Autism and maternal antibodies that attack the fetal brain

Autism spectrum disorders and maternal autoantibodies  have been linked in early research. A study just published in Translational Psychiatry now pins down some of the specific antibodies made by the mother's immune system that attack the fetal brain, leading to autism. The authors state:

"Findings of dysregulated immune function, neuroinflammation, as well as the presence of maternal autoantibodies directed against rodent, human and non-human primate fetal brain tissue, strongly support an etiological role for the immune system in some forms of ASD...We previously described ASD-specific maternal autoantibodies that recognize fetal brain antigens."

Moreover...

"An etiological role for maternal antibodies in ASD is plausible because of the gestational transfer of maternal IgG during pregnancy where maternal IgG is detected in fetal circulation as early as 13 weeks of gestation in humans. By 30 weeks of gestation, levels in the fetal compartment reach approximately 50% of circulating levels in the mother, with levels at birth exceeding maternal IgG levels...The developing blood–brain barrier is actively changing during fetal neurodevelopment and is permissive to IgG molecules during this period...Recognizing that identification of the target antigens for MAR autism is the next critical step toward advancing this area of research, we employed a proteomic approach to attain this goal."

To do so they enrolled consenting mothers through the Center for Children’s Environmental Health as part of the continuing CHARGE (CHildhood Autism Risks from Genetics and Environment) Study at the University of California at Davis which included included 246 children diagnosed with autism or ASD and 149 children from the general population. Using multiple procedures to identify and verify antibodies and antigen-binding specificity and link them with behavioral correlates, they found clear evidence of specific IgG antibodies reacting to proteins that are highly expressed in the developing human brain:

"Herein, we demonstrate that lactate dehydrogenase A and B (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein to comprise the seven primary antigens of maternal autoantibody-related (MAR) autism. Exclusive reactivity to specific antigen combinations was noted in 23% of mothers of ASD children and only 1% of controls. ASD children from mothers with specific reactivity to LDH, STIP1 and CRMP1 and/or cypin (7% vs 0% in controls) had elevated stereotypical behaviors compared with ASD children from mothers lacking these antibodies."

The authors elaborate on their evidence:

"Several studies have implicated maternal immune dysregulation during pregnancy in association with ASD. Prominent among them are reports of maternal antibodies that react against fetal brain proteins. The hypothesis is that gestational exposure to maternal antibodies directed against proteins abundantly expressed in the fetal brain could lead to alterations in the neurodevelopment characteristic of ASD is further supported by the identification of specific IgG reactivity to LDH, YBX1, cypin, STIP1, CRMP1 and CRMP2, six proteins highly expressed in developing brain. Thus, MAR autoantibodies could represent one mechanism underlying the development of one or more of the ASD core features in a subgroup of cases. Moreover, with their exceptionally high specificity, several of the MAR autoantibody profiles could serve as the first true biomarkers of ASD risk...Consistent with our early studies on fetal brain homogenates, each of the identified antigens is expressed at significant levels in the human fetal brain and has an established role in neurodevelopment."

The authors conclude:

"Addressing the basis for the association between maternal autoantibodies and autism risk in the child is also of urgent concern...We describe the first panel of clinically significant biomarkers with over 99% specificity for autism risk thereby advancing our understanding of the etiologic mechanisms and therapeutic possibilities for MAR autism...The clinical significance of these findings may be twofold: (1) early diagnosis of a MAR-ASD child would allow for early behavioral intervention and (2) if pathologically significant, medical interventions that would limit fetal exposure to these antibodies might prove helpful in reducing risk of ASD symptom development in the children of affected mothers."

Clinical note: While further research needs to be done to grade the predictive capability of these antibodies, these findings offer a compelling reason for the clinician to be thorough in evaluating the integrity of immune regulation, presence of established predictive antibodies and quality of immune tolerance in female patients anticipating pregnancy.