In:
Arthritis & Rheumatology, Wiley, Vol. 72, No. 12 ( 2020-12), p. 2040-2049
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
2326-5191
,
2326-5205
Language:
English
Publisher:
Wiley
Publication Date:
2020
detail.hit.zdb_id:
2754614-7
