title: Monoclonal antibody against citrullinated peptides obtained from rheumatoid arthritis patients reacts with numerous citrullinated microbial and food proteins.
abstract: OBJECTIVE
  To investigate the reactivity of monoclonal anti-citrullinated protein antibody (ACPA) obtained from peripheral blood B cells of rheumatoid arthritis (RA) patients with human autoantigens as well as environmental proteins by determining the essential epitope for the ACPA.
  
  
  METHODS
  A human monoclonal ACPA (cyclic citrullinated peptide antibody 1 [CCP-Ab1]) was obtained by screening peripheral blood lymphocytes from 31 patients with RA using a novel monoclonal antibody-secreting cell (ASC) screening system, the immunospot-array assay on a chip. The essential epitope for CCP-Ab1 was determined using epitope mapping. Then, human, microbial, and plant proteins that share the essential epitope identified were searched using BLAST. Finally, representative proteins identified by the search were produced in vitro, and their reactivity with CCP-Ab1 was examined.
  
  
  RESULTS
  CCP-Ab1 bound CCP in a citrulline-indispensable manner. In CCP, the 6 amino acid residues required for CCP-Ab1 binding were identified. In the BLAST search, 38 human, 56 viral, 1,383 fungal, 547 bacterial, and 1,072 plant proteins were found to share the essential epitope, and CCP-Ab1 reacted with all of the recombinant citrullinated proteins tested, which included the various environmental factors, such as various plant proteins that are part of the daily diet.
  
  
  CONCLUSIONS
  Our findings demonstrate, for the first time, that a monoclonal ACPA (CCP-Ab1) derived from RA patients cross-reacts not only with various autoantigens but also with numerous plant and microbial proteins. We propose that countless environmental factors, including microbes and diet, may trigger the generation of ACPAs that then cross-react with various citrullinated human autoantigens through molecular mimicry to induce RA.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Tsuda
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamana
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Taki
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugiyama
authors.affiliation: Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Johji
authors.initials: J
authors.lastname: Imura
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishi
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts), Hiroshi Hamana, PhD, Hirofumi Taki, MD, PhD, Kazuyuki Tobe, MD, PhD, Eiji Sugiyama, MD, PhD (current address: Hiroshima University Hospital, Hiroshima, Japan), Johji Imura, MD, PhD, Hiroyuki Kishi, PhD, Atsushi Muraguchi, MD, PhD: University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Sugitani Campus, Toyama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muraguchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology*; D003429:Cross Reactions; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D005260:Female; D005656:Fungal Proteins / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D010940:Plant Proteins / Q000276:immunology; D014674:Plant Proteins, Dietary / Q000276:immunology*; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D001426:Bacterial Proteins; D000939:Epitopes; D005656:Fungal Proteins; D010456:Peptides, Cyclic; D010940:Plant Proteins; D014674:Plant Proteins, Dietary; D014764:Viral Proteins; C487763:cyclic citrullinated peptide