title: Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice.
abstract: Autism spectrum disorder (ASD) occurs in 1 in 68 births, preferentially affecting males. It encompasses a group of neurodevelopmental abnormalities characterized by impaired social interaction and communication, stereotypic behaviors and motor dysfunction. Although recent advances implicate maternal brain-reactive antibodies in a causative role in ASD, a definitive assessment of their pathogenic potential requires cloning of such antibodies. Here, we describe the isolation and characterization of monoclonal brain-reactive antibodies from blood of women with brain-reactive serology and a child with ASD. We further demonstrate that male but not female mice exposed in utero to the C6 monoclonal antibody, binding to contactin-associated protein-like 2 (Caspr2), display abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as impairments in sociability, flexible learning and repetitive behavior. Anti-Caspr2 antibodies are frequent in women with brain-reactive serology and a child with ASD. Together these studies provide a methodology for obtaining monclonal brain-reactive antibodies from blood B cells, demonstrate that ASD can result from in utero exposure to maternal brain-reactive antibodies of single specificity and point toward the exciting possibility of prognostic and protective strategies.
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Brimberg
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mader
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: V
authors.initials: V
authors.lastname: Jeganathan
authors.affiliation: Laboratory of Functional Neuroanatomy, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Berlin
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Coleman
authors.affiliation: Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: P K
authors.initials: PK
authors.lastname: Gregersen
authors.affiliation: Laboratory of Immune & Neural Networks, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: P T
authors.initials: PT
authors.lastname: Huerta
authors.affiliation: Laboratory of Functional Neuroanatomy, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Volpe
authors.affiliation: Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Diamond
mesh_terms: D000328:Adult; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000378:metabolism; D000067877:Autism Spectrum Disorder / Q000209:etiology / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003183:Complement C6; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007858:Learning; D008431:Maternal-Fetal Exchange; D008565:Membrane Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009035:Mothers; D009419:Nerve Tissue Proteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism; D012737:Sex Factors; D012919:Social Behavior
chemical_list: D000906:Antibodies; C403049:CNTNAP2 protein, human; D003183:Complement C6; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins