BACKGROUND: IgG anti-nuclear antibodies (ANA) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in autoimmune disease are not fully understood.
OBJECTIVES: To study whether autoreactive plasma cells in lupus models and SLE patients arise as a consequence of defective antigen-specific selection or a global enhancement of IgG PC differentiation.
METHODS AND RESULTS: We optimized and validated a novel technique to detect naturally occurring ANA+ B cells and PC. We observed a major checkpoint for generation of ANA+ IgG+ PC in both non-autoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA+ IgG+ PC despite normal tolerance checkpoints in immature and naïve B cells in lupus-prone MRL/lpr and NZB/W mice as well as patients with systemic lupus erythematosus (SLE). This increase was due to increased numbers of total IgG+ PC rather than lack of selection against ANA+ PC.
CONCLUSION: Using a method that permits quick and accurate quantification of autoreactive B cells and PC in vivo within a native B cell repertoire in mice and humans, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANA. 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.
CLINICAL IMPLICATION: Therapies for SLE might need to be targeted at IgG plasma cell differentiation rather than antigen-specific tolerance.