Immunology of pregnancy

Fetal tissue is half foreign – has to be protected from rejection Mother’s immune defence must be sufficient during pregnancy to ensure survival Fetus often immunologically immature at birth – must have maternal antibodies to ensure survival The maternal/fetal interface is central to overcoming these problems. This interface occurs at the placenta

1.Syncytiotrophoblast layer covering the placenta is bathed in maternal blood The syncytiotrophoblast is a multi-nucleated layer which arises from fused cytotrophoblasts. It forms a barrier and performs endocrine functions as well as gas and nutrient exchange from maternal blood. 2.Invading trophoblast come into contact with decidual immune cells The extravillous trophoblast are differentiated fetal cells which invade into the maternal decidua to transform maternal spiral arteries. • Invading trophoblast come into contact with decidual blood vessels

syncytiotrophoblasts lining the chorionic villi and maternal blood in the intervillous space invasive extravillous trophoblasts and maternal blood in the spiral arteries invasive extravillous trophoblasts and infiltrated maternal immune cells in the decidua

Decidua >40% decidual cells are leukocytes in early pregnancy Of these, approximately 70% are NK cells (subpopulation of cytotoxic lymphocytes) function by cell killing or cytokine production approximately 20% are macrophages T and B cells make up the remaining 10% Intervillous space and spiral arteries same as maternal blood

dNK cells are different to peripheral blood (pb)NK cells Their pattern of receptor expression is unique and they are identified by CD56hiCD16lo They have been identified as being essential to pregnancy in the mouse and they may play a role in human decidual remodelling through the cytokines which they secrete

Another immune cell found in the decidua is the macrophage: makes up about 20% of immune cells in the decidua so is the second most abundant immune cell dMac have a different phenotype to peripheral blood monocytes Broadly, macrophages may be: M1: pro-inflammatory, secrete TNF-α, IL-6 M2: anti-inflammatory, secrete IL-10, VEGF Decidual macrophages are more M2-like than M1-like

1) Physical separation of maternal and fetal tissues Fetus separated from the mother by the fetal trophoblast cells Fetal and maternal circulation is separated Maternal cells cannot reach the fetus But In humans, IgG can cross into the fetal blood via a placental transport mechanism. Therefore IgG directed against fetal antigens could also be transferred Why doesn’t this harm the baby? 2) Most fetal blood group and histocompatibility antigens are widely distributed on the fetal cells and tissues - IgG would be diluted out. 3) Many fetal antigens are also present as soluble forms in the fetal blood and amniotic fluid - IgG would be mopped up by free soluble antigen. Antigenic immaturity of fetal tissues Mother is immunologically inert

Histocompatibility antigens are targets for rejection MHC haplotypes inherited from both parents and are co-dominantly expressed Class Ia HLA-A, HLA-B, HLA-C (classical) presenting antigens to CD8+ T cells interacting with NK cells highly polymorphic Class Ib HLA-E, HLA-F, HLA-G (non-classical) minimally polymorphic Class II HLA-DP, HLA-DQ, HLA-DR presenting antigen to CD4+ T cells

Syncytiotrophoblasts lack both MHC Class I and II antigens Extravillous trophoblasts lack Class II but express an unusual combination of MHC class I antigens – HLA-C, HLA-E and HLA-G (non-classical)

Maternal blood in pregnancy is able to respond immunologically to the fetus and fetal cells are detectable in the maternal blood BUT Pre-sensitisation to paternal antigen does not prevent pregnancy There is neither a generalised or specific depression of maternal immune responsiveness The quality of the maternal immune response may be what differs

Role for natural killer cells in the decidua Selective local induction of programmed cell death in maternal immune cells Alteration in the cytokine balance Local indoleamine 2,3-dioxygenase synthesis Complement regulatory proteins

dNK cells are different to peripheral blood (pb)NK cells Their pattern of receptor expression is unique and they are identified by CD56hiCD16lo They have been identified as being essential to pregnancy in the mouse and they may play a role in human decidual remodelling through the cytokines which they secrete

