# Regulation of B cell Responses in SLE and Other Autoimmune Diseases

> **NIH NIH U19** · EMORY UNIVERSITY · 2024 · $312,998

## Abstract

Project Summary/Abstract
Systemic lupus erythematosus (SLE) is a debilitating systemic autoimmune disease that results from the
breakdown in B cell tolerance and ultimately the generation of pathogenic autoreactive antibodies. Multiple
factors contribute to SLE including genetic predisposition and environmental influences. Our Emory
Autoimmunity Center of Excellence has characterized a pathogenic lineage of extrafollicular (EF) B cells in Black
SLE subjects in the US South and demonstrated that these EF B cells harbor a unique epigenetic and
transcriptional profile. Importantly, EF B cells are predisposed to differentiate into antibody secreting plasma
cells (ASC), are highly expanded in SLE disease flares, and harbor autoreactive B cell receptors. Despite these
studies, we still do not know which genes underpin EF B cells in SLE and contribute to the secretion of
autoreactive antibodies. This Pilot Project will use sophisticated CRISPR/Cas9 gain and loss-of-function screens
in primary SLE and healthy B cells to unravel the gene networks and interactions that promote the differentiation
of naïve and EF B cells in SLE. Importantly, we will assay two distinct stages of B cell differentiation to answer
the following questions. Do antigen inexperienced SLE naive B cells have distinct differentiation requirements
from healthy? How do EF B cells differ from classical memory cells in their requirements to form ASC? Can
over expression of EF genes in naive B cells drive more rapid ASC differentiation? Do driver genes in SLE also
promote ASC formation in healthy B cells or do they require other SLE specific changes, such as cofactors or
epigenetic remodeling? To answer these questions, we propose two aims. In Aim 1, we will define the genes
required for SLE B cells to form ASC using loss-of-function screens. Importantly we will also test which genes
require or synergize with TLR7 signaling to promote ASC formation. In Aim 2, we will identify driver genes of
SLE B cell differentiation to ASC using gain-of-function screens. Here, genes upregulated in different EF SLE B
cell compartments will be over expressed in antigen-inexperienced naïve B cells to determine if they are sufficient
to enhanced ASC formation. Finally, we will perform the screen while simultaneously overexpressing TBET to
identify genes that collaborate with this known driver of EF B cell fate and autoimmunity. The outcomes of this
Pilot Project will derive the genes required for SLE B cells to form ASC and establish a genome engineering
platform that can be leveraged for future mechanistic studies of human autoimmunity.

## Key facts

- **NIH application ID:** 10845045
- **Project number:** 2U19AI110483-11
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Christopher D Scharer
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $312,998
- **Award type:** 2
- **Project period:** 2014-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845045

## Citation

> US National Institutes of Health, RePORTER application 10845045, Regulation of B cell Responses in SLE and Other Autoimmune Diseases (2U19AI110483-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10845045. Licensed CC0.

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