Maternal Anti-Fetal Brain IgG Autoantibodies and Autism Spectrum Disorder: Current Knowledge and its Implications for Potential Therapeutics

Abstract

Several studies have found a correlation between the presence of circulating maternal autoantibodies and neuronal dysfunction in the neonate. Specifically, maternal anti-brain autoantibodies, which may access the fetal compartment during gestation, have been identified as one risk factor for developing autism spectrum disorder (ASD). Studies by our laboratory elucidated seven neurodevelopmental proteins recognized by maternal autoantibodies whose presence is associated with a diagnosis of maternal autoantibody-related (MAR) autism in the child. While the specific process of anti-brain autoantibody generation is unclear and the detailed pathogenic mechanisms are currently unknown, identification of the maternal autoantibody targets increases the therapeutic possibilities. The potential therapies discussed in this review provide a framework for possible future medical interventions.

Figure 1

Ex vivo maternal anti-brain autoantibody removal. The identification of the specific peptide epitopes targeted by maternal anti-brain autoantibodies enables the specific removal of these antibodies using plasmapheresis. First (1) the blood cells are separated from the blood plasma and returned to the maternal blood stream. Subsequently(2), the plasma is filtered using affinity chromatography. In this procedure, the anti-brain autoantibodies are selectively removed from the maternal blood stream by filtering the plasma through a peptide-bound column. Autoantibodies with reactivity to the peptide epitopes will bind to the column and are removed from circulation, while the remaining, unbound antibodies are returned to the maternal blood stream.

Figure 2

In vivo maternal anti-brain autoantibody removal. Treatments that saturate the neonatal Fc Receptor (FcRn) increase the degradation of immunoglobulin G (IgG) and will potentially increase the degradation of maternal anti-brain autoantibodies. A. Under normal conditions, the FcRn preferentially binds IgG and albumin to increase their half-life within the blood plasma. B. Intravenous immunoglobulin therapy (IVIG) increases the amount of innocuous IgG within the blood plasma, leading to the dilution of anti-brain autoantibodies while also decreasing their half-life in the blood stream via FcRn competition. C. Antibodies that enhance IgG degradation (Abdegs) are recombinant antibodies with high affinity for the FcRn, and are another potential therapeutic that could increase the clearance rates of anti-brain autoantibodies by out-competing endogenous IgG for binding to the FcRn.

Figure 3

Inhibition of placental maternal antibody transfer. A. Antibodies are transferred to the fetus during gestation to provide the neonate with a temporary immune system at birth. B. This process can be inhibited with the use of the neonatal Fc Receptor (FcRn) blockers in order to prevent the transfer of maternal anti-brain autoantibodies during critical periods of neurodevelopment. However, this would not be a specific process and would block all Immunoglobulin G (IgG).

Figure 4

Small molecule inhibition of maternal anti-brain autoantibodies. A. Anti-brain autoantibodies, which cross the placenta during gestation, can bind to fetal brain proteins and potentially inhibit important mechanisms in neurodevelopment. B. Small molecules that mimic the protein antigens can be used to compete with the endogenous antigens expressed in the fetal brain and neutralize the maternal autoantibodies to prevent antibody-mediated damage.

Figure 5

Plasma cell depletion using proteasome inhibitions. A. Autoreactive plasma cells are thought to have increased rates of antibody synthesis, because self-antigens are present in vast amounts and are not eliminated like antigens from pathogens. B. Proteasome Inhibitors, like bortezomib, which selectively deplete plasma cells due to their high protein synthesis rates, may be a potential therapeutic to remove autoreactive plasma cells secreting anti-brain autoantibodies.