TY - JOUR
T1 - Monoclonal antibody against citrullinated peptides obtained from rheumatoid arthritis patients reacts with numerous citrullinated microbial and food proteins
AU - Tsuda, Reina
AU - Ozawa, Tatsuhiko
AU - Kobayashi, Eiji
AU - Hamana, Hiroshi
AU - Taki, Hirofumi
AU - Tobe, Kazuyuki
AU - Sugiyama, Eiji
AU - Iwamoto, Masahiro
AU - Imura, Johji
AU - Kishi, Hiroyuki
AU - Muraguchi, Atsushi
N1 - Publisher Copyright:
© 2015, American College of Rheumatology.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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. Conclusion 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.
AB - 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. Conclusion 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.
UR - http://www.scopus.com/inward/record.url?scp=84938149885&partnerID=8YFLogxK
U2 - 10.1002/art.39161
DO - 10.1002/art.39161
M3 - 学術論文
C2 - 25892475
AN - SCOPUS:84938149885
SN - 2326-5191
VL - 67
SP - 2020
EP - 2031
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 8
ER -