MORE ON THE MOTHER’s IMMUNE SYSTEM IN PREGNANCY: How it affects the maternal and infant brain
NORBERT GLEICHER, MD, Is Medical and Laboratory Director as well as Chief Scientist at the Center for Human Reproduction (CHR) in NYC
September 6, 2024, Revised with permission from the June 2024 issue of the CHR VOICE.
BRIEFING: To reemphasize the importance of the female immune system for successful reproduction, this article points out how the maternal immune system in pregnancy not only affects the pregnant woman’s brain but also, long-term, that of her offspring.
During pregnancy the maternal brain undergoes long-lasting structural changes involving reductions in gray matter volume in regions subserving social cognition.1 On a long-term basis, neural and biological states of the adult female are, therefore, significantly altered by parity and motherhood.2 What induces this remarkable degree of plasticity of the brain is, however still largely unknown. In rats, microglia, the brain’s innate immune cells, were significantly reduced in density during late pregnancy and the postpartum period in basolateral amygdala, medial prefrontal cortex, nucleus accumbent shell and dorsal hippocampus as well as in all four brain regions but unaffected in the motor cortex, while IL-6 and IL-10 levels were postpartum increased in the hippocampus.3 This is exactly the time period when postpartum depression and other psychiatric disorders frequently become clinically apparent in humans.4
These observations suggest a quite significant shift in the maternal neuroimmune environment during the peripartum period, which appears to contribute to the significant neural as well as behavioral plasticity occurring during the transition to motherhood. For a number of reasons, pregnancy-induced changes to maternal brains deserve more attention than they currently receive.
Our understanding of how the immune system affects maternal brains was significantly enhanced only in 2015 with the reported discovery of a structural as well as functional lymphatic system in the brain.5 Up to that point, conventional wisdom assumed that, because the so-called blood-brain barrier (a semipermeable membrane) prevented cellular components of blood and, therefore, immunologically-important cells from accessing the central nervous system (CNS), the immune system could not interact with the brain. Over just a few short years it has now become obvious that not only does the immune system have access to the brain, but that interactions between brain and immune system are extremely intimate and may be responsible for a variety of neurological and psychiatric diseases in women who go through pregnancy. The degree of interaction, indeed, appears so intense, that a prominent neuroimmunologist designated the immune system as the “seventh sense.”6
Since it is now confirmed that blood products and cells have access to the CNS during pregnancy, the behavior of a number of neurological and psychiatric diseases in association with pregnancy deserve renewed scrutiny. Pregnancy has for the longest time been considered a stress test for all female organs. Evolutionary theory, indeed, predicts accelerated aging in parallel with increasing pregnancy numbers because of diversion of more energy during pregnancy from routine somatic body maintenance, and was recently confirmed in a study of Filipino women.7 Because pregnancy so typically serves as a universal stress test, phenotypical disease presentations in association with pregnancy 8 and cardio-vascular disease9 are common.
Likely the most typical so associated pregnancy phenotype is maternal autoimmunity in all of its presentations, even if only sub-clinically present. Likely because of inadequate induction of tolerance pathways for the implanting embryo (a paternal semi-allograft) by women with hyper-active immune systems, autoimmunity in early and late pregnancy is typically associated with maternal immune system hyperresponsiveness toward the fetus. In early pregnancy, this results in implantation failure and enhanced miscarriage risks,10 while in late gestation, premature termination of tolerance leads to premature initiation of labor, a typical presentation in practically all autoimmune diseases.11 The most characteristic phenotypical presentation of autoimmunity is, however, first expression and/or flaring of autoimmune diseases with and/or after termination of pregnancies, establishing a maternal risk period of up to five months into the postpartum period.12,13
Several neuropsychiatric disorders, especially depression (in the form of so-called postpartum depression or postpartum “blues”) and bipolar disorders, typically present with above-described autoimmune phenotype, characterized by initial presentation or flaring peripartum and in the postpartum period (therefore, the name postpartum depression and more recently, peripartum depression). Women with depression typically also present with premature labor,14,15 practically a uniform finding in women with all autoimmune diseases.11An autoimmune etiology is also supported by the strong association between thyroid autoimmunity and postpartum dysphoria.16-18 Investigators at the CHR, therefore, for quite some time have been proposing a potential autoimmune etiology for the psychiatric disease of depression, even if not related to pregnancy15,19 and have done so even before publication of the groundbreaking discovery that, contrary to prior assumptions, the CNS is privy to a complex immune system (reviewed in reference20).
Maternal immune system activation, however, does not only affect the mother. There is, indeed, ever more evidence that it represents a highly significant risk factor for neuropsychiatric disorders (including autism) in offspring,21-27 summarized by Estes and McAllister in a special section on neuro-immunology in Science magazine.28
It is also in this context of interest that the late-pregnancy complication of preeclampsia, likely consequence of preterm declines in maternal tolerance levels ,10 has been statistical associated with maternal depression and anxiety.29 Moreover, postpartum females appear to exhibit significant changes in expression of cytokines within the brain that are associated with depressive-like behavior.30
J.S. Scott already suggested in 1966 that pregnancy offered investigators a natural “disease model” for the investigation of autoimmunity.31 This contribution would like to make the same suggestion to neurobiologists who are trying to decipher the effects of the immune system on neuro-psychiatric diseases in mothers and their offspring.
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