Protection or susceptibility to devastating childhood epilepsy: Nodding syndrome associates with immunogenetic fingerprints in the hla binding groove

Gil Benedek*, Mahmoud Abed El Latif, Keren Miller, Mila Rivkin, Ally Ahmed Ramadhan Lasu, Lul P. Riek, Richard Lako, Shimon Edvardson, Sagit Arbel Alon, Eithan Galun, Mia Levite

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Nodding syndrome (NS) is a devastating and enigmatic childhood epilepsy. NS is accompa-nied by multiple neurological impairments and neuroinflammation, and associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. Moreover, NS seems to be an ‘Autoimmune Epilepsy’ since: 1. ~50% of NS patients have neurotoxic cross-reac-tive Ov/Leimodin-I autoimmune antibodies. 2. Our recently published findings: Most (~86%) of NS patients have glutamate-receptor AMPA-GluR3B peptide autoimmune antibodies that bind, induce Reactive Oxygen Species, and kill both neural cells and T cells. Further-more, NS patient’s IgG induce seizures, brain multiple damage alike occurring in brains of NS patients, and elevation of T cells and activated microglia and astrocytes, in brains of nor-mal mice. Human Leukocyte antigen (HLA) class I and II molecules are critical for initiating effective beneficial immunity against foreign microorganisms and contributing to proper brain function, but also predispose to detrimental autoimmunity against self-peptides. We analyzed seven HLA loci, either by next-generation-sequencing or Sequence-Specific-Oli-gonucleotide-Probe, in 48 NS patients and 51 healthy controls from South Sudan. We discovered that NS associates significantly with both protective HLA haplotype: HLA-B*42:01, C*17:01, DRB1*03:02, DQB1*04:02 and DQA1*04:01, and susceptible motif: Ala24, Glu63 and Phe67, in the HLA-B peptide-binding groove. These amino acids create a hydro-phobic and sterically closed peptide-binding HLA pocket, favoring proline residue. Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves tentatively associate with protection or susceptibility to NS. Accordingly, different HLA molecules may explain why under similar environmental factors, only some children, within the same fami-lies, tribes and districts, develop NS, while others do not.

Original languageAmerican English
Article numbere0008436
Pages (from-to)1-15
Number of pages15
JournalPLoS Neglected Tropical Diseases
Volume14
Issue number7
DOIs
StatePublished - Jul 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020 Benedek et al.

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