PMID- 32639997
OWN - NLM
STAT- MEDLINE
DCOM- 20200821
LR  - 20200821
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Print)
IS  - 1935-2727 (Linking)
VI  - 14
IP  - 7
DP  - 2020 Jul
TI  - Protection or susceptibility to devastating childhood epilepsy: Nodding Syndrome 
      associates with immunogenetic fingerprints in the HLA binding groove.
PG  - e0008436
LID - 10.1371/journal.pntd.0008436 [doi]
LID - e0008436
AB  - Nodding syndrome (NS) is a devastating and enigmatic childhood epilepsy. NS is 
      accompanied 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-reactive 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. Furthermore, 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 normal 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-Oligonucleotide-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 
      hydrophobic 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 families, tribes and 
      districts, develop NS, while others do not.
FAU - Benedek, Gil
AU  - Benedek G
AUID- ORCID: 0000-0003-3761-9467
AD  - Tissue Typing and Immunogenetics Laboratory, Department of Genetics, Hadassah 
      Hebrew University Hospital, Jerusalem, Israel.
FAU - Abed El Latif, Mahmoud
AU  - Abed El Latif M
AD  - Tissue Typing and Immunogenetics Laboratory, Department of Genetics, Hadassah 
      Hebrew University Hospital, Jerusalem, Israel.
FAU - Miller, Keren
AU  - Miller K
AD  - Tissue Typing and Immunogenetics Laboratory, Department of Genetics, Hadassah 
      Hebrew University Hospital, Jerusalem, Israel.
FAU - Rivkin, Mila
AU  - Rivkin M
AD  - Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, 
      Jerusalem, Israel.
FAU - Ramadhan Lasu, Ally Ahmed
AU  - Ramadhan Lasu AA
AD  - Public Health Consultant, Juba, Republic of South Sudan.
FAU - Riek, Lul P
AU  - Riek LP
AD  - External Coordination & Research, Ministry of Health, Juba, Republic of South 
      Sudan.
FAU - Lako, Richard
AU  - Lako R
AD  - Ministry of Health South Sudan, Juba, Republic of South Sudan.
FAU - Edvardson, Shimon
AU  - Edvardson S
AD  - Department of Pediatrics, Neurology Unit, Hadassah Hebrew University Hospital, 
      Jerusalem, Israel.
FAU - Alon, Sagit-Arbel
AU  - Alon SA
AD  - Department of Obstetrics and Gynecology, Hadassah Hebrew University Hospital, 
      Jerusalem, Israel.
FAU - Galun, Eithan
AU  - Galun E
AD  - Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, 
      Jerusalem, Israel.
FAU - Levite, Mia
AU  - Levite M
AD  - Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, 
      Jerusalem, Israel.
AD  - Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200708
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
RN  - 0 (Autoantibodies)
RN  - 0 (HLA Antigens)
RN  - 0 (Receptors, AMPA)
RN  - 0 (glutamate receptor ionotropic, AMPA 3)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Amino Acid Motifs
MH  - Autoantibodies/immunology
MH  - Case-Control Studies
MH  - Child
MH  - Child, Preschool
MH  - Disease Susceptibility
MH  - Female
MH  - HLA Antigens/*chemistry/genetics/*immunology
MH  - Humans
MH  - Male
MH  - Nodding Syndrome/genetics/*immunology/prevention & control
MH  - Receptors, AMPA/genetics/immunology
MH  - South Sudan
MH  - Young Adult
PMC - PMC7371228
COIS- The authors have declared that no competing interests exist.
EDAT- 2020/07/09 06:00
MHDA- 2020/08/22 06:00
PMCR- 2020/07/08
CRDT- 2020/07/09 06:00
PHST- 2020/01/27 00:00 [received]
PHST- 2020/05/30 00:00 [accepted]
PHST- 2020/07/20 00:00 [revised]
PHST- 2020/07/09 06:00 [pubmed]
PHST- 2020/08/22 06:00 [medline]
PHST- 2020/07/09 06:00 [entrez]
PHST- 2020/07/08 00:00 [pmc-release]
AID - PNTD-D-20-00136 [pii]
AID - 10.1371/journal.pntd.0008436 [doi]
PST - epublish
SO  - PLoS Negl Trop Dis. 2020 Jul 8;14(7):e0008436. doi: 10.1371/journal.pntd.0008436. 
      eCollection 2020 Jul.