Patterns of ANA+ B cells for SLE patient stratification.

IgG antinuclear antibodies (ANAs) are a dominant feature of several autoimmune diseases. We previously showed that systemic lupus erythematosus (SLE) is characterized by increased ANA+ IgG plasmablasts/plasma cells (PCs) through aberrant IgG PC differentiation rather than an antigen-specific tolerance defect. Here, we aimed to understand the differentiation pathways resulting in ANA+ IgG PCs in SLE patients. We demonstrate distinct profiles of ANA+ antigen-experienced B cells in SLE patients, characterized by either a high frequency of PCs or a high frequency of IgG+ memory B cells. This classification of SLE patients was unrelated to disease activity and remained stable over time in almost all patients, suggesting minimal influence of disease activity. A similar classification applies to antigen-specific B cell subsets in mice following primary immunization with T-independent and T-dependent antigens as well as in lupus-prone mouse models (MRL/lpr and NZB/W). We further show that, in both lupus-prone mice and SLE patients, the classification correlates with the serum autoantibody profile. In this study, we identified B cell phenotypes that we propose reflect an extrafollicular pathway for PC differentiation or a germinal center pathway, respectively. The classification we propose can be used to stratify patients for longitudinal studies and clinical trials.

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

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.