Cytokines are small proteins in the human body that are a very crucial component of the immune system. They help with immunity and protect the body from unknown bacteria. They also play an essential role in many developmental processes. The correct balance between proinflammatory and anti inflammatory cytokines is important for normal brain development. During pregnancy, when the maternal immune system is activated cytokines are released and make their way to the fetus. In the brain, cytokines affect many pathological processes, such as sleep, memory, and learning. Because of the abnormal amount of cytokine in the fetal brain, there is risk for neurodevelopmental disorders in the offspring. 

Dendritic spines are structures that are important to carry out the normal functions of the brain. Dendritic spines are connected to the dendrites of neurons in the shape of small protrusions, but they come in different sizes and forms. Their density changes while the brain is developing. They make contact with the neighboring axon and receive information from the axon. Learning and memory are connected to dendritic spines. Abnormalities in dendritic spine density are linked to neurodevelopmental disorders, such as autism spectrum disorder and schizophrenia[6]. Maternal immune activation is also connected to this because the cytokines from the mother change the offspring’s dendritic spine morphology. Abnormal spine morphology affects the brain’s plasticity and this can hinder the brain’s aging process from childhood to adulthood. When someone who is pregnant has an infection, it is more likely for their offspring to have a neurodevelopmental disorder. Changes in dendritic spine density affects the amount of information that can be transmitted to the axons which can lead to neurodevelopmental disorders. The cytokines that are released from the maternal immune system, because of infection, can go through the placenta and into the fetus, which is how maternal immune activation affects the offspring. Cytokines have the ability to disrupt and change neurons that affect learning and behavior in the human body.

Similar to how inflammatory conditions can cause maternal immune activation, COVID-19 can have the same effect on mothers and their offspring. Maternal immune activation produces an abnormal amount of proinflammatory cytokines and can create a cytokine storm. A cytokine storm is when the body releases increased amounts of cytokines in a small amount of time. Cytokines are connected to the immune system and without a precise balance between proinflammatory and anti-inflammatory cytokines, the maternal immune system can suffer. This can then lead to poor brain development in the offspring, and this has been seen with COVID-19. A relationship between maternal fever during a specific period of gestation and neurodevelopmental disorders in the offspring was found [2]. Although COVID-19 is not transmitted vertically from mother to offspring, because of MIA, the effects are still seen. 

A recent maternal-child cohort study [1] showed that there are some abnormalities in cytokine levels during the mid-gestational period in mothers whose children are diagnosed with autism spectrum disorder. This study profiled cytokines at 20 weeks gestation in a cohort with set characteristics of expectant mothers. There were 2,137 infants recruited in a span of three years. There were eight different cytokines that were selected as a part of the study that were picked based on previous findings. There were 25 cases to 50 controls (neuro-typical). Out of the eight cytokines that were observed, IL-4 was seen to be altered the most in mothers of children with ASD at 20 weeks gestation. In past studies, IL-4 levels were found to increase in the ASD affected group compared to the control group. In this study however, it was found that IL-4 levels decreased in the ASD affected group. IL-4 plays a role in the development of T-cells, which are a part of the immune system and affect immunity to foreign substances. T-cells control inflammation during pregnancy and with non-increasing levels of IL-4 during pregnancy, a more proinflammatory environment is likely. This environment can affect maternal health and obstetric outcomes as well as the child's health and development, which can lead to neurodevelopmental disorders such as autism spectrum disorder.

When a mother is infected with a disease, COVID-19 for instance, the maternal immune system reacts to the unwanted virus or bacteria and that reaction makes its way to the offspring and can have a negative effect on the offspring’s brain development. Maternal immune activation causes an excess amount of cytokines and those cytokines transfer to the offspring. These cytokines affect the spine morphology of the offspring and that affects the development of neural disorders, such as autism spectrum disorder and schizophrenia. The close relationship between the immune system and the nervous system is seen through this, as a disruption to the maternal immune system has immediate impacts on an offspring’s nervous system. 

References:

[1] Carter, M., Casey, S., O'Keeffe, G. W., Gibson, L., & Murray, D. M. (2021). Mid-gestation cytokine profiles in mothers of children affected by autism spectrum disorder: a  case-control study. Scientific reports, 11(1), 22315. 

[2] Forestieri, S., Pintus, R., Marcialis, M. A., Pintus, M. C., & Fanos, V. (2021). COVID-19 and   developmental origins of health and disease. Early human development, 155, 105322.  

[3] Shook, L. L., Sullivan, E. L., Lo, J. O., Perlis, R. H., & Edlow, A. G. (2022). COVID-19 in pregnancy: implications for fetal brain development. Trends in molecular medicine, 28(4), 319–330.

[4] Joma, M., Fovet, C. M., Seddiki, N., Gressens, P., & Laforge, M. (2021). COVID-19 and Pregnancy: Vertical Transmission and Inflammation Impact on Newborns. Vaccines, 9(4), 391.

[5] Forestieri, S., Pintus, R., Marcialis, M. A., Pintus, M. C., & Fanos, V. (2021). COVID-19 and developmental origins of health and disease. Early human development, 155, 105322

[6] Pekala, M., Doliwa, M., & Kalita, K. (2021). Impact of maternal immune activation on dendritic spine development. Developmental neurobiology, 81(5), 524–545.