By binding to receptors on NK cells NK cell receptors Killer-cell immunoglobulin-like receptors (KIRs) CD94/NKG2 receptors Leukocyte immunoglobulin-like receptor (LILRs) There are both inhibitory and activating members of these families of receptors

Binding of HLA class I molecules to inhibitory NK cell receptors inhibits the cytotoxic action of the NK cell, therefore the trophoblast is not attacked Inhibitory NK receptor- CD94/NKG2A, KIR2DL / S1, LILRB-1 Trophoblast- HLA C, E, G

Inhibitory receptors are expressed at higher levels in uterine NK cells than peripheral blood NK cells HLA-E has higher affinity for the inhibitory receptor than the activating receptor More uNK cells found in women with a history of recurrent pregnancy loss But Trophoblast HLA molecules can also bind to activating NK cell receptors may alter the NK cytokine repertoire may contribute to how the trophoblast behaves

Soluble HLA-G can be released from trophoblasts In vitro studies have shown that sHLA-G can induce apoptosis in maternal T cells May be an additional way of protecting trophoblasts from attack IVF: an association between the presence of soluble human leukocyte antigen G (sHLA-G) in human embryo culture supernatants (ES) and implantation success

xperimental evidence that trophoblasts can induce programmed cell death (apoptosis) in maternal immune cells. Apoptosis Cell shrinks, nucleus reorganises, DNA fragments, membranes bleb and cell fragments into membrane bound apoptotic bodies. Regulation of apoptosis depends on a balance between pro- and anti-apoptotic factors. Mechanisms Fas-Fas L TRAIL-TRAIL R

T cells differentiate into Th1 or Th2 cells in response to signals given during antigen presentation Th1 type reaction in placenta mainly generates inflammatory responses, activates T cells and NK cells and is correlated with miscarriages. eg IFNg, IL-2 Th2 type reaction generates non-inflammatory reactions that are consistent with the survival of the fetus. eg IL-4, IL-6, IL-10, IL-13 Trophoblasts may be producing cytokines and hormones that promote a Th2 balance.

Skewing the nature of the T cell response to active tolerance rather than active rejection is important T helpers – Th1, Th2, Th17, Treg Sufficient Tregs needed in the endometrium for implantation and pregnancy Tregs CD4+CD25+ – anti-inflammatory, immune suppressive Act on other immune cells, produce suppressive cytokines such as TGFb and IL10 How is this regulated? Appropriate cytokine balance Correct phenotype of endometrial leukocytes to allow Treg activation Stabilisation of Treg phenotype by estrogen and progesterone Priming of Tregs by male partner seminal fluid-stimulates expansion of endometrial Treg population.

Enzyme that catabolises tryptophan Synthesised and secreted by syncytiotrophoblasts Shown to be essential for successful pregnancy IDO may break down tryptophan in maternal T cells in the decidua This can reduce or inhibit immune responses

In normal pregnancies, excessive complement activation is prevented by complement regulatory proteins that are highly expressed on trophoblast membranes(MCP, DAF, and CD59) This prevents cell lysis CD46 – MCP – membrane co-factor protein CD55 – DAF – decay accelerating factor CD59 - MAC-IP- MAC inhibitory protein

This is a controversial and heavily-researched area Some incidences of pre-eclampsia and miscarriage may have a basis in maternal-fetal immunological mismatch

PE lower risk with different partner for 2nd pregnancy Donor egg pregnancies at higher risk (non-self) Prolonged exposure to paternal semen may lower PE risk dNK receptors may be Type A or B, and trophoblast receptors may be type C1 or C2 If the match is KIR-A and HLA-C2, pre-eclampsia risk is increased This may be because this interaction leads to less cytokine production which helps the trophoblast invade

dNK cells Promote trophoblast invasion Fail to promote trophoblast invasion dNK cells Promote spiral artery remodelling Fail to promote spiral artery remodelling dNK cells Differ in cell surface receptors dNK cells Differ in cytokine secretion dMacrophage Do not induce trophoblast apoptosis Induce trophoblast apoptosis