Metabolic enforcement of selection in anti-DNA B cells vs. antigen-specific B cells

PROJECT SUMMARY/ABSTRACT Autoantibodies initiate inflammation and tissue injury in patients with autoimmune disease. Antibody specificity (for both foreign- and self-antigens) is determined by clonal selection, which is a function of survival and proliferation of B cells at key developmental and peripheral activation bottlenecks. Autoreactive B cell clones

are primarily removed by apoptosis-dependent negative selection, and foreign antigen-specific B cells are mainly amplified by proliferation-driven positive selection. The same extracellular ligands (e.g., CD40L and BAFF) that drive positive selection of protective B cells also rescue self-specific B cells from apoptotic negative selection. A

key limitation in the field is that we do not currently understand the mechanisms underlying B cell responses to selection ligands that distinguish between foreign-reactive and autoreactive B cells. We have found that the ubiquitin ligase Itch, an essential autoimmune suppressor, specifically promotes apoptosis in negatively selected

B cells exposed to survival ligands, but not B cells responding to normal positive selection cues. CD40L and BAFF activate the mammalian target of rapamycin complex 1 (mTORC1) in B cells, inducing an array of metabolic changes to support proliferation and survival, ultimately dictating selection. Mitochondrial oxidative

phosphorylation has recently emerged as an essential regulator of apoptosis. We found that Itch regulates a downstream branch of mTORC1-dependent mitochondrial oxidative phosphorylation through a distinct mechanism from its role in limiting upstream mTORC1 activation. This proposal will define Itch-regulated

metabolic pathways in B cells that distinguish selection of foreign-antigen specific as compared to autoreactive B cell responses.