Dual-targeted Autoimmune Sword in fatal epilepsy: Patient's glutamate receptor AMPA GluR3 autoimmune antibodies bind, induce ROS, and kill both human neural cells and T cells

Abstract Nodding Syndrome (NS) is a fatal pediatric epilepsy of unknown etiology, accompanied by multiple neurological impairments, and associated with Onchocerca volvulus (Ov), malnutrition, war-induced trauma, and other insults. NS patients have neuroinflammation, and ∼50% have cross-reactive Ov/Leiomodin-1 neurotoxic autoimmune antibodies. Results Studying 30 South Sudanese NS patients and healthy subjects, revealed autoimmune antibodies to 3 extracellular peptides of glutamate receptors in NS patients: anti-AMPA-GluR3B-peptide antibodies (86%), anti-NMDA-NR1-peptide antibodies (77%) and anti-NMDA-NR2-peptide antibodies (87%) (in 1:10, 1:100 or 1:1000 serum dilution), but not 26 other well-known autoantibodies. We demonstrated high GluR3 and NMDA-R expression in human neural cells, and normal human T cells - both CD4+and CD8+. Patient's anti-GluR3B-peptide antibodies were affinity-purified, and by themselves precipitated short 70 kDa neuronal GluR3, and bound, induced Reactive Oxygen Species in, and killed both human neural cells and T cells. NS patient's purified IgGs, or serum, induced similar effects. NS patient's purified IgGs were released continuously (1 week) in normal mouse brain, and induced: seizures, Purkinje cells loss, degeneration in hippocampus and cerebellum, and elevation of T cells and activated microglia and astrocytes. NS patient's serum cytokines: IL-1β, IL-2, IL-6, IL-8, TNFα, IFNγ, are reduced by 85–99%, suggesting severe immunodeficiency. Conclusions Regardless of NS etiology, patients suffer from ‘Dual-targeted Autoimmune Sword’: autoimmune anti-AMPA-GluR3B-peptide antibodies that kill both neural cells and T cells. These neurotoxic and immunotoxic anti-GluR3B-peptide autoimmune antibodies, and the NMDA-NR1/NR2A and Ov/Leiomodin-1 antibodies, must be silenced/removed. Other anti-neurotransmitter-receptors autoantibodies, in other neurological and psychiatric diseases, might also act as ‘Dual-targeted Autoimmune Sword’ and damage both neural cells and T cells that express multiple similar neurotransmitter-receptors.