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Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic inflammation of the joints. Anti-citrullinated protein antibodies (ACPA) are highly specific for RA and are associated with a more severe disease progression. ACPA have also been shown to have a pathological role in RA. In animal models of RA, ACPA enhances arthritis. Furthermore, in vitro generated immune complexes with ACPA can activate macrophages and the complement system in the human system. Recently, a direct functional and specific response of Fc epsilon RI+ immune cells towards citrullinated proteins was demonstrated. Basophils of ACPA+ RA patients are activated by citrullinated proteins that cross link the Fc epsilon RI receptor via IgE-ACPA, physiologically bound to the receptor. In addition, synovial mast cells from ACPA+ RA patients show a more activated phenotype than mast cells from ACPA-patients. These findings underline the suggestion that ACPA+ and ACPA-RA are two different disease entities and point to a possible functional role of ACPA and Fc epsilon RI+ cells in the pathogenesis of RA.