Immunty and Pregnancy Flashcards
What does the human blastocyst consist of after fertilization?
1) . The inner cell mass which gives rise to the embryo
2) . External layer which gives rise to the placenta
When is implantation initiated?
When the trophoblast cells breach the surface d epithelial lining of the decidua to attach and invade, leading to the formation of the placenta
Besides decidual cells and endothelial cells, what else is a major cellular component of the maternal decidua?
Infiltrating immune cells
What is the primary role of the trophoblast cells?
To shape the receptive immunimodulatory milieu of the maternal decidua ~ promoted by commensalism microbiota
What is the host-graft model?
The presence of immune cells at the maternal-fetal interface represents an immune response that is directed against the semi-allogenic fetus
Is the host Graft model accurate?
No~ evidence suggests the immune response at the maternal-fetal interface supports the reception, establishment and growth of the implanting blastocyst
Why was the host graft model believed?
It was thought the fetal-placental unit, which expresses foreign paternal proteins, is in continuous antagonism with the maternal immune system, and that the successful implantation of the blastocyst and its further development into a growing fetus occur as a result of constant suppression of the maternal immune system
What does the host graft model resemble?
Organ transplant immunology and parallels graft-host interactions
What aspect of immunosuppression cause the loss of pregnancy ?
- deletion of immune cells at the implantation site
- inhibition of key signaling pathways (pathway mediated by FAS and FAS ligand)
What happens if NK cells are deleted?
Leads to poor endometrial vascularity and impedes trophoblast invasion
What happens if decidual DCs are deleted?
Results in improper decidual formation and poor endometrial vascularity, which impair blastocyst implantation
What is pregnancy immunology paralleled to?
Cancer immunology
How is the receptivity of maternal invading blastocyst similar to cancer immunology?
Similar to the receptivity of a secondary organ site to a cancer micrometastasis
What does the attachment of a micrometastatic tumor to a new tissue initiate?
Initiates a proinflammatory process that is characterized by the presence of angiogenic factors, growth and survival factors, and cytokines and chemokines
Once established in the tissue, how do tumor cells modify the tissue micrownvironemnt?
Change it towards a T helper 2 or antiinflammatory milieu, which can increase recruitment of M2-like macrophages, myeloid derived suppressor cells and regulatory T cells
How does pregnancy progress?
1) . Begins in a proinflammatory environment that allows implantation and placentation
2) . Shifts to antiinflammatory stage that allows fetal growth
3) . Shifts back to proinflammatory stage that promotes labor and delivery
What does the stage of implantation and placentation resemble?
Process of tissue injury and repair
At the implantation site, what is inflammation characterized by?
- presence of IL-6, IL-8, IL-5
- granulocyte macrophage colony stimulating factor
- chemokine ligand 1
- chemokine ligand 4
- tumor necrosis factor
What is the inflammatory environment crucial for?
- transfer of stored adhesion molecules to the cell surface of epithelial cells at the uterus lumen and the expression of new adhesion molecules
- removal of preexisting layer of mucins present at the luminal surface epithelium of the uterus
- increased affinity of adhesion molecules on the uterine epithelium
- reorganization of adhesion molecules on the social surface of the epithelium of the Lynne
How do uterine DCs help during pregnancy?
They govern uterine receptivity by regulating tissue remodeling and angiogenesis
Early role in the process of promoting tolerance to paternal antigens
What happens during the stage of fetal growth?
Anti inflammatory stage (Th2 type)
Mother and fetus are symbiotic
Longest period of pregnancy
Which cells contribute to establishing an anti inflammatory micro environment?
- macrophages
- decidual NK cells
- T regulatory cells
How do decidual macrophages help the pregnancy?
- have an M2 phenotype that helps tissue renewal
- secrete antiinflammatory cytokines
- remove dying trophoblast cells, preventing the release of paternal antigens
What do decidual NK cells do?
- classified as CD56bright or CD 16-negative
- show low toxicity
- interact with CD14+ decidual macrophages and induce the generation of Treg cells
What do Treg cells do?
Key players in tissue repair process
Maintain an anti inflammatory environment by preventing effector type immune response against paternal antigens
Protect fetal cells that express paternal antigens from rejection by maternal immune system
What do Th17 cells do?
Help protect the maternal fetal interface from microbial infections
What happens during labor?
A proinflammatory environment
Proinflammatory nuclear factor (NF-kB) signaling pathway initiates labor
Influx of immune cells into myometrium is crucial in order to promote the contraction of the uterus, delivery of the baby and separation of the placenta
How is the NF-kB signal king pathway induced?
Till like receptor 4 (TLR4) activation by ligands such as surfactant protein A and endogenous damage associated molecular patterns (DAMPs), such as high mobility box 1 (HMGB1)
What does the trophoblast represent?
The first point of contact between the blastocyst and the maternal decidua
How do trophoblasts shape the immunological milieu at the implantation site?
By attracting and educating immune cells
Shaking the subsequent response of immune cells to external stimuli
What happens after trophoblast secrete cytokines at the implantation site?
Promoted the recruitment of peripheral monocytes, neutrophils, NK cells, T cells and Treg cells
Trophoblasts express cell surface receptors such as TLRs and NOD like receptors (NLRs), what do they do?
Recognize DAMPs that are released from dying cells and damaged tissues
Recognize pathogen associated molecular patterns (PAMPs) from bacteria, viruses, etc
Overall what do trophoblasts do?
- attract and educate immune cells
- respond to signals from the microenvironment that supports decidual differentiation, trophoblast migration and invasion, angiogenesis and spiral artery remodeling, and placental and fetal development
How can bacteria access the maternal-fetal interface?
- ascending from the lower reproductive tract
- descending from the peritoneal cavity
- through the maternal circulation
What do maternal microbiota do?
Aid in the induction of a Tolerogenic immune system
Exposure to maternal microbiota during pregnancy can markedly affect early development of the post natal immune system in the offspring
Contributes to the tolerogenic, antiinflammatory stage
What do type 1 IFNs do? (IFN-alpha and IFN-beta)
Induction of antimicrobial state
Modulation of innate immune responses
Activation of adaptive immune system
What do viral infections do to commensal microbiota?
Virus infections abolish the beneficial effects of the commensal microbiota
What are the possible outcomes of viral infections during pregnancy?
- benign asymptomatic event
- overt pregnancy loss
- occurrence of fetal congenital malformations
Can IFN-beta affect viruses?
Can exert antiviral responses
But viruses can also inhibit this pathway (type 1 IFN)
How do viral infections affect TLR4-induced responses?
Modify them, causing them to change from being antiinflammatory to proinflammatory
What is the result of the loss of IFNbeta?
Reduced receptivity of the immune cells at the maternal fetal interface and would reduce their capacity to control and respond to other micro organisms
Suggests that a viral infection can change how trophoblast cells respond to bacterial products in a way that abolishes the immunomodulatory effects of the normal microbiota
Double hit hypothesis of preterm labor
How do undetected viral infections affect fetal development?
- death
- fetal and neonatal brain (autism, schizophrenia)
- immune system
- behavioral problems
How does the placenta affect the mother during viral infections?
The placental response to virus infection is directly responsible for disease severity
Placenta can act as a viral reservoir and can induce a maternal response that can lead to maternal death
True or false: pregnancy does not involved changes in the immune response?
False
