Maternal Autoantibodies in Autism

Abstract

s epidemiologic studies continue to note a striking increase in rates of autism spectrum disorder (ASD) diagnosis around the world, the lack of identified causative agents in most cases remains a major hindrance to the development of treatment and prevention strategies. Published observations of immune system abnormalities in ASD have increased recently, with several groups identifying fetal protein reactive IgG antibodies in plasma from mothers of children with autism. Furthermore, other gestational immune parameters, including maternal infection and dysregulated cytokine signaling, have been found to be associated with ASD in some cases. While detailed pathogenic mechanisms remain to be determined, the hypothesis that some cases of ASD may be influenced, or even caused, by maternal fetal brain-reactive antibodies or other in utero immune-related exposures is an active area of investigation. This article reviews the current literature in this area and proposes several directions for future research.

Evidence supporting an altered immune response in ASD

“…However, as well as protective antibodies, harmful antibodies that bind to selfproteins can also be transferred. Immunoglobulin G (IgG) reactive to fetal brain proteins can potentially disrupt neurodevelopment by blocking the function of the target molecules it has bound to, activating a receptor that it has bound to, or inducing inflammation of the brain [51]. Studies have shown that sera and plasma, from mothers with children who were diagnosed with autism, which were taken either during the second trimester of pregnancy or several years later, contained antibodies with auto reactivity to human fetal brain [50,52,53] (see Table 3 for a comprehensive list of findings in utero in children who are later diagnosed with ASD).…”

“…Sera and plasma, which were taken either during the second trimester of pregnancy or several years later, contained antibodies with auto reactivity to human fetal brain [49,51,52] Significant association between the MET promoter variant rs1858839C allele and the presence of ASD-associated maternal autoantibodies against fetal brain proteins [56] Archived sera taken during the second trimester of pregnancy showed significant increases in IFN-␥, IL-4, and IL-5 [77] cohort of children with ASD who had previously been shown to have many autoimmune phenomena, increased sera levels of IL-17 were shown [84]. Rather than a skewing in any one direction (T H 1, T H 2, T H 17) the dysfunction of the immune response in ASD may be due to a lack of regulation.…”

Pharmaceuticals and Stem Cells in Autism Spectrum Disorders: Wishful Thinking?

“…96,103 In fact, Braunschweig et al found a significant correlation between maternal IgG reactivity to fetal brain proteins and a childhood diagnosis of autism. 104 Altogether, the evidence suggests that environmentally driven peripheral immune dysfunctions and associated neuropathological consequences form a series of interlinked events, which can manifest in autistic features.…”

Immune Involvement in Autism Spectrum Disorder as a Basis for Animal Models

“…Such "autoantibodies" have been identified in plasma from mothers of ASD children and from ASD individuals themselves, and some have been shown to react against neural components, including myelin basic protein and GAD65 in cerebellar Purkinje cells [70][71][72]. Although the majority of these autoantibodies are also detected at some frequency in non-ASD, typical controls, particular maternal autoantibodies that react against fetal brain proteins at approximately 37 kDa and 73 kDa display high specificity to autism cases, with striking reproducibility across large experimental cohorts [70]. Importantly, autoantibodies with the same reactivity have also been identified in plasma collected during the gestational period from ASD mothers, in contrast to typical studies that isolate the autoantibodies from samples collected up to 18 years post-partum [73].…”