Targeting of B cell class-switching and plasma cell survival pathways by a Rab7 inhibitor suppresses autoantibody responses in murine lupus

Abstract

Abstract B cell class switch DNA recombination (CSR) and generation/maintenance of plasma cells underpin the production of pathogenic IgG autoantibodies in lupus. To address whether these two B cell lineage-specific processes can be targeted to inhibit the autoantibody response in lupus, we used a small molecule compound to specifically block the activity of the small GTPase GTPase, as prompted by our previous findings that Rab7 plays a B cell-intrinsic role in antibody responses. Inhibition of Rab7, which was upregulated in lupus B cells, suppressed pathogenic autoantibody production, arrested disease development and extended the life-span in MRL/Fas and Sle1/Sle2/Sle3 lupus-prone mice. The reduction in class-switched autoantibody response occurred despite normal numbers and functions of T cells, dendritic cells and macrophages, but was associated with significantly decreased numbers of IgG-expressing B cells and plasma cells. Accordingly, B cell class-switching and plasma cell survival, but not B cell differentiation into plasma cells, were inhibited by the Rab7 inhibitor through suppression of NF-kB activation, as revealed by impairment in NF-kB-dependent gene expression. Conversely, CSR and plasma cell survival could be rescued by an IKKb constitutively active mutant. These findings suggest a small molecule that targets two important B cell differentiation stages to effectively blunt autoantibody responses in lupus. Supported by NIH grants AI 079705 and AI 105813 and the Alliance for Lupus Research (ALR) grant ALR 295955 to P.C.