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Rheumatoid arthritis (RA) is a systemic autoimmune disease involving inflammation of the joints. Among the autoantibodies described in RA, anticitrullinated protein antibodies (ACPAs) are highly specific and predictive for RA. In addition, ACPAs have been implicated in the pathogenesis of RA. However, a direct functional response of immune cells from [ACPA.sup.+] RA patients toward citrullinated proteins has not been demonstrated. In this study, we show that exposure to citrullinated antigens leads to activation of basophils from [ACPA.sup.+] RA patients within 20 minutes. This was not observed after exposure of basophils to noncitrullinated control antigens or after stimulation of basophils from [ACPA.sup.-] RA patients and healthy controls. Basophil activation was correlated with the binding of citrullinated proteins to basophils. Furthermore, serum from [ACPA.sup.+] RA patients in contrast to that from [ACPA.sup.-] RA patients could specifically sensitize human Fc[epsilon]RI expressing rat basophil cells (RBL), enabling activation by citrullinated proteins. Mast cell degranulation products such as histamine levels were enhanced in synovial fluid of [ACPA.sup.+] RA patients as compared with [ACPA.sup.-] RA and osteoarthritis patients. In addition, histamine levels in synovial fluid from [ACPA.sup.+] RA patients correlated with IgE levels, suggesting degranulation of mast cells by cross-linking IgE. Immunohistochemistry on synovial biopsies demonstrated an increased number of degranulated [CD117.sup.+] mast cells in [ACPA.sup.+] RA patients; IgE and Fc[epsilon]RI expression in synovial mast cells from [ACPA.sup.+] RA patients was increased. In conclusion, our results show an immunological response of immune cells from [ACPA.sup.+] RA patients in a citrulline-specific manner. Moreover, these data indicate a role for IgE-ACPAs and Fc[epsilon]RI-positive cells in the pathogenesis of RA. basophil | histamine | mast cell | citrullination | synovium www.pnas.org/cgi/doi/10.1073/pnas.0913054107