immunologic infertility,
recurrent spontaneous abortion, and preeclampsia
 Excessive dNK cell recruitment and/or expansion, as well as elevated cytotoxic
activity, have been associated with pregnancy disorders such as implantation
failure and miscarriage.
 However, some studies suggest the opposite that deficiencies in uNK numbers
are associated with recurrent pregnancy loss,

41. Dr Hamdi Ahmed Jama
2022-08-12020

42. Innate lymphoid cells (ILCs)
 Innate lymphoid cells (ILCs) distinct from NK cells have been characterized in
the human decidua-although their function is still unclear
 ILC3 regulate the recruitment and function of other maternal immune cells,
and contribute to vascular remodeling.
 At term, both ILC2s and ILC3s have been found in the decidua, and levels
may increase in preterm birth

43. Dendritic Cells
 The role of decidual dendritic cells (dDCs) is less clear, mouse studies have
showed that these cells are critical for successful implantation and involved sin
remodeling of the maternal vasculature.
 dendritic cells may promote systemic immune tolerance during pregnancy.
 Another is that dendritic cells are trapped in the decidua to prevent the
exposure of peripheral T cells to fetal antigens
 Uterine dendritic cells are also thought to contribute to pregnancy success by
influencing NK cell function and the cytokine profile at the maternal-fetal
interface

44. T cells
 Gamma-delta T cells and a population of double-negative T lymphocytes
(CD4-/CD8-) have been reported in the pregnant uterus.
 Their roles are unclear, although immunosuppressive gamma-delta T cells may
play a role in regulating the maternal immune system to protect the maternal-
fetal interface from aggressive immune responses. Increased no's of gamma-
delta T cells may be a/w pregnancy loss
 studies have suggested that there are highly differentiated CD8+ effector
memory T cells within the pregnant decidua. The antigenic target of these cells
is still unclear, as is their function and whether they are protective

45.  CD4+CD25+ regulatory T cells (Tregs) are also present in the decidua of
normal pregnant females, and their presence and expansion during pregnancy
are thought to be triggered in both alloantigen-dependent and alloantigen–
independent manners
 There are decreased numbers of peripheral blood and decidual Treg cells in
females with preeclampsia compared with normal pregnancy subjects.
 findings suggest that Tregs play a role in maternal tolerance to the fetus

47.  CD4+ interleukin (IL) 17-producing T cells (T helper cell type 17 -Th17) have
also been described in pregnancy.
 Their numbers are also expanded in the pregnant uterus, although not as much as
CD4+CD25+ Tregs.
 While they are inflammatory in nature, the presence of Th17 cells may play a role
in protecting the maternal-fetal interface from microbes, and the Tregs present may
serve to regulate their function.
 Thus, altered numbers of Th17 and/or ratio of Th17 to Tregs are associate with
complications, such a spontaneous abortion, preeclampsia, and preterm birth

49. Mast cells
 classically associated with allergic immune responses.
 However, in pregnancy, their presence in the decidua may contribute to
successful placentation.
 higher in human pregnancies compared with non-pregnant females.
 In the mouse, they have been shown to promote an anti-inflammatory state and
contribute to tissue remodeling, angiogenesis, and spiral artery transformation

50.  A subset of IL-10-producing regulatory B cells (CD19+CD5+CD1d+) has
been shown to expand peripherally in mice and humans during pregnancy.
 In abortion-prone mice, expansion of these regulatory B10 cells is not seen,
and fetal rejection can be prevented by adoptive transfer of these cells from
normal pregnant mice.
 While the presence of CD19+ B cells in the human decidua throughout
pregnancy has been reported, the importance of regulatory B cells in the
human decidua remains to be determined.

51. Soluble immunomodulatory agents
 Uterine immune regulation is also provided by the induction of
immunomodulatory molecules that permeate the uterine environment.
 These include progesterone, prostaglandins, and some cytokines.
 High concentrations of progesterone can suppress the maternal immune
response . progesterone alters the T helper cell type 1 (Th1)/T helper cell type 2
(Th2) balance and inhibits production of tumor necrosis factor (TNF) alpha in
human macrophages
 Prostaglandin E2 (PGE2) is produced by resident macrophages and decidual
cells. Lymphocytes proliferate poorly in the presence of this compound.

52. Cytokines
 Many still consider human pregnancy to be a Th2 antiinflammatory condition
and that a shift towards Th1 cytokines will lead to abortion or pregnancy
complications
 Th1 cytokines include interleukin (IL-2, tumor necrosis factor (TNF)-α, and
interferon (IFN)-γ, whereas IL-4, IL-5, and IL-10 are considered Th2 cytokines
 Elevated levels of IL-6 in cervicovaginal and amniotic fluid, but not plasma, was
associated with spontaneous preterm birth. Similarly high levels of
proinflammatory IL-1-beta and TNF-alpha in the amniotic fluids are associated
with preterm birth

53. References
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 Gil Mor, Ingrid Cardenas (2010)The Immune System in Pregnancy: A Unique Complexity
 Vikki M Abrahams (2021): Immunology of the maternal-fetal interface,up to date article
 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction,
Fourth Edition
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Thyroid Association, 9(7), 643–646. https://doi.org/10.1089/thy.1999.9.643
 Salge AKM et al. (2017) Immunological aspects of pregnancy: a literature review. J Neonatol
Clin Pediatr 4: 016.
 Marie Tsampalas, Virginie Gridelet, Sarah Berndt, Jean-Michel Foidart, Vincent Geenen, Sophie
Perrier d’Hauterive,
 Human chorionic gonadotropin: A hormone with immunological and angiogenic properties,
Journal of Reproductive Immunology,Volume 85, Issue 1,2010, Pages 93-98,
https://doi.org/10.1016/j.jri.2009.11.008.
 Peterson, L.S., Stelzer, I.A., Tsai, A.S. et al. Multiomic immune clockworks of pregnancy. Semin
Immunopathol 42, 397–412 (2020). https://doi.org/10.1007/s00281-019-00772-1

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