title: Nodding syndrome may be an autoimmune reaction to the parasitic wormOnchocerca volvulus.
abstract: Nodding syndrome is an epileptic disorder of unknown etiology that occurs in children in East Africa. There is an epidemiological association withOnchocerca volvulus, the parasitic worm that causes onchocerciasis (river blindness), but there is limited evidence that the parasite itself is neuroinvasive. We hypothesized that nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, we detected autoantibodies to leiomodin-1 more abundantly in patients with nodding syndrome compared to unaffected controls from the same village. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with nodding syndrome. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive withO. volvulusantigens. This study provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry withO. volvulusantigens and suggests that patients may benefit from immunomodulatory therapies.
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tory P
authors.identifier: 0000-0001-7468-3586
authors.initials: TP
authors.lastname: Johnson
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Richa
authors.identifier: 0000-0003-3627-1972
authors.initials: R
authors.lastname: Tyagi
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Paul R
authors.identifier: 0000-0003-0402-386X
authors.initials: PR
authors.lastname: Lee
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Myoung-Hwa
authors.identifier: 0000-0002-8546-8272
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Bioinformatics Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kory R
authors.identifier: 0000-0001-7678-3812
authors.initials: KR
authors.lastname: Johnson
authors.affiliation: Clinical Proteomics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jeffrey
authors.identifier: 0000-0002-2758-438X
authors.initials: J
authors.lastname: Kowalak
authors.affiliation: Microarray Core Facility, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Abdel
authors.identifier: 0000-0001-7085-0762
authors.initials: A
authors.lastname: Elkahloun
authors.affiliation: Neural Differentiation Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Medynets
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Hategan
authors.affiliation: Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Joseph
authors.identifier: 0000-0001-8167-0230
authors.initials: J
authors.lastname: Kubofcik
authors.affiliation: Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: James
authors.identifier: 0000-0002-2536-3276
authors.initials: J
authors.lastname: Sejvar
authors.affiliation: Division of Global Health Protection, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ratto
authors.affiliation: Division of Global Health Protection, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Bunga
authors.affiliation: Ministry of Health, Kampala, Uganda.
authors.forename: Issa
authors.identifier: 0000-0003-3579-2485
authors.initials: I
authors.lastname: Makumbi
authors.affiliation: Ministry of Health, Kampala, Uganda.
authors.forename: Jane R
authors.initials: JR
authors.lastname: Aceng
authors.affiliation: Helminth Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Thomas B
authors.identifier: 0000-0001-6887-4941
authors.initials: TB
authors.lastname: Nutman
authors.affiliation: Bill & Melinda Gates Foundation, Seattle, WA 98109, USA.
authors.forename: Scott F
authors.identifier: 0000-0002-3878-5056
authors.initials: SF
authors.lastname: Dowell
authors.affiliation: Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. natha@ninds.nih.gov.
authors.forename: Avindra
authors.identifier: 0000-0003-0927-5855
authors.initials: A
authors.lastname: Nath
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000134:cerebrospinal fluid; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology; D001327:Autoimmune Diseases / Q000097:blood / Q000469:parasitology*; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003429:Cross Reactions / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000276:immunology; D005260:Female; D015801:Helminth Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D064128:Nodding Syndrome / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology* / Q000469:parasitology*; D017181:Onchocerca volvulus / Q000502:physiology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D003598:Cytoskeletal Proteins; D015801:Helminth Proteins; C103926:LMOD1 protein, human