title: PhIP-Seq characterization of autoantibodies from patients with multiple sclerosis, type 1 diabetes and rheumatoid arthritis.
abstract: Autoimmune disease results from a loss of tolerance to self-antigens in genetically susceptible individuals. Completely understanding this process requires that targeted antigens be identified, and so a number of techniques have been developed to determine immune receptor specificities. We previously reported the construction of a phage-displayed synthetic human peptidome and a proof-of-principle analysis of antibodies from three patients with neurological autoimmunity. Here we present data from a large-scale screen of 298 independent antibody repertoires, including those from 73 healthy sera, using phage immunoprecipitation sequencing. The resulting database of peptide-antibody interactions characterizes each individual's unique autoantibody fingerprint, and includes specificities found to occur frequently in the general population as well as those associated with disease. Screening type 1 diabetes (T1D) patients revealed a prematurely polyautoreactive phenotype compared with their matched controls. A collection of cerebrospinal fluids and sera from 63 multiple sclerosis patients uncovered novel, as well as previously reported antibody-peptide interactions. Finally, a screen of synovial fluids and sera from 64 rheumatoid arthritis patients revealed novel disease-associated antibody specificities that were independent of seropositivity status. This work demonstrates the utility of performing PhIP-Seq screens on large numbers of individuals and is another step toward defining the full complement of autoimmunoreactivities in health and disease.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA. hblarman@scripps.edu
authors.forename: H Benjamin
authors.initials: HB
authors.lastname: Larman
authors.forename: Uri
authors.initials: U
authors.lastname: Laserson
authors.forename: Luis
authors.initials: L
authors.lastname: Querol
authors.forename: Katrijn
authors.initials: K
authors.lastname: Verhaeghen
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Solimini
authors.forename: George Jing
authors.initials: GJ
authors.lastname: Xu
authors.forename: Paul L
authors.initials: PL
authors.lastname: Klarenbeek
authors.forename: George M
authors.initials: GM
authors.lastname: Church
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Robert M
authors.initials: RM
authors.lastname: Plenge
authors.forename: Peter A
authors.initials: PA
authors.lastname: Nigrovic
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: Ilse
authors.initials: I
authors.lastname: Weets
authors.forename: Geert A
authors.initials: GA
authors.lastname: Martens
authors.forename: Kevin C
authors.initials: KC
authors.lastname: O'Connor
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000918:Antibody Specificity; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood* / Q000134:cerebrospinal fluid*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005260:Female; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D019151:Peptide Library; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D019151:Peptide Library