Rheumatoid arthritis (RA) is a severe autoimmune disorder of unknown etiology. Major autoantigens include immunoglobulin G (which is targeted by rheumatoid factor), citrullinated proteins, and the heterogeneous nuclear ribonucleoprotein (hnRNP) A2. To obtain more insight into the pathogenic role of arthritogenic autoantigens, we studied autoimmune responses in two animal models of RA, which are independent of immunization with exogenous antigens, namely human tumor necrosis factor-alpha (TNF-alpha)-transgenic (hTNFtg) mice and rats with pristane-induced arthritis (PIA). Serologic and cellular studies revealed autoantibodies to hnRNP-A2 in these animals and pronounced T-cell reactivity to hnRNP-A2 and the presence of rheumatoid factor in PIA, while citrullinated antigens were not targeted. Furthermore, hnRNP-A2 was found to be highly overexpressed in the joints of mice and rats affected by arthritis. Thus, unspecific proinflammatory stimuli, such as TNF-alpha or pristane, may induce pathogenic autoimmune reactions that may drive an inflammatory process, leading to the development of erosive arthritis.