Background/Purpose
Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and also believed to play a pathogenic role in RA. Porphyromonas gingivalis (P. gingivalis), a Gram negative oral pathogen associated with periodontitis, has long been speculated as a trigger for the anti-citrulline autoimmune responses in RA patients. However, the detail relation between ACPA and P. gingivalis is still unclear.
Methods
In this study, we made 195 recombinant monoclonal antibodies from anti-cyclic citrullinated peptide (CCP)-positive RA patients (N=6), 23 recombinant monoclonal antibodies from CCP-negative RA patients (N=1), and 110 recombinant monoclonal antibodies from healthy controls (N=4) using a single cell-based antibody cloning approach. All the 7 RA patients satisfied the 2010 ACR classification criteria. Monoclonal ACPAs were determined by commercial anti-CCP test and fine specificity with 3 synthesized citrullinated peptides. Cross-reactivity of ACPA to P. gingivalis was tested by ELISA against P. gingivalis outer membrane protein and citrullinated peptide from P. gingivalis enolase. Immunoglobulin genes of 5 ACPAs were reverted to the germ line sequences and the corresponding antibodies were also expressed for the above tests.
Results
The relative frequencies of circulating plasmablasts were significantly higher in RA patients than in healthy donors ( p = 0.0015). About 19.5% of circulating plasmablast-derived recombinant antibodies from CCP-positive RA patients, but none from the CCP-negative RA patient or healthy donors, specifically recognized citrullinated RA autoantigens ( p = 0.0001). The immunoglobulin genes encoding these ACPAs were highly mutated with increased replacement/silent mutation ratios, suggesting that the generation of ACPAs involved active antigen selection. Interestingly, 63% of these ACPAs cross-reacted with the outer membrane antigens and/or citrullinated enolase from P. gingivalis. Germ-line reversions of some ACPAs completely eliminated their reactivity to citrullinated RA autoantigens but retained their reactivity to P. gingivalis antigens.
Conclusion
These results suggest that circulating plasmablasts in RA patients produce ACPAs and this process may be, in part, initiated by the anti-P. gingivalis immune responses.
Disclosure:
S. Li,
None;
Y. Yu,
None;
Y. Yue,
None;
H. Liao,
None;
W. Xie,
None;
J. Thai,
None;
T. R. Mikuls,
None;
G. M. Thiele,
None;
M. J. Duryee,
None;
J. Payne,
None;
L. W. Klassen,
None;
J. R. O’Dell,
None;
Z. Zhang,
None;
K. Su,
None.
ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibodies-from-single-circulating-plasmablasts-react-with-citrullinated-antigens-and-porphyromonas-gingivalis-in-rheumatoid-arthritis/