Approximately 2/3 of RA patients develop antibodies towards a common posttranslational modification - citrullination. Such anti-citrullinated protein antibodies, ACPA, are strongly associated with the HLA-DR locus but consist of multiple fine specificities towards several different proteins. The strongest HLA association is seen for autoantibodies to citrullinated a-enolase and vimentin, while ACPA also targets additional proteins such as fibrinogen.

Whether ACPA represents a cause or a consequence remains a matter of discussion. Especially given the appearance of such autoantibodies many years prior to clinical onset, which suggests dissociation from joint disease. Also, many of the proteins that ACPA target are not joint-restricted, but of ubiquitous nature.

In order to dissect the contribution of ACPA to disease manifestations, we have established a technology to clone and express the immunoglobulin genes from patient-derived B cells.

The molecular information generated from the sequences gives clues to the mutation and maturation processes the B cell has undergone. This may prove useful to address the issue whether some ACPA may be the result of innate rather than adaptive immune responses.

The generated recombinant monoclonal antibodies represents tools to dissect pathogenic effects mediated by ACPA in vitro as well as in experimental systems.

We are utilizing this approach to study B cells from different anatomical sites, with synovial fluid being the proof-of-principle study (Amara et al J Exp Med 2013, 210:455-55).

Disclosure of Interest None Declared