AbstractRo52/TRIM21 plays a key role in antibody-dependent pathogen neutralization and is a major autoantigen in systemic lupus erythematosus, Sjögren’s syndrome (SS), and other autoimmune diseases. Here we evaluated immunoreactivity against Ro52-related molecules in SS and healthy volunteers. Although most proteins examined were not antigenic, several TRIM paralogs, including TRIM22, and TRIM38, showed sporadic immunoreactivity in SS. In contrast, the murine Ro52 ortholog with limited linear homology demonstrated high levels of autoantibodies implicating the importance of shared conformational epitopes. To further explore the autoantigencity of Ro52, deletion and point mutant analyses were employed revealing previously hidden, robust autoantibodies directed against its C-terminal immunoglobulin-binding domain. Another autoantibody, rheumatoid factor, targeting the Fc region of IgG, strongly overlapped with Ro52 seropositivity (odds ratio 14; P < 0.0001). These convergent mechanistic findings support a model whereby intracellular Ro52-bound antibody-coated pathogen complexes, released or misprocessed from infected cells, drive autoantigenicity against Ro52 and the Fc region of IgG.