# BCAP regulation of TLR7/9 signaling in Lupus

> **NIH NIH R01** · BENAROYA RESEARCH INST AT VIRGINIA MASON · 2021 · $354,843

## Abstract

PROJECT SUMMARY
 Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence
of circulating autoantibodies to nucleic acids and to proteins with which they associate. Signaling through the
nucleic acid sensing TLRs, TLR7 and TLR9, is critical in SLE pathogenesis, and dysregulated TLR signaling
can promote lupus in humans and in mouse models. Plasmacytoid dendritic cells (pDC) and B cells both
express these nucleic acid sensing TLR and are important in SLE pathogenesis. Autoreactive B cells produce
pathogenic autoantibodies in SLE, and B cell antibody production is promoted by TLR7 and TLR9 signaling.
pDC use TLR7 and TLR9 to respond to nucleic acids in immune complexes resulting in the secretion of large
quantities of type I IFN cytokines, which have pleiotropic effects on the immune response, including enhancing
dendritic cell (DC) maturation, plasma cell formation, and T cell responses, all of which can promote a feed
forward loop of immune activation. Therefore, understanding the mechanisms by which TLR7 and TLR9
signaling are regulated in these two critical cell types is important for understanding the pathogenesis of SLE
and in defining therapeutic targets for this disease. We have identified the signaling adapter B cell adapter for
PI3-kinase (BCAP) as a key modulator of TLR signaling in multiple immune lineages. First, we found that in
macrophages BCAP inhibits TLR-induced inflammatory cytokine production via activation of PI3-kinase. We
recently showed that BCAP promotes pDC IFNα, but not IL-6, secretion. We have also begun to examine how
BCAP regulates B cell TLR7/9 responses, an understudied area. Our preliminary data show that BCAP is a
key regulator of B cell TLR7/9 responses in all B cell subsets, with a particularly striking decrease in
proliferation and IgG secretion from splenic marginal zone B cells. Additionally, we have found that BCAP-
deficiency protects the TLR7.1 mouse lupus model from disease. Together, our findings show an important
role of BCAP in endosomal TLR signaling in pDC and B cells, both important in SLE pathogenesis. Given the
importance of TLR7 and TLR9 signaling in both B cells and pDC in SLE, the premise of this application is that
BCAP regulation of pDC and B cell TLR7/9 signaling is critical in the development of lupus-like disease.
Specifically, we will 1) determine the mechanism by which BCAP regulates TLR7/9-induced IFNα production in
pDCs, 2) determine the mechanism by which BCAP regulates B cell TLR7/9 responses, and 3) determine the
relative contribution of BCAP in pDCs and B cells to lupus-like disease using two mouse models.

## Key facts

- **NIH application ID:** 10265641
- **Project number:** 3R01AI150178-02S1
- **Recipient organization:** BENAROYA RESEARCH INST AT VIRGINIA MASON
- **Principal Investigator:** Jessica A Hamerman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $354,843
- **Award type:** 3
- **Project period:** 2020-07-06 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265641

## Citation

> US National Institutes of Health, RePORTER application 10265641, BCAP regulation of TLR7/9 signaling in Lupus (3R01AI150178-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10265641. Licensed CC0.

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