# Regulation of Pathogenic Plasma Cells in Human SLE

> **NIH NIH P01** · EMORY UNIVERSITY · 2020 · $392,476

## Abstract

PROJECT 4 - ABSTRACT
Systemic Lupus Erythematosus (SLE), is the prototype of human autoimmune disease mediated by
autoantibodies. In contrast to antibodies directed against dsDNA which fluctuate with disease activity and
treatment, highly pathogenic autoantibodies against RNA-binding proteins (RBP), are present years before
disease onset and persist in very high titers throughout disease irrespective of disease activity and treatment,
including B cell depletion. These features support the notion that RBP antibodies are produced by plasma
cells (PC) of prolonged longevity that don't require replenishment from B cell precursors. However, this
concept and multiple other aspects of PC biology and its subversion in human autoimmunity in general and
SLE in particular remain poorly understood. These limitations are created to a large extent by the lack of
definition of different PC populations and a precise identification of the cellular phenotype of human LLPC. Our
laboratory has recently provided the first characterization of the diversity and origin of peripheral PC in active
SLE and in collaboration with Dr. Lee (Project 3) has also provided the first description of LLPC in the human
BM. These studies and additional preliminary results suggest that SLE PC are characterized by prolonged
survival even at an early stage of differentiation. In all, we hypothesize that SLE is characterized by increased
generation of PC with prolonged survival and that these feature lead to the accumulation of autoreactive LLPC
in the SLE BM. We further hypothesize that pathogenic RBP LLPC accumulate through a process of ongoing
generation from precursor B cells, sequential differentiation through consecutive maturation stages and
prolonged survival within the BM microenvironment. The generation and survival of SLE PC will be tested
using state-of-the-art methods for deep sequencing of PC repertoires; ultra-high throughput single cell PC
antibody interrogation; in vivo labeling with heavy glucose; and in vitro PC cultures supported by innovative BM
microenvironments developed by Dr. Lee in Project 3. Studies will be performed with PC generated during the
natural course of SLE and in response to patient vaccination. Finally, through Core B, we will provide a
comprehensive definition of the molecular programs responsible for the behavior of SLE PC using integrated
transcriptional and epigenetic studies. The knowledge generated by this project will be invaluable to
understand the pathogenic role and mechanisms of PC in SLE and to design better and safer therapeutic
strategies for this disease. Specifically, establishing the continued production of RBP PC would indicate the
need for combined targeting of PC and their B cell precursors. Our results will also identify PC biomarkers to
monitor disease development, segment patients for personalized treatment and monitor the outcome of
therapeutic interventions.

## Key facts

- **NIH application ID:** 9930042
- **Project number:** 5P01AI125180-05
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Ignacio E. Sanz
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,476
- **Award type:** 5
- **Project period:** 2016-06-25 → 2022-05-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930042

## Citation

> US National Institutes of Health, RePORTER application 9930042, Regulation of Pathogenic Plasma Cells in Human SLE (5P01AI125180-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9930042. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*