Autoantibodies from single circulating plasmablasts react with citrullinated antigens and Porphyromonas gingivalis in rheumatoid arthritis.

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Autoantibodies from single circulating plasmablasts react with citrullinated antigens and Porphyromonas gingivalis in rheumatoid arthritis.

Arthritis Rheumatol. 2015 Oct 16;

Authors: Li S, Yu Y, Yue Y, Liao H, Xie W, Thai J, Mikuls TR, Thiele GM, Duryee MJ, Sayles H, Payne JB, Klassen LW, O'Dell JR, Zhang Z, Su K

Abstract
OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA). However, the molecular basis for ACPA production is still unclear. The purpose of this study was to determine if circulating plasmablasts from RA patients produce ACPAs and if Porphyromonas gingivalis (P. gingivalis) facilitates the generation of ACPAs.
METHODS: Using a single cell antibody cloning approach, we generated 217 and 110 monoclonal recombinant antibodies from circulating plasmablasts of 7 RA patients and 4 healthy controls, respectively. Antibody reactivity to citrullinated antigens was tested by the 2(nd) generation of anti-cyclic citrullinated peptide (CCP) kit and ELISAs against citrullinated human antigens. Antibody reactivity to P. gingivalis was tested by ELISAs against outer membrane antigens (OMAs) and citrullinated enolase from P. gingivalis.
RESULTS: 19.5% of plasmablast-derived antibodies from CCP-positive RA patients, but none from the CCP-negative RA patient or healthy controls, specifically recognized citrullinated antigens. The immunoglobulin genes encoding these ACPAs were highly mutated with increased replacement/silent mutation ratios, suggesting the involvement of active antigen selection in ACPA generation. Interestingly, 63% of the ACPAs cross-reacted with OMAs and/or citrullinated enolase from P. gingivalis. The reactivity of ACPAs against citrullinated proteins from P. gingivalis was confirmed by immuno blot and mass spectrometry. Furthermore, germ-line reversions of some ACPAs completely eliminated their reactivity to citrullinated human antigens but retained their reactivity to P. gingivalis.
CONCLUSION: These results suggest that circulating plasmablasts in RA patients produce ACPAs and this process may be facilitated by the anti-P. gingivalis immune responses. This article is protected by copyright. All rights reserved.

PMID: 26474325 [PubMed - as supplied by publisher]