L8 Inflammation and Pregnancy Flashcards
Why is controlled heterogenous inflammation crucial during gestation?
- Need to carefully modulate immune responses at different stages to facilitate gestation and parturition
- e.g. Proper implantation and placentation require proinflammatory conditions (allowing invasion and remodelling of maternal tissue)
- e.g. Fetal growth requires anti-inflammatory conditions (preventing graft rejection of the fetus)
- e.g. Parturition requires pro-inflammatory conditions to evict the baby
- Various adverse outcomes come about when these inflammatory programmes go wrong
Give 5 adverse pregnancy outcomes caused by disrupted inflammation:
- Preeclampsia
- Preterm birth
- Miscarriage
- Stillbirth
- Fetal growth restriction
What are the two types of immune response?
- Innate immunity (rapid with no memory) -> macrophages, dendritic cells, NK cells, neutrophils and more
- Adaptive immunity (slower with specificity to insult) -> B cells producing Abs, T cells differentiating
- Some cells play a role in both (e.g. types of NK and T cells)
- The two systems support each other
How are naive T-cells differentiated?
- Antigen-presenting cells recognise DAMPs/PAMPs/toll-like receptors of pathogens -> engulfed with antigen presented at surface
- Stimulates differentiation of naive T cells in coordination with cytokines and other costimulatory signals
- Key lines: Th1, Th2, Th17 and Treg
What are the cytokines required for differentiation of key T-cell lines?
- Th1 (pro-inf): exogenous IL-12, IFNy from self
- Th2 (anti-inf): exogenous IL-4
- Th17 (similar behaviour to Th1): exogenous IL-6, IL-23, TGF-B
What types of inflammatory cells are important immediately following implantation (including proportion):
- 70% NK
- 20-25% Macrophages
- 1.7% dendritic cells
- ~3 - 10% T cells
- These populations have an active role in implantation, placentation and immune tolerance
What cytokines and dendritic cells are part of the pro-inflammatory conditions during implantation and what is their general function?
- Endometrial stroma and infiltrating inflammatory cells release: IL-1, IL-8, IL-15, GM-CSF, CXCL1, CCL4
- CD11c+ dendritic cells are crucial
- These cytokines facilitate receptive conditions in the endometrium (expression, transport and modification to adhesion molecules promoting and accelerating blastocyst attachment)
How does Th1 dominance promote blastocyst attachment and invasion?
- Transfer and expression of new adhesion molecules to cell surface of uterine lumen
- Removal of mucin layer -> promoting blastocyst adhesion
- Increasing affinity for adhesion molecules like L-selectin on uterine epithelium
- Once attached, blastocysts stimulated to release MMPs -> degrading matrix and allowing invasion (inflammatory-mediated response)
What are the 3 key components of Th2 dominance during gestation and what are their general roles?
- Macrophages, dNK cells and T-reg cells -> antiinflammatory, Th2 dominant environment from weeks 13 to 27
- M2 type macrophages -> tissue renewal during placental development, breaking down apoptotic trophoblasts to prevent release of paternal antigens
- dNKs interact with macrophages (CD14+) and induce generation of T-reg cells
- T-reg cells are crucial for tissue repair (anti-inf, anti-apoptotic); also preventing Teff immune response against paternal antigens
What role do T-reg cells have in facilitating new pregnancies after birth?
- Capacity for memory
- Systematically raised in the endometrium during the first pregnancy against paternal antigens of the fetus
- Some T-reg cells remain after birth, and will accumulate with each subsequent pregnancy
What role do Th17-type cells have during fetal development?
- This period is generally Th2-dominant and anti-inflammatory, but Th17 cells have a pro-inflammatory phenotype
- This small population expands during pregnancy and is thought to be important for protecting against microbial infection at the maternal-fetal interface (under regulation by T-reg cells)
- As such, an imbalance between these two populations is associated with various pathologies (spontaneous abortion, pre-eclampsia, preterm birth)
What soluble factors maintain Th2 type inflammation and where are they secreted?
- Decidual M2 macrophages: IL-10, TGF-B, IDO
- Decidual gamma-delta T cells: IL-10, TGF-B and PIBF
What fetal antigens maintain the Th2 type inflammation and how do they achieve this?
- HLA-E
- HLA-G
- Both expressed on trophoblast cells -> interact with inhibitory receptors on NK cells and T cells
How is NF-kB signalling induced at the end of pregnancy and why is it important?
- Endogenous damage-associated molecular patterns (DAMPs) and surfactant protein A (maturing fetal lung) produced at end of pregnancy -> activation of NF-kB signalling via TLR-4 activation
- Leads to switch back to Th1-dominance and production of pro-inflammatory cytokines
- Causes influx of immune cells into myometrium which are involved in initiating contractions
What are the 3 effects of trophoblast cells on immunological milieu at the implantation site?
- Recruitment of peripheral NK cells and monocytes, Treg cells etc (via chemokines and cytokines) to boost the existing immune population at the implantation site
- Immune cell education to tailor their phenotypes in supporting pregnancy
- Environmental sensing to protect against external threat
How do trophoblasts recruit immune cells to the implantation site?
- Secretion of cytokines
- e.g. CXCL12, CXCL8/IL-8, TGF-B, CCL1
How do trophoblasts ‘educate’ the immune milieu at the implantation site?
