Judy Van de Water, Ph.D., discusses immunological dysregulation during gestation. She examines the etiology of autism and explores the interplay of genetic markers and environmental factors by examining correlations in infections, gestational immune system dysregulation, and autoimmune and autism diagnosis. Van de Water outlines studies on early markers in autism (EMA), maternal autoantibody-related autism (MAR), and intracellular MAR staining, demonstrating the significance of maternal antibodies both as biomarkers and developmental contributors. She highlights the findings and emphasizes their value in future research, screening, treatments, and prevention before opening to questions.
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In this presentation:
4:01 – Research goals
6:55 – Conceptual model of autism etiology
14:05 – Immune function in autism
15:44 – Maternal immune function
18:10 – Maternal infection and autism
21:49 – Maternal immune-mediated diseases and autism
24:30 – Study: Early markers of autism (EMA)
30:10 – Studies: Maternal autoantibody-related autism (MAR)
44:31 – Study: Intracellular MAR staining
46:58 – Conclusions, ongoing analysis, future directions, and importance
52:00 – Q&A
The etiology of autism spectrum disorder is a combination of genetic susceptibilities and environmental factors (5:22). Understanding how these factors interplay can help researchers develop screening tools for earlier diagnosis and interventions (51:00). Van de Water explains that studies increasingly find a connection between prenatal/gestational maternal immune system dysfunction and autism diagnosis. This connection has to do with the neuroimmunological (9:00) interactions between the body’s immune and nervous systems. The three main components of neuroimmunology are:
– Cytokines (10:40): mediate immune responses via cell-to-cell communication
– Chemokines (13:00): chemical trails showing cells where they need to go
– Antibodies: proteins created to fight infection
The immune-neuro interface (11:40) comprises inflammatory and leukocyte pathways that control development, fever response, neuromodulation, inflammation, etc. Van de Water and her colleagues focus on understanding immune dysfunctions during and before pregnancy that may impact this interface and how the brain develops (15:50).
Studies on maternal infection
The speaker highlights the large volume of studies showing a correlation between an autism diagnosis and maternal infection (specifically fever) during pregnancy (18:10). She also outlines studies on the frequency of maternal autoimmune diagnosis. She posits that “some immune dysregulation during pregnancy… could contribute to a change in immune function (i.e. autoimmune diagnosis), resulting in changes to neurodevelopment” (22:30). In all cases, timing at immune system disruption seems important. The presenter notes the difference in clinical and scientific significance (20:50).
Dr. Van de Water outlines a study on early markers of autism (EMA) aiming to 1) identify early biological markers of susceptibility and exposure in fetal brain development and 2) determine etiologic contribution and interplay of neuroimmunological and environmental factors. Phase I (25:20) maternal prenatal cytokine profiles were consistent with allergy/asthma phenotypes and demonstrated the formation of a selective barrier between maternal and fetal circulation (26:26). Phase II results suggested a lack of typical immune regulation during pregnancy in mothers of autistic children and children with intellectual disabilities (27:45).
The speaker describes how some mothers of autistic children produce anti-brain antibodies that can interfere with nervous system development and lead to maternal autoantibody-related (MAR) autism (30:10). Early studies show that these antibodies are associated with enlarged brain and autistic trait presentation (32:45). Previous studies have found a correlation between MAR patterns and autism behavior (38:32) and between the presence of MAR antibodies and an increased likelihood of having another child with autism (39:30). Studies are underway to identify children with this sub phenotype and screen at-risk women to develop preventative strategies and focused treatment plans (34:30).
Van de Water outlines animal studies that show the pathological significance of these antibodies (40:25). For example, Rhesus monkey offspring showed core autism behavior patterns and elevated total brain volume after passive transfer of maternal IgG during gestation (43:20). Mouse models produced the same findings that mimic human cerebral size and behavior under the same conditions (44:02). Finally, intracellular staining (44:31) showed that MAR antibodies could bind to and alter early neural progenitor cells.
Van de Water asserts that these studies show (46:58) gestational immune dysregulation may contribute to altered neurodevelopment and that maternal autoantibodies are specific for autism spectrum disorder. She outlines future studies involving epitopes (47:38) and re-emphasizes the importance of this research in early intervention of developmental trajectory and the potential for prevention (51:00).
About the speaker:
Judy Van de Water, Ph.D. describes gestational influences on neurodevelopment.
Dr. Van de Water joined the faculty in the Department of Internal Medicine at the University of California, Davis in 1999. In 2000, she also joined the faculty of the newly formed UC Davis M.I.N.D. Institute when she began her research on the immunobiology of autism. Dr. Van de Water’s laboratory pursues research programs pertaining to autoimmune and clinical immune-based disorders including the biological aspects of autism spectrum disorders. The application of Dr. Van de Water’s immunopathology background has been instrumental in the dissection of the immune anomalies noted in some individuals with autism, and in the differentiation of various autism behavioral phenotypes at a biological level. Most notable of these is the investigation of the maternal immune system as it relates to autism spectrum disorders, with particular emphasis on the presence of highly specific maternal autoantibodies to fetal brain proteins. Dr. Van de Water’s seminal work in this area has led to a highly specific biomarker of autism risk as well as three patents leading to the commercialization of this technology. Dr. Van de Water is currently the Director of the NIEHS funded Center for Children’s Environmental Health at UC Davis, investigating potential environmental risk factors contributing to the incidence and severity of childhood autism. In addition, Dr. Van de Water’s work is also part of a comprehensive and multidiscipline analysis known as the Autism Phenome Project (APP). Prior to working in autism spectrum disorder research, Dr. Van de Water’s research interests were focused on the immunopathologic mechanisms associated with the autoimmune liver disease, primary biliary cirrhosis (PBC). Her research during PBC led to the discovery of the PBC autoantigen, pyruvate dehydrogenase E2, and the B cell epitope recognized by these autoantibodies.
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