# Cytokine-mediated B-cell development in lupus

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2024 · —

## Abstract

The overall goal of this project is to determine if the IKAROS transcription factor regulates a program that
maintains IL-4 receptor (IL-4R)-mediated B-cell quiescence to ribonuclear protein (RNP) autoantigens
(autoAgs). We propose that B cell activation through the type I interferon (IFN)/TLR7 activation pathway is
inhibited by this B-cell quiescence program. We also propose that failure to maintain B cell quiescence is
associated with the development of RNP autoantibody in systemic lupus erythematosus (SLE). Our
preliminary data suggest that in both lupus mice and in human SLE, multiple immune disease phenotypes can
be initiated by loss of quiescence at the earliest stage of B cell development; that is, the transitional B cell. The
key forces that promote quiescence is an IKAROS (or IKZF1)-based program that is sustained through IL-4R
signaling on IgD+CD23+ B cells. The major opposing program that promotes loss of quiescence is mediated
through the type I interferon receptor (IFNAR) signaling, assembly and signaling competency of the TLR7
pathway, and development of B cells that can produce autoantibodies. We hypothesize that early-stage loss
of quiescence leads to a series of B cell development defects after the transitional stage involving progression
from a resting naïve to an activated naïve predominance and then to development of the pathogenic
CD11c+Tbet+IgD−CD27− double negative 2 (DN2) or germinal center (GC) B cells that ultimately lead to the
development of RNP autoantibody producing plasmablasts and plasma cells (PB/PC). In Aim 1, we will use
several knockout and knock-in mouse strategies in lupus prone mice to determine if type I IFN and IL-4 act at
the Tr B cells to regulate autoreactive B cell development and survival. The specific effects of Ikaros in
modulating type I IFN and IL-4 signaling-mediated RNP-reactive B-cell quiescence at the Tr and naïve stage
will also be analyzed. In Aim 2, we will determine if SLE patients exhibit a loss of IL-4R/IKZF1-mediated B cell
quiescence program starting at the Tr stage of B-cell development. We will determine if the loss of this
pathway disrupts B-cell tolerance to type I IFN and TLR7 stimulation, leading to the development of RNP-
reactive DN2 B cells and PB/PC. The innovative scientific basis of this proposal will be its ability to interpret
the broad spectrum of immune and disease characteristics of SLE by understanding the key initiating events of
loss of B cell quiescence at the transitional stage. B cells from mouse models of lupus and from SLE subjects
will be characterized by high dimension flow cytometry and transcriptomics analyses for well-established cell
surface protein antigen markers that define B cell development at all major developmental stages. We have
established a team of coordinators at the BVAMC to facilitate recruitment and have acquired numbers of SLE
subjects necessary for definitive and statistically meaningful results. A state-of-the-art immunologic laboratory
...

## Key facts

- **NIH application ID:** 10781925
- **Project number:** 5I01BX006099-02
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** John D Mountz
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10781925

## Citation

> US National Institutes of Health, RePORTER application 10781925, Cytokine-mediated B-cell development in lupus (5I01BX006099-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10781925. Licensed CC0.

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