# Regulation of B cell activation in lupus

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $379,654

## Abstract

PROJECT SUMMARY
Systemic lupus erythematosus (SLE) is a disorder of the immune system that is characterized by autoantibody
production, hyperactive B cell antigen receptor (BCR) signaling and B cell hyperresponsiveness; however, the
mechanisms that regulate aberrant B cell function are poorly understood. Investigation of proteins and
processes that drive BCR signaling, B cell hyperactivation and autoantibody production in SLE should
offer mechanistic insights and lead to development of more effective therapies. B cell activation is kept
under check by a potent inhibitory pathway, a key component of which is the Src family kinase Lyn. Human
GWAS studies have shown a strong association between lower expression of Lyn and incidence of SLE. Mice
with genetic deletion of Lyn lose peripheral tolerance and display all the symptoms associated with human
SLE, including exacerbated BCR signaling, B cell hyperactivation, high levels of serum autoantibodies, and
glomerulonephritis. Therefore, Lyn-/- mice represent a clinically relevant model to investigate the molecular
regulation of B cell autoimmunity in SLE. We have previously reported that the membrane-cytoskeleton linker
protein Ezrin regulates multiple facets of B cell function by undergoing dynamic phosphorylation-
dephosphorylation. Interