# Project-002

> **NIH NIH U19** · EMORY UNIVERSITY · 2021 · $254,427

## Abstract

SLE is the prototypical systemic autoimmune disease with high production of autoantibodies and
dramatic abnormalities in B cell homeostasis including enhanced activation and increased
numbers of Antibody Secreting Plasmablasts (PB). However, the molecular regulome of
abnormal SLE B cell activation and differentiation into effector cells and the nature of the
autoantigens that trigger these processes are not understood. The central goal of the Emory
Autoimmunity Center of Excellence is to understand the interplay between these determinants of
pathogenic B cell behavior in SLE (Principal Project) and other autoimmune diseases
(Collaborative Project). During the current funding cycle, the Emory ACE U19 has delineated
the cellular complexity of the human B cell compartment and defined novel singular populations
of activated naïve cells and effector B cells. We have demonstrated the contribution of this
effector pathway to active disease and gained insight into the extrinsic factors and internal
molecular programs underlying its dysregulation in SLE. Importantly, we have found that even
the resting naïve cells at the apex of this pathogenic cascade are epigenetically poised for
activation and ASC differentiation. In all, the combined evidence suggests that SLE B cells
undergo stimulation at early, pre-naïve developmental stages and remain epigenetically imprinted
for activation after returning to a resting state. This Principal Project will test this model through
a comprehensive investigation of the molecular programs and antigenic reactivity of the
aforementioned B cell subsets and PB. Our goals will be accomplished through the following
aims: Aim 1. Molecular programming of B cell development in SLE; Aim 2. Molecular programs
and antigenic triggers of B cell tolerance breakdown in SLE; Aim 3. Epigenetic regulation of newly
generated effector B cells during acute lupus flares. In addition to providing new fundamental
insights into the pathogenesis of SLE, we expect to identify new therapeutic targets and a
theoretical framework for the rational application of new therapies to individual patients and
specific phases of the disease. Moreover, we will generate powerful candidate biomarkers with
the potential to predict disease activity and outcome; determine reversal of disease programs
post-B cell depletion; predict disease development in high-risk subjects; and segment different
types of disease including B cell-independent SLE.

## Key facts

- **NIH application ID:** 10148628
- **Project number:** 5U19AI110483-08
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ignacio E. Sanz
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $254,427
- **Award type:** 5
- **Project period:** 2014-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148628

## Citation

> US National Institutes of Health, RePORTER application 10148628, Project-002 (5U19AI110483-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10148628. Licensed CC0.

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