- Specific cytokines influence different immune populations
- e.g. IL-15 and TGF-B differentiate the decidual NK phenotype from peripheral NKs
- e.g. M-CSF, IL-10 differentiate M2-like macrophages from CD14+ monocytes (note that they retain C14 expression so are still able to secrete immunomodulatory cytokines like TGF-B, IFNs)
How do trophoblasts sense environmental threats during immunoregulatory activity?
- Sensing via expression of receptors like TLRs, NOD-like receptors (NLRs)
- Able to recognise DAMPs (from dying tissue) and PAMPs (from pathogens) allowing a response to be mounted against potential threats
What 3 hormones have a key role in immunoregulation during pregnancy?
- Progesterone
- Oestrogen
- Oxytocin
How does progesterone act as an immunomodulator? (5 points)
- Blocks lymphocyte proliferation and alters antibody production in existing B lymphocytes
- Prolonging allograft survival
- Reduces production of proinflammatory cytokines of macrophages
- Upregulates TLR-4 expression and suppresses TLR-2 response to intrauterine infection
- Inhibits MMP1 and MMP3 expression in decidual cells
How is progesterone affected during pathological intrauterine inflammation?
- Functional withdrawal
- Diminishing immunomodulatory effect
- Big link between infection and miscarriage
What are the 2 immunomodulatory effects of oestrogen during pregnancy?
- Inhibits Th1 proinflammatory cytokines (IL12, TNF-a, IFN-y)
- Stimulates Th2 antiinflammatory cytokines (IL10, IL4, TGF-B)
How is oxytocin involved in immune response during parturition?
- Oxytocin receptor upregulated by CEBP, NF-kB -> these TFs are activated by proinflammatory cytokines
- Potentiating oxytocin action on labour
How is maternal tolerance of the fetus maintained? (Overview with 5 examples)
- Broadly speaking, tolerance is achieved by restriction and modulation of leukocytes at the maternal-fetal interface
- Antiinflammatory cytokines (IL-10, TGF-B) at interface induce differentiation of circulating immune cells into M2 type macrophages and Treg cells
- Synctiotrophoblasts secrete exosomes containing TRAIL and Fas death ligands -> triggering apoptosis of leukocytes
- Lack of HLA expression by STB
- Placental EVTs express HLA-G which binds to dNK inhibitory receptors
- M2 macrophages release IDO -> hinders T cell activation and phagocytosis of apoptotic trophoblasts
How does HLA matching influence viability?
- Category 1: Low-level matching between maternal and fetal HLA 1 antigen -> succesful pregnancy
- Category 2: High-level matching -> fetal loss, women with recurrent spontaneous abortion
How common is preeclampsia:
- Presents in ~7% of pregnancies
- Leading cause of maternal-perinatal morbidity and mortality
Clinical features of PE:
- Hypertension
- Proteinuria
- HELLP (haemolysis, elevated liver enzymes, low platelets)
- Visual disturbances
Outline the pathogenesis of PE and how immune imbalance is involved:
- Failure of trophoblast and immune cells to remodel spiral arteries into high-capacity, low resistance vessels due to disruption by pro-inf DC, NK and Th cells
- Results in a breakdown of placental perfusion and placental ischaemia (i.e. not enough blood) -> hypoxia induces production of inflammatory modulators and antiangiogenic factors via presentation of fetal antigens on apoptotic trophoblasts -> vascular dysfunction in placenta and peripheral vessels
- Circulating placental factors cause endothelial dysfunction and oxidative stress -> further contribution to hypertension and multiorgan dysfunction
How are the spiral arteries remodelled during placentation?
- Trophoblasts and immune cells secrete proteases and angiogenic factors
How is late-onset PE different from typical pathology?
- Spiral artery remodelling occurs normally, but placental needs eventually exceed uterine perfusion capacity
- Results in hypoxia and consequent inflammation, eventual hypertension and widespread effects
Link between PE and postpartum inflammation:
- Immune memory of immune response to placental ischaemia
What are HLAs and where are they expressed in the fetus?
- Highly genetically diverse system of antigen (human leukocyte antigen)
- Expressed primarily on extravillous trophoblasts
- Pivotal to immune tolerance
- Three classes: Class I divided into Ia (A, B, C) and Ib (E, F, G)
Outline the mechanism through which low level HLA matching promotes successful pregnancy:
- Fetal antigens processed and presented by maternal CD8+ T cells -> differentiate int CD8TFLCs
- CD8TFLCs interact w/ maternal B cells, inducing formation of plasma B cells
- These produce IgG Abs specific to the fetal HLA I -> blocked from interaction with CD8+ to produce cytotoxic T cells
- Trophoblasts protected and pregnancy preserved
Outline the mechanism through which high level HLA matching promotes spontaneous abortion:
- High level HLA matching alters the processing of fetal HLA by CD8+, so IgG Abs are not raised against them in differentiated plasma B cells
- Instead, the processing and presentation of fetal HLA activates CD8+ into CD8+ cytotoxic cells -> release of cytolytic mediators (perforin, granzymes)
- Leads to trophoblast cell death, initiating a cascade into spontaneous abortion
How have therapeutic approaches addressed the issue of high-level HLA matching?
- The mother is injected with paternal lymphocytes in advance of pregnancy
- This induces the low-level matching pathway raising antibodies against paternal HLA resulting in protection from cytotoxic CD8+ cells
