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 a similar number of healthy subjects from the same geographical region, revealed autoimmune
antibodies to 3 extracellular
peptides of
ionotropic glutamate receptors in NS patients: AMPA-GluR3B
peptide antibodies (86%), NMDA-NR1
peptide antibodies (77%) and NMDA-NR2
peptide antibodies (87%) (in either 1:10, 1:100 or 1:1000 serum dilution). In contrast, NS patients did not have 26 other well-known
autoantibodies that target the nervous system in several autoimmune-mediated neurological diseases. We demonstrated high expression of both AMPA-GluR3 and NMDA-NR1 in human neural cells, and also in normal human CD3+ T cells of both helper CD4+ and cytotoxic CD8+ types. Patient's GluR3B
peptide antibodies were affinity-purified, and by themselves precipitated short 70 kDa neuronal GluR3. NS patient's affinity-purified GluR3B
peptide antibodies also bound to, induced
Reactive Oxygen Species (ROS) in, and killed both human neural cells and T cells within 1-2 hours only. NS patient's purified IgGs, or serum (1:10 or 1:30), induced similar effects. In vivo video EEG experiments in normal mice, revealed that when NS patient's purified IgGs were released continuously (24/7 for 1 week) in normal mouse brain, they induced all the following: 1.
Seizures, 2. Cerebellar Purkinje cell loss, 3. Degeneration in the hippocampus and cerebral cortex, and 4. Elevation of CD3+ T cells, and of activated Mac-2+microglia and GFAP+astrocytes in both the gray and white matter of the cerebral cortex, hippocampus, corpus calossum and cerebellum of mice. NS patient's serum
cytokines: IL-1β,
IL-2,
IL-6,
IL-8, TNFα, IFNγ, are reduced by 85-99% compared to healthy subjects, suggesting severe immunodeficiency in NS patients. This suspected immunodeficiency could be caused by combined effects of the: 1. Chronic Ov
infection, 2.
Malnutrition, 3. Killing of NS patient's T cells by patient's own GluR3B
peptide autoimmune
antibodies (alike the killing of normal human T cells by the NS patient's GluR3B
peptide antibodies found herein in vitro). CONCLUSIONS: Regardless of NS etiology, NS patients suffer from 'Dual-targeted Autoimmune Sword': autoimmune
AMPA GluR3B
peptide antibodies that bind, induce ROS in, and kill both neural cells and T cells. These neurotoxic and immunotoxic GluR3B
peptide autoimmune
antibodies, and also NS patient's
NMDA-NR1/NR2A and Ov/Leiomodin-1 autoimmune
antibodies, must be silenced or removed. Moreover, the findings of this study are relevant not only to NS, but also to many more patients with other types of
epilepsy, which have GluR3B
peptide antibodies in serum and/or CSF. This claim is based on the following facts: 1. The GluR3 subunit is expressed in neural cells in crucial brains regions, in motor neurons in the spinal cord, and also in other cells in the body, among them T cells of the immune system, 2. The GluR3 subunit has diverse neurophysiological role, and its deletion or abnormal function can: disrupt oscillatory networks of both sleep and breathing, impair motor coordination and exploratory activity, and increase the susceptibility to generate
seizures, 3. GluR3B
peptide antibodies were found so far in ~27% of >300
epilepsy patients worldwide, which suffer from various other types of severe, intractable and enigmatic
epilepsy, and which turned out to be 'Autoimmune
Epilepsy'. Furthermore, the findings of this study could be relevant to different neurological diseases besides
epilepsy, since other
neurotransmitter-receptors autoantibodies are present in other neurological and
psychiatric diseases, e.g. autoimmune
antibodies against other GluRs,
Dopamine receptors,
GABA receptors,
Acetylcholine receptors and others. These
neurotransmitter-receptors autoimmune
autoantibodies might also act as 'Dual-targeted Autoimmune Sword' and damage both neural cells and T cells (as the
AMPA-GluR3B
peptide antibodies induced in the present study), since T cells, alike neural cells, express most if not all these
neurotransmitter receptors, and respond functionally to the respective
neurotransmitters - a scientific and clinical topic we coined 'Nerve-Driven Immunity'.