Increased PKC signaling in lupus La reactive B cells promotes development of the transitional T3 population and memory B cells in autoimmune BXD2 mice (BA3P.108)

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Abstract We recently identified that lupus prone BXD2 mice exhibited defective clearance of apoptotic debris. In vivo administration of excessive autologous apoptotic cells lead to elevation of IgG anti-La13-27 responses in BXD2 mice but not normal B6 mice, suggesting chronic self-antigen stimulation plus B-cell tolerance defects may be related to the IgG anti-La13-27 responses. To interrogate if there was abnormal maturation of anti-La13-27 B cells in naïve BXD2 mice, a recently developed La13-27 tetramer was used with CD80 and PD-L2 co-staining to reveal that there was a significantly higher frequency of memory CD80+PD-L2+ La13-27+ B cells in BXD2 (17%), compared to that in B6 (3%) mouse spleens. Tetramer analysis of CD93+ transitional B cells showed that there was an abnormal skewing of the La13-27+ T3 population, but not T1 or T2 B cells, in BXD2 (40%) compared to that in B6 (18%) mouse spleens. Survival of anti-La13-27 producing B cells in BXD2 but not B6 mice was associated with increased protein kinase C (PKC) activation, as stimulation of B cells with PMA+ionomycin which promotes survival of BCR stimulated transitional B cells resulted in an increase in IgG. As T3 B cells are considered anergic B cells maintaining self-tolerance through rapid turnover in vivo, the abnormal expansion of these B cells coupled with increased BCR signaling response in BXD2 mice may present a risk for B-cell tolerance loss to La13-27, leading to maturation into IgG secreting cells.