Abstract
BACKGROUND: IgG antinuclear antibodies (ANAs) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in patients with autoimmune disease are not fully understood. OBJECTIVES: We sought to study whether autoreactive plasma cells in lupus models and patients with systemic lupus erythematosus (SLE) arise as a consequence of defective antigen-specific selection or a global enhancement of IgG plasma cell differentiation. METHODS: We optimized and validated a novel technique to detect naturally occurring ANA(+) B cells and plasma cells. RESULTS: We observed a major checkpoint for generation of ANA(+) IgG(+) plasma cells in both nonautoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA(+) IgG(+) plasma cells despite normal tolerance checkpoints in immature and naive B cells of lupus-prone MRL/lpr and NZB/W mice, as well as patients with SLE. This increase was due to increased numbers of total IgG(+) plasma cells rather than lack of selection against ANA(+) plasma cells. CONCLUSION: Using a method that permits quick and accurate quantification of autoreactive B cells and plasma cells in vivo within a native B-cell repertoire in mice and human subjects, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANAs. Our observations suggest a fundamentally revised understanding of SLE: that it is a disease of aberrant B-cell differentiation rather than a defect in antigen-specific B-cell tolerance.