Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the overproduction of autoantibodies. Recent studies showed that CD11c+ extrafollicular (EF) B-cells plays a central role for the development of lupus. We investigated the role of mitochondria in CD11c+ EF B cells and autoimmune plasmablasts in lupus.
Methods We investigated EF B cells, CD11c+ plasmablasts in B6 mice stimulated with CpG-Oligodeoxyribonucleotides (ODN) every other day for 10 days. Immune cell subtypes were analyzed by flow cytometry. Mitochondria membrane potential and mass were measured by JC-1, MTDR, and MTG. Generation of autoimmune plasmablasts were evaluated by measuring serum anti-dsDNA antibody by ELISA and anti-dsDNA antibody secreting cells by ELISPOT. Furthermore, mouse spleen B cells and human peripheral blood B cells from lupus patients were stimulated with CpG-ODN for 3 days and generation of EF B cells and mitochondria were evaluated by FACS. Mitochondria were inhibited by IM156 (complex I inhibitor), and CB-839 (GLS1 inhibitor) with in vivo or in vitro CpG-ODN stimulation.
Results In vivo injection of CpG-ODN induced anti-DNA antibody in mice. Mitochondria membrane potential and mass of EF B cells and plasmablasts were increased by CpG-ODN. Autoimmune plasmablasts measured by anti-dsDNA antibody ELISPOT were increased in bone marrow from CpG-ODN injected mice. CpG-ODN induced EF B cells and plasmablasts in in vitro culture condition with mouse splenic B cells and lupus B cells. Furthermore, CpG-ODN also increased mitochondria membrane potential and mass in in vitro culture condition. IM156 or CB-839 inhibited EF B cells and autoimmune plasmablasts in vivo and in vitro.
Conclusions This study demonstrated that the central role of mitochondria in generation of autoimmune plasmablasts in lupus. CpG-ODN induced autoimmune plasmablasts while IM156, or CB-839 inhibited autoimmune plasmablasts by suppression of mitochondria.
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