Loss of an IgG plasma cell checkpoint in patients with lupus.

Abstract

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. 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. We optimized and validated a novel technique to detect naturally occurring ANA⁺ B cells and plasma cells. 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. 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.