The presence of the antiperinuclear factor, an autoantibody that recognizes cytoplasmic antigens, was detected in sera from patients with rheumatoid arthritis (59%), seronegative rheumatoid arthritis (36%), systemic lupus erythematosus (46%), systemic sclerosis (a%), and in nonautoimmune controls (10%). The antigenic perinuclear granules were found in the stratum intermedium layer of the buccal mucosa. Granules exhibited histologic features of nucleoproteins, stained for ribonucleoprotein, and showed the ultrastructural characteristics of aggregated rough endoplasmic reticulum. The antiperinuclear factor may recognize a common autoantigen in connective tissue disease.Rheumatoid arthritis (RA) patients, similar to those with related disorders, can form a variety of autoantibodies against nuclear, cytoplasmic, and tissue-specific antigens ( 1,2). Antiperinuclear factor (APF). first described in the mid-1960s by Nienhuis and Mandema (3). is an autoantibody that recognizes cytoplasmic granules in human buccal mucosal cells. geneous-appearing granules, 0.54.0 pm in diameter, located in the cytoplasm around the nucleus. Investigators have found APF in the sera of 50436% of RA patients (4-15), 31-3% of patients with Sjogren's syndrome (5,9,13), as many as 10% of healthy controls, and rarely in other rheumatic disease patients (3-7). A recent study suggested that APF determination in rheumatic disease patients by indirect immunofluorescence had a sensitivity and specificity for RA of 86% and 96%. respectively (7). The presence of APF correlates most closely with the presence of rheumatoid factor and rheumatoid nodules, but the antibody has also been detected in 37-76% of patients with seronegative RA (5-8).The APF antibody binds to cytoplasmic granules in human buccal mucosal cells, which have presumptively been termed "keratohyaline granules" (4.16) based on their rough histologic resemblance to the keratohyaline bodies in the stratum granulosum of human epidermis. The biologic and biochemical nature of the APF-reactive granules is unknown. Attempts to characterize the antigen have thus far been hampered by a lack of availability of suitable human donors (5-7) or alternate animal tissue substrates for the assay (16). However, independent studies in oral medicine (17-20) have documented the presence of at least 3 types of cytoplasmic granules in human oral keratinocytes, including "membrane-coated" granules, "epidermaltype" keratohyaline granules, and "buccal-type'' keratohyaline granules; these findings have not been related to the APF antigen.In this report, we extend our preliminary observations regarding the prevalence of APF in various rheumatic diseases (21) and the staining characteristics of the perinuclear antigen-containing granules (22). The diagnostic specificity of the APF assay (by indi-