POS1036 NF-ΚB SIGNALLING IS CRITICALLY IMPORTANT FOR FUNCTIONAL RESPONSES OF ACPA-PRODUCING B CELL CLONES FROM PATIENTS WITH RHEUMATOID ARTHRITIS

Background Anti-citrullinated protein antibodies (ACPA) play a role in rheumatoid arthritis (RA) pathogenesis, and their presence is associated with disease severity. Moreover, high serum levels of ACPA the preclinical phase are one major risk factors for RA progression. Consequently, detailed analysis pos B cells required to disentangle these RA. Multiple intracellular signalling pathways involved functional cell responses. NF-κB prime regulators proliferation, differentiation (auto)antibody production. activation leads pro-inflammatory cytokine chemokine JAK-STAT induced after receptor (BCR) also proliferation maturation. Targeting or may advance our understanding mechanisms ACPA-producing cells. We make use clones, since peripheral present at low frequencies blood. Objectives To identify whether inhibition using small molecule inhibitors (SMIs) effective targeting responses clones from patients, including survival, differentiation, antibody Methods Previously generated neg [1] (see Figure 1A method) were expanded cultured anti-CD40 IL-21. Canonical non-canonical targeted by validated SMIs Inhibitor κB kinase β (IKKβi, canonical signalling) inducing (NIKi, signalling), respectively. Tofacitinib (a JAK1/JAK3 specific inhibitor) was used target signalling. Cell viability, evaluated flow cytometry. Antibody production measured ELISA. Results observed dose-dependent reduction treated either IKKβi (12.5 µM IKKβi: 39.12±9.86% decrease, 25 56.55±1.84% 50 65.65±3.1% decrease; data normalised on DMSO) NIKi NIKi: 12.13±19.42% 26.63±17.37% 41.69±2.00% upon T cell-dependent stimulation 2.25 µg/ml 1.0 ng/ml IL-21 (Figure 1B). Similarly, we IgG 1C). treatment seemed have stronger effect than while did not observe clear difference between 6.90±5.38% 33.32±2.15% 50.11±3.15% 12.5 6.09±3.61% 17.83±6.53% 54.67±20.37% DMSO). These effects caused cytotoxic as viability affected treatment. In contrast treatment, tofactinib only had limited At results being corroborated freshly isolated lineage patients. Conclusion Our point towards critical cells, whereas observed. beneficial limiting (autoreactive) Reference Germar K, et al. Generation Characterization Anti-Citrullinated Protein Antibody-Producing Clones From Rheumatoid Arthritis Patients. Rheumatol. 2019 Mar;71(3):340-350. Acknowledgements: NIL. Disclosure Interests None Declared.