Immunological Issues in ASD – Gestational Influences

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

Introduction 

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). 

Animal studies

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).