OP0200 Circulating, Auto-Reactive B Cells Specific for Citrullinated Antigens in Patients with Rheumatoid Arthritis Display An Activated, Proliferative Phenotype

Background Rheumatoid arthritis (RA) is characterized by the formation of autoantibodies against citrullinated antigens (CA). Intriguingly, depletion of CD20+ B cells leads to significant clinical improvement in the majority of patients, despite the persistence of high titer autoantibodies. This indicates that the CD20+ B cell compartment, potentially more than the autoantibodies themselves, contributes to the pathogenesis and/or chronicity of RA. Auto-reactive B cells within this compartment could be the main drivers of this effect, but evidence for this hypothesis is lacking. We recently developed the technology to visualize and characterize CA-specific B cells in patients and demonstrated that a large proportion has a CD20+ memory phenotype 1 . Objectives To study the phenotype of CA-specific B cells in comparison to tetanus-toxoid (TT)-specific B cells in peripheral blood of individual patients. Methods Differentially labeled CA and their arginine control variants were used as tetramers to identify CA-specific B cells in peripheral blood of patients with RA. TT-specific B cells were identified in the same samples using differentially labeled TT. Both antigen-specific cell populations were enumerated and phenotypically characterized by flow cytometry. Results CA-specific B cells and TT-specific B cells were detected in peripheral blood in comparable frequency (median 0.012% vs. 0.014%). Both CA- and TT-specific B cells displayed mainly markers of class-switched memory B cells. Intriguingly, CA-specific memory B cells showed remarkable overexpression of co-stimulatory molecules and markers of active proliferation. Conclusions This is the first phenotypic analysis of auto-reactive, CA-specific memory B cells in comparison to recall antigen-specific memory B cells in individual patients with RA. CA-specific memory B cells overexpress co-stimulatory molecules and proliferation markers, indicative of an active immune response against CA in these patients. These data support the hypothesis that CA-specific memory B cells contribute to RA pathogenesis and fuel efforts for their antigen-specific depletion. References Kerkman PF et al. Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis. Ann Rheum Dis. 2015 Jun 1. doi: 10.1136/annrheumdis-2014-207182. Acknowledgement Supported by grants from the Dutch Arthritis Foundation, The Netherlands Organization for Scientific Research and the Innovative Medicines Initiative funded project BeTheCure. Disclosure of Interest H. Kristyanto: None declared, P. Kerkman: None declared, E. van der Voort: None declared, H. Spits Employee of: AIMM Therapeutics, D. Baeten: None declared, T. Huizinga: None declared, R. Toes: None declared, H. Scherer: None declared