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

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $530,791

## Abstract

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.

## Key facts

- **NIH application ID:** 10953874
- **Project number:** 1R01AI185774-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Emily K. Moser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $530,791
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10953874

## Citation

> US National Institutes of Health, RePORTER application 10953874, Metabolic enforcement of selection in anti-DNA B cells vs. antigen-specific B cells (1R01AI185774-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10953874. Licensed CC0.

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