Divergent and dominant anti-inflammatory effects of patient-derived anti-citrullinated protein antibodies (ACPA) in arthritis development

About two thirds of rheumatoid arthritis (RA) patients develop anti-citrullinated protein antibodies (ACPA), which are a characteristic of the disease and sparsely observed in other clinical settings or in the healthy population. ACPA are used as a diagnostic criterion and often develop prior to diagnosis. Therefore, ACPA titers are important in the identification of individuals at risk of developing RA. Interestingly, the titers and target cross-reactivity of ACPA increase by time of diagnosis, suggesting a causality between anti-citrulline reactivity and the development of RA. However, only 50% of ACPA-positive at-risk individuals will progress to a clinical RA diagnosis. This observation suggests that there are different types of ACPA and that their relationship with RA development is more complex than presently assumed. To address the biological effect of ACPA in the establishment and development of inflammatory arthritis, we made use of the collagen antibody-induced arthritis (CAIA) model of passive arthritis. Using seven unique patient derived monoclonal ACPA, we observed that ACPA are predominantly anti-inflammatory, with some clones (C03 and BVCA1) completely inhibiting disease development. We have also identified a clone (C04) as having a disease-prone effect, by increasing and sustaining disease prevalence. This clone had previously been reported as being pro-inflammatory in a different model of joint inflammation. The anti-inflammatory effects of C03 were dependent on Fc{gamma}R, since neither F(ab)2 or a mutated Fc-null GRLR-C03 clone could mediate disease protection. Most importantly, mice receiving polyclonal ACPA enriched from RA sera were also partially protected from disease. Looking at the cell and tissue of origin of the ACPA clones, their V(D)J sequences, Fc glycosylation pattern and fine-specificities, we could not identify a common feature between anti-inflammatory ACPA distinguishing them from those without the properties. Together, our data demonstrates that circulating ACPA in RA patients are predominantly anti-inflammatory, emphasizing the need to study ACPA repertoires in order to determine their influence on the clinical outcome of the patient or at-risk individual.