Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain

Urakubo, Ari; Jarskog, L. Fredrik; Lieberman, Jeffrey A.; Gilmore, John H.

doi:10.1016/s0920-9964(00)00032-3

Cited by 366 publications

(234 citation statements)

References 70 publications

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“…The MIA model in its most common design involves challenging pregnant rodents via direct infection (eg, influenza, Escherichia coli) or the dsRNA mimic poly (I:C); significant immunological, neurodevelopmental, and behavioral changes are then observed in the offspring (Gilmore et al, 2005;Meyer et al, 2005;Urakubo et al, 2001;Zuckerman and Weiner, 2005). These changes have been linked and employed to model several neurodevelopmental disorders, including schizophrenia (Meyer and Feldon, 2009;Meyer et al, 2005;Zuckerman and Weiner, 2005), cerebral palsy (Boksa, 2010), and autism (Brown et al, 2015).…”

Section: Maternal Immune Activationmentioning

confidence: 99%

The Role of the Immune System in Autism Spectrum Disorder

Meltzer

Water

2016

Neuropsychopharmacol

387

293

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Autism is a neurodevelopmental disorder characterized by deficits in communication and social skills as well as repetitive and stereotypical behaviors. While much effort has focused on the identification of genes associated with autism, research emerging within the past two decades suggests that immune dysfunction is a viable risk factor contributing to the neurodevelopmental deficits observed in autism spectrum disorders (ASD). Further, it is the heterogeneity within this disorder that has brought to light much of the current thinking regarding the subphenotypes within ASD and how the immune system is associated with these distinctions. This review will focus on the two main axes of immune involvement in ASD, namely dysfunction in the prenatal and postnatal periods. During gestation, prenatal insults including maternal infection and subsequent immunological activation may increase the risk of autism in the child. Similarly, the presence of maternally derived anti-brain autoantibodies found in~20% of mothers whose children are at risk for developing autism has defined an additional subphenotype of ASD. The postnatal environment, on the other hand, is characterized by related but distinct profiles of immune dysregulation, inflammation, and endogenous autoantibodies that all persist within the affected individual. Further definition of the role of immune dysregulation in ASD thus necessitates a deeper understanding of the interaction between both maternal and child immune systems, and the role they have in diagnosis and treatment.

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Section: Maternal Immune Activationmentioning

confidence: 99%

The Role of the Immune System in Autism Spectrum Disorder

Meltzer

Water

2016

Neuropsychopharmacol

387

293

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“…Upon maternal immune activation, there are elevated levels of pro-inflammatory cytokines in the maternal circulation, as well as in the placenta and fetal circulation (Ashdown et al, 2006;Bell et al, 2004;Urakubo et al, 2001). However, a number of studies report that neither immune molecules (e.g., LPS) nor maternal cytokines enter fetal circulation suggesting that fetal cytokine levels are elevated due to exposure to placental cytokines or self-production (e.g., Cai et al, 2000;Gayle et al, 2004;Gilmore et al, 2005;Urakubo et al, 2001).…”

Section: Animal Models Of Pathogenic Immune Activationmentioning

confidence: 99%

“…However, a number of studies report that neither immune molecules (e.g., LPS) nor maternal cytokines enter fetal circulation suggesting that fetal cytokine levels are elevated due to exposure to placental cytokines or self-production (e.g., Cai et al, 2000;Gayle et al, 2004;Gilmore et al, 2005;Urakubo et al, 2001). The mechanism by which cytokines, once induced in the fetal brain, cause their effects is not yet known, however they have been found to regulate cell growth and differentiation (Heinrich et al, 1998).…”

Section: Animal Models Of Pathogenic Immune Activationmentioning

confidence: 99%

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Rana

Aavani

Pittman

2012

Hormones and Behavior

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Humans are exposed to potentially harmful agents (bacteria, viruses, toxins) throughout our lifespan; the consequences of such exposure can alter central nervous system development. Exposure to immunogens during pregnancy increases the risk of developing neurological disorders such as schizophrenia and autism. Further, sex hormones, such as estrogen, have strong modulatory effects on immune function and have also been implicated in the development of neuropathologies (e.g., schizophrenia and depression). Similarly, animal studies have demonstrated that immunogen exposure in utero or during the neonatal period, at a time when the brain is undergoing maturation, can induce changes in learning and memory, as well as dopaminemediated behaviors in a sex-specific manner. Literature that covers the effects of immunogens on innate immune activation and ultimately the development of the adult brain and behavior is riddled with contradictory findings, and the addition of sex as a factor only adds to the complexity. This review provides evidence that innate immune activation during critical periods of development may have effects on the adult brain in a sex-specific manner. Issues regarding sex bias in research as well as variability in animal models of immune function are discussed.

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“…41,43 Recent work has focused on the roles of cytokines and pro-inflammatory effects of tumor necrosis factor (TNF)-␣, interleukin-6, and interleukin-1␤. 12,[41][42][43][44][45] Interleukin-10 appears to modulate more protection in animal models. 46 These models may reflect the same process of chronic activation of pro-inflammatory cytokines in brain tissue and cerebrospinal fluids.…”

Section: Immune Models In Animalsmentioning

confidence: 99%

“…This auto-antibody connection may be most active when children undergo language and social development between the ages of 12 and 24 months, which correlates with the ages when most regression is observed to occur. 12,41,42,45 Pregnancy normally results in some degree of elevated maternal immune systemic inflammation. However, exposure to pro-inflammatory inducers may trigger abnormally exaggerated inflammation.…”

Section: Immune Models In Animalsmentioning

confidence: 99%

Immune Therapy in Autism: Historical Experience and Future Directions with Immunomodulatory Therapy

Chez

Guido-Estrada

2010

Neurotherapeutics

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Summary: Autism affects 1 in 110 new births, and it has no single etiology with uniform agreement. This has a significant impact on the quality of life for individuals who have been diagnosed with autism. Although autism has a spectrum quality with a shared diagnosis, it presents a uniquely different clinical appearance in each individual. Recent research of suspected immunological factors have provided more support for a probable immunological process or for processes that may play a role in the acquisition of an autistic condition. These factors include prenatal, genetic, and postnatal findings, as well as the discovery of a dysfunctional chronic pro-inflammatory state in brain tissue and cerebrospinal fluid in subsets of autistic patients. These findings offer new theories that may lead to the development of disease modification or preventative therapeutic options in the near future. This article reviews prenatal, genetic, and observed immune aspects of the autism condition that may be risk factors in the presentation of the autistic clinical phenotype. Historical immune interventions in autism are reviewed and potential new therapies and interventions are discussed.

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Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain

Cited by 366 publications

References 70 publications

The Role of the Immune System in Autism Spectrum Disorder

The Role of the Immune System in Autism Spectrum Disorder

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

Immune Therapy in Autism: Historical Experience and Future Directions with Immunomodulatory Therapy

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