# B cell intrinsic interferon-beta regulates autoreactive B cell development

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $471,309

## Abstract

Project Summary/Abstract
A considerable body of evidence implicates type I interferons (IFNs) in systemic lupus erythematosus (SLE);
however, the “interferon signature” does not address the source and the key pathogenic type I IFNs in SLE,
making it challenging to design effective precision medicine for SLE. We propose the novel hypothesis that it is
the endogenous production of IFNβ by B cells that plays a defining role in shaping the autoantibody response
and disease activity in a substantial subset of patients with SLE. We have found, in humans and mice, that the
transitional (Tr) stage of B-cell development is characterized by heterogeneity in IFNβ expression at the single-
cell level. Our preliminary data further suggest that: (i) Tr B cells with high endogenous production of IFNβ
undergo strong IFNβ autocrine signaling and changes in the transcriptome signature in a manner that supports
RNA/RNP-associated TLR7 responses. This imprinted signature promotes subsequent survival and
development of RNP-reactive B cells including their differentiation into long-lived memory B cells; and (ii) Anti-
dsDNA autoAb producing cells are derived from Tr cells that do not express high levels of endogenous IFNβ
expression; however, high levels of endogenous IFNβ in memory B cells play a critical role in the differentiation
of short-lived anti-dsDNA memory B cells. The model is supported by compelling preliminary data including
analyses of PBMCs from SLE patients that indicated significantly higher IFNβ expression in B cells from SLE
patients with renal involvement and significantly higher expression of intracellular IFNβ in B cells from female
African-American (AA) SLE patients as compared with non-AA patients and healthy controls. In Aim 1, we will
establish if lupus flare is associated with increases in IFNβhi memory B cells and if this phenotype is more
common in AA SLE patients. High-throughput single-cell transcriptome analysis coupled with state-of-the-art
computational analysis will be used to identify transcriptional signatures in DNA- and RNA-reactive B cells to
refine this marker; to establish if, as predicted, there is commonality between the RNP-reactive Tr and memory
B cell transcriptome; and to identify the association of enhanced IFNβ signaling with stage-specific
dysregulation of downstream pathways. Functional and target-specific analysis of sorted human PBMCs will
then be used to determine if endogenous B-cell IFNβ and its downstream pathways are essential for RNA- vs
DNA-ligand mediated Tr and memory B-cell activation and survival. In Aim 2, we will use the same
approaches in the BXD2 lupus model and BCR transgenic mice to determine if endogenous IFNβ is essential
for, and differentially regulates, anti-RNP and anti-DNA B cell development in vivo. This hypothetical model
does not negate the contributions of other cells and factors to the pathogenesis of SLE but reframes the
current paradigm. The data generated will provide novel insights ...

## Key facts

- **NIH application ID:** 10326335
- **Project number:** 5R01AI134023-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** John D Mountz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $471,309
- **Award type:** 5
- **Project period:** 2018-02-13 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326335

## Citation

> US National Institutes of Health, RePORTER application 10326335, B cell intrinsic interferon-beta regulates autoreactive B cell development (5R01AI134023-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10326335. Licensed CC0.

---

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