# IRF7-mediated development of autoreactive B cells and SLE

> **NIH NIH R01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2022 · $536,688

## Abstract

Project Summary
Mechanisms that drive the development of autoreactive B cells in an autoimmune disorder systemic lupus
erythematosus (SLE) is incompletely understood. Overall goal of the Rahman lab is to delineate the
mechanisms that promote the development of autoreactive B cells, autoantibody production and SLE, a
debilitating autoimmune disease that affects millions of Americans and people worldwide. Developing a
complete understanding of such mechanisms will help develop targeted therapies that would be preferable to
currently available SLE treatment options that globally suppress the immune system, and result in recurrent
infections and increase disease-associated morbidity and mortality. GWAS studies have identified risk variants
in the interferon regulatory factor 7 (IRF7) gene, which increase the risk of developing SLE. IRF7 is the key
transcription factor that regulates type I interferon (T1-IFN) response downstream of nucleic acid sensing toll-
like receptor (TLR) that promote SLE in mice and humans. Our preliminary data highlight the significance of
IRF7 in autoreactive B cell development and SLE manifestations in a well-characterized FcgRIIB-/- SLE model.
Published and preliminary data from the FcgRIIB-/- model indicate a critical role for IRF7 and a modest role for
T1-IFN signaling in autoimmune responses and SLE development. These data suggest T1-IFN-dependent and
-independent roles of IRF7 in autoreactive B cell and SLE development, and point to IRF7 as a potentially
better therapeutic target for SLE than T1-IFN blocking therapies alone, although recent clinical trials for T1-IFN
receptor blocking therapy showed promising outcome. However, we know little about the cell type-specific role
of IRF7 in SLE development, although its role in T1-IFN production by pDCs is well established. Importantly, B
cell-intrinsic and -extrinsic roles of IRF7 in autoreactive B cell development via extrafollicular antibody-forming
cell (AFC) and follicular germinal center (GC) pathways in SLE are not known. Also, T1-IFN-independent IRF7
role in SLE remains unknown. We hypothesize that IRF7 regulates B cell-intrinsic and -extrinsic, and T1-IFN-
dependent and -independent mechanisms in autoreactive B cell development in the AFC and GC pathways,
leading to pathogenic autoantibody production and SLE. This hypothesis is supported by our preliminary data
showing 1) a significant upregulation of IRF7 in AFCs (plasmablasts/plasma cells), GC B cells and myeloid
cells 2) increased IRF7 expression in activated B cells from SLE patients 3) a drastic reduction in autoimmune
AFC and GC responses, autoantibodies and immune complex deposition in SLE-prone FcgRIIB-/- mice deficient
in IRF7 4) IRF7 involvement in altered B cell metabolic activity in SLE-prone B cells, and published data
revealing 5) a role for IRF7 in mouse and human SLE. The current proposal will help determine B cell-intrinsic
and -extrinsic roles and mechanisms by which IRF7 promote autoreactive B ce...

## Key facts

- **NIH application ID:** 10437008
- **Project number:** 5R01AI162971-02
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Ziaur Rahman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $536,688
- **Award type:** 5
- **Project period:** 2021-06-23 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437008

## Citation

> US National Institutes of Health, RePORTER application 10437008, IRF7-mediated development of autoreactive B cells and SLE (5R01AI162971-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10437008. Licensed CC0.

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