Maternal Immune Activation Flashcards
Which immune cells dominate the uterus in early pregnancy?
Innate
What type of inflammatory response is there in the first few weeks of pregnancy?
Pro-inflammatory
Describe a healthy maternal immune system during pregnancy
Pregnancy involves complex changes to the maternal immune system that can be categorised into 3 stages
1. Initially pro inflammatory for the first few weeks
2. For the longest part of gestation (the late 1st to early 3rd trimester), in general, there is an anti-inflammatory phenotype
3. Towards the end of a healthy pregnancy, there is another pro-inflammatory response
what effect does a heightened immune response have during the late 1st trimester to early 3rd trimester?
this can be detrimental to mother and fetus, can lead to placental disorders and miscarriage
what is the role of the proinflammatory response towards the end of pregnancy?
it is key in preparing the body for labour and childbirth
what cytokine is particularly important for triggering childbirth
IL-6
Why is there an increased risk of schizophrenia if you are born in Spring?
because there is a higher risk of the mother contracting a seasonal flu/common cold virus during her pregnancy which can interfere with the dampened immune response optimal for late 1st to early 3rd trimester, particularly if infection occurs in second trimester
what increases the risk of ASD
maternal hospitalisation due to infection increases the risk of ASD for the fetus
vertical transmission of pathogens?
pathogens that can be transmitted directly from the mother to the fetus
acronym TORCH
Vertically transmitted viruses: Toxoplasma gondii, other, rubella, CMV, HSV
viruses that have a high degree of neurotropism
HSV and Zika virus affect neurodevelopment directly
maternal immune activation?
stimulation of a proinflammatory state by the mother’s immune system during pregnancy, occurs in response to infection and other stimuli, and certain maternal or gestational disorder
How to to induce MIA in animals
LPS (to mimic gram -ve infection like e. coli)
Poly IC (dsDNA to mimic viral infection like influenza)
Enterotoxins (mimic gram +ve bacteria like s. aureus)
transgenic animals (with receptors expressed in humans to mimic pathogens that are human-specific)
what does early prenatal LPS exposure do in rats?
It alters reward seeking behaviour
what does late prenatal exposure to LPS do in rats?
Motor defects
what effect does poly IC exposure in mice have?
causes dopamine and serotonin imbalances, similar to what is seen in schizophrenia
MIA increases ___ ___ and affects ___ ___ and ___ activity in the brain of a prenatal mouse
MIA increases microglial activity and affects cortical cytoarchitechture and neural activity
what is the cytokine hypothesis of Neurodevelopmental Disorders
that the increased risk of neurodevelopmental disorders caused by maternal infection is not due to the specific pathogen itself, but the MIA it induces and as a result, high levels of cytokines reaching the fetal brain
what characteristics must cytokines produced in response to maternal infection have to cause neurodevelopmental disorders?
cytokines must cross the placenta and the BBB
have been found in elevated conc in brains of offspring of MIA animal models
have potent effects on neurons in vitro
What does IL-6 promote?
IL-6 promotes neuronal differentiation, growth, and survival, induces death in serotonin neurons, activates microglia
What is elevated levels of maternal IL-6 associated with?
elevated maternal IL-6 levels is associated with altered structural and functional connectivity in offspring
Describe IL-6 signaling
A JAK1/2-bound gp130 co-receptor is recruited to heterodimerise with IL-6Ralpha
JAK1 and JAK2 transphosphorylate
p-JAK1 and p-JAK2 phosphorylate their respective gp130 proteins
cytosolic STAT3 is recruited to each gp130
STAT3 is phosphorylated on tyr705 by pJAK1/2
p-STAT3 dissociates from receptor complex, dimerizes and translocates to nucleus
p-STAT3 dimer acts as a transcription factor, enhancing the expression of target genes
Another cytokine observed in increased levels in MIA in maternal circulation and the fetal brain?
IL-17
Describe IL-17 signalling
Uses adapter protein Act1
Act1 ubiquitinates Traf6
this activates NF-kB
Risk factors for maternal obesity
Chronic stress
Genetics
High caloric diets
Lack of physical activity
