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Chapter 41
Immunology of Pregnancy
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
FIGURE 41.1 Multiple mechanisms underlie maternal tolerance of the fetus. Both maternal and fetal mechanisms contribute to
successful gestation of the genetically different fetal semi-allograft. Mothers revise the roster of the different leukocyte lineages
(macrophages, dendritic cells, NK cells, lymphocytes; see Box 41.1) in the decidua to disallow residence of most antigen-specific
immune cells. Production of soluble immuneregulatory molecules including hormones, prostaglandins, cytokines, and chemokines from
both uterine and placental cells occurs; the placenta and extraplacental membranes produce many of the same immune-suppressive
molecules but also display specially selected members of multigene families that bypass or inactivate immune cells. NK cells, natural
killer cells; Treg, CD4+ regulatory T cells; HLA, human leukocyte antigen family; TNF superfamily, tumor necrosis factor superfamily;
B7, B7 peripheral membrane protein co-stimulator family.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.2 Anatomy of the maternal–fetal interface. The fetus is entirely surrounded and encased by
placental and chorion membrane trophoblast cells. Maternal cells and fetal cells are intermixed in the decidua
basalis, the site of attachment of the placenta to the uterus (upper insert) and between the chorion membrane
and decidua parietalis (left insert). CTB, cytotrophoblast cells; sTB, syncytiotrophoblast.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.3 Microchimerism and exchange of fetal–maternal material across the placental barrier. A small number of fetal cells
circulate systemically in the maternal blood, and conversely, maternal cells are present in the fetal circulation (upper insert). In addition
to intact cells, substantial amounts of subcellular material are shed from placental syncytiotrophoblasts in the form of fragments ranging
in size from large multinucleated syncytial knots and microvesicles (middle insert) to nanoscale-sized exosomes (lower insert). This
shed material is thought to provide antigens that can be presented by maternal antigen-presenting cells and other immune-regulatory
signals that influence the maternal immune response in a systemic manner (right insert). Source: Reprinted from Placenta 32
(Supplement B, Trophoblast Research vol. 25), M. Petroff: Fetal antigens: identity, origins and influences on the maternal immune
system, S176-S181, Copyright 2011, with permission from Elsevier.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.4 Funtional differentiation of Treg cells. The microenvironmental context in which naive CD4+ Th0
cells encounter their cognate antigen is a principal determinant of their differentiation fate and development into
Treg cells as opposed to Th1, Th2, or Th17 cells. Treg cells confer immune tolerance and suppress inflammation
while Th1, Th2, and Th17 cells mediate protective immunity and are linked with inflammation. Signals originating
from the dendritic cell presenting antigen to the Th0 cell, as well as the relative concentrations of key cytokines in
the immediate vicinity, are instrumental. IL = interleukin; Th1, Th2, Th17 = T-helper type 1, type 2, and interleukin
17-producing Th cell; TGF = transforming growth factor.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.5 Placental contribution to tolerance. In this scheme, HLA-G along with immunosuppressive
cytokines, prostaglandins, and progesterone, inhibit maternal cell-mediated immunity. Effector cells are impaired
by special adaptations on the placental syncytiotrophoblast that include expression of inhibitory cytokines.
Antibody-mediated immunity may be promoted by nonapoptosis-inducing members of the TNF superfamily of
ligands, BAFF and APRIL. Cytotoxic antibodies directed to placental antigens are inhibited by expression of the
complement regulatory proteins on syncytiotrophoblast while beneficial IgG is transported into the fetus.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.6 Suppressive pathways of Treg cells. Treg cells act to exert their immune regulatory and antiinflammatory effects through inhibiting proliferation and cytokine production in both CD4 + and CD8+ T cells,
suppressing cytotoxic function of NK cells, and inhibiting maturation and inflammatory activation of dendritic cells
and macrophages. IL, interleukin; TGF, transforming growth factor.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.7 Suppressive pathways of Treg cells. Tolerogenic dendritic cells, together with regulatory
cytokines and other immunedeviating agents, control Treg cell activation and proliferation. Cytokines G-CSF,
GM-CSF, IL-4, and IL-10, together with IDO and HLA-G, regulate dendritic cell differentiation into a tolerogenic
phenotype. IL-2 and/or IL-15, acting at the site of antigen presentation by tolerogenic dendritic cells, are required
for Treg cell activation and proliferation. TGFβ and PGE2 drive further rounds of proliferation of mature Treg cells.
Treg cells release IDO, IL-4, and IL-10 to amplify effects on dendritic cells and Treg cell generation. Ag, antigen;
G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage CSF; IDO, indoleamine 2,3dioxygenase; IL, interleukin; TGFβ, transforming growth factor-β; PGE2, prostaglandin E2; DC, dendritic cell;
tDC, tolerogenic dendritic cell.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.8 The human major histocompatibility on chromosome 6. The HLA class I genes, which are
telomeric to HLA class II, include HLA class Ia (HLA-A, -B, -C) and Ib (HLA-E, -F, -G), and trophoblast cells
strictly regulate the expression of each of these genes. Three of the 10 known, unexpressed HLA pseudogenes
are shown. Each of the class I genes differ significantly in the numbers of alleles known and proteins expressed
(bottom panel). HLA, human leukocyte antigen.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.9 Trophoblast HLA and immune cell interactions. Each subpopulation of leukocytes expresses
its own pattern of receptors for HLA class I, which permits diversity in responses. Note that the leukocyte
immunoglobulin-like receptors (LILR) comprise a large family, and that individual leukocyte subgroups express
specific members such as TCR (T cell receptor), ILT (immunoglobulin-like transcript), or KIR (killer inhibitory
receptor).
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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FIGURE 41.10 Treg and reproductive dysfunctions. Deficiencies in Treg cell numbers and/or suppressive
function are associated with reproductive disturbances including infertility, recurrent spontaneous abortion, and
preeclampsia in women. Current understanding is that adequate Treg cell numbers and function acts to suppress
inflammation as well as Th1/Th17-mediated cytotoxic attack on the semiallogeneic conceptus, but Treg cell
depletion leads to insufficient suppression and increased inflammation, with Th1/ Th17-mediated fetal loss.
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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BOX 41.1
© 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition
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