TY - JOUR
T1 - Physiologic Target, Molecular Evolution, and Pathogenic Functions of a Monoclonal Anti–Citrullinated Protein Antibody Obtained From a Patient With Rheumatoid Arthritis
AU - Ozawa, Tatsuhiko
AU - Ouhara, Kazuhisa
AU - Tsuda, Reina
AU - Munenaga, Syuichi
AU - Kurihara, Hidemi
AU - Kohno, Hiroki
AU - Hamana, Hiroshi
AU - Kobayashi, Eiji
AU - Taki, Hirofumi
AU - Tobe, Kazuyuki
AU - Sugiyama, Eiji
AU - Muraguchi, Atsushi
AU - Kishi, Hiroyuki
N1 - Publisher Copyright:
© 2020, American College of Rheumatology
PY - 2020/12
Y1 - 2020/12
N2 - Objective: In plasma from a patient with rheumatoid arthritis (RA), we previously isolated a human monoclonal anti–citrullinated protein antibody (ACPA), CCP-Ab1, that recognizes various citrullinated antigens. In this study, we aimed to explore the physiologic target of CCP-Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA. Methods: The target protein of CCP-Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline-reverted (GL-rev) CCP-Ab1 was generated, and its reactivity was compared to that of mature CCP-Ab1. The functions of CCP-Ab1 and GL-rev CCP-Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis–prone SKG mice. Results: CCP-Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL-rev CCP-Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (P < 0.05). The elements implicated in GL-rev CCP-Ab1 binding to a citrullinated peptide, cfc1-cyc, were almost identical to those implicated in CCP-Ab1 binding. In arthritis-prone SKG mice, CCP-Ab1, but not GL-rev CCP-Ab1, induced significant exacerbation of experimental arthritis (P < 0.05). Increased production of interleukin-6, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP-Ab1 compared to those treated with GL-rev CCP-Ab1 (P < 0.05). Furthermore, the immune complex formed by CCP-Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP-Ab1 (P < 0.05 versus control treatment groups). Conclusion: These data show that germline-encoded CCP-Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA.
AB - Objective: In plasma from a patient with rheumatoid arthritis (RA), we previously isolated a human monoclonal anti–citrullinated protein antibody (ACPA), CCP-Ab1, that recognizes various citrullinated antigens. In this study, we aimed to explore the physiologic target of CCP-Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA. Methods: The target protein of CCP-Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline-reverted (GL-rev) CCP-Ab1 was generated, and its reactivity was compared to that of mature CCP-Ab1. The functions of CCP-Ab1 and GL-rev CCP-Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis–prone SKG mice. Results: CCP-Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL-rev CCP-Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (P < 0.05). The elements implicated in GL-rev CCP-Ab1 binding to a citrullinated peptide, cfc1-cyc, were almost identical to those implicated in CCP-Ab1 binding. In arthritis-prone SKG mice, CCP-Ab1, but not GL-rev CCP-Ab1, induced significant exacerbation of experimental arthritis (P < 0.05). Increased production of interleukin-6, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP-Ab1 compared to those treated with GL-rev CCP-Ab1 (P < 0.05). Furthermore, the immune complex formed by CCP-Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP-Ab1 (P < 0.05 versus control treatment groups). Conclusion: These data show that germline-encoded CCP-Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA.
UR - http://www.scopus.com/inward/record.url?scp=85093954178&partnerID=8YFLogxK
U2 - 10.1002/art.41426
DO - 10.1002/art.41426
M3 - 学術論文
C2 - 32621659
AN - SCOPUS:85093954178
SN - 2326-5191
VL - 72
SP - 2040
EP - 2049
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 12
ER -