Abstract Text: In systemic lupus erythematosus (SLE), IgG antibodies directed against nuclear antigens (ANA) are pathogenic. Healthy individuals (HC) harbor a similar frequency of autoreactive mature B cells, without producing pathogenic IgG antibodies. While overall B cell hyperresponsiveness has been described in SLE, differences in behavior between ANA+ and ANA- cells in SLE patients and HC have not been explored. The aim of this study was to measure the intensity of the response to BCR activation in IgG+ memory B cells in SLE patients and HC. B cells from seven SLE patients and five HC were isolated by negative magnetic selection and activated with F(ab)'2 fragments of anti-IgG antibodies. Calcium flux was measured using indo-1 AM. The response was quantified by area under the curve (AUC) using the bound/unbound ratio of the marker for the duration of 5 minutes after activation. Values were compared using Wilcoxon rank sum test. In SLE patients, ANA+ IgG memory cells have a stronger calcium signaling response than ANA- cells (AUC for ANA+ vs ANA-: 89.46±18.51 vs 76.17±12.65; p=0.05). This difference is not present in HC (AUC for ANA+ vs ANA-: 88.02±16.51 vs 89.52±14.49; p=ns). These results show that ANA+ IgG memory B cells are hyperreactive in patients with SLE. The data also suggests a mechanism for the breach in tolerance that is observed in SLE. Further studies are warranted to explore the mechanism and how this affects plasma cells differentiation and autoantibody generation in SLE.
