Autism spectrum disorders (ASD) are pervasive, highly prevalent lifelong disorders for which pharmacological interventions are not readily available. While genetic factors are likely contributors to these disorders, heritability estimates indicate strong environmental contributions. Of particular interest is the link between fetal gestation and the activation of the maternal immune system during critical periods of development. Epidemiological reports suggest a strong association between periods of maternal immune activation and an increased risk of having a child with ASD including immune conditions such as allergies and asthma. Unique immune cascades representative of asthma and allergy responses have been detected in amniotic fluid and maternal serum mid-pregnancy of mothers whose child was later diagnosed with ASD. Acute exacerbations are common in pregnant asthmatic women with as many 45% suffering attacks during pregnancy. However, little is known about the consequences of maternal allergic asthma (MAA) responses on fetal development. We have described the first set of preclinical studies to test the hypothesis that MAA induced during gestation imparts alterations in brain neurobiology and functional behavioral outcomes in the offspring that have a high degree of face validity for ASD symptoms. Pregnancy is a time when epigenetic changes help a static genome adapt to the maternal environment, so that if the maternal immune system is overly activated, the fetal immune system will also be over activated at the expense of brain development. The proposed studies will examine whether MAA alters epigenetic landscape of microglia, alters microglia activation and impacts early brain development (Aim #1). We will test the hypothesis that MAA exposures during gestation leads to a susceptibility to further challenges or stressors in juvenile offspring that can impact inflammation in the offspring, including neuroinflammation and elevated microglia activation, neuropathology and behavioral outcomes (Aim #2). If successful, this research will validate the transformative concept that ASD is, for some, a disorder due to the direct effects of aberrant immune activation and will identify a novel mechanism for one of the most visible public health concerns of our time.
In the last 20 years, rates of diagnoses for autism have increased at an alarming rate, and yet little is understood about its causes and treatment options are limited. By examining an established and relatively common risk-related environmental factor ? namely maternal immune activation by allergies / asthma ? we will challenge current paradigms and isolate specific mechanisms contributing to pathophysiology of autism. This hypothesis-driven integrative study combines immune, neuropathology, epigenetic and behavioral approaches to address a major gap in autism research and will provide critical information on the consequences of neuroimmune contributions to risk for autism, helping to translate epidemiological observation into a functional model that can be utilized for further investigations and identify possible paths for prevention or treatment.
|Rose, Destanie R; Yang, Houa; Serena, Gloria et al. (2018) Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptoms. Brain Behav Immun 70:354-368|
|Vogel Ciernia, Annie; Careaga, Milo; LaSalle, Janine M et al. (2018) Microglia from offspring of dams with allergic asthma exhibit epigenomic alterations in genes dysregulated in autism. Glia 66:505-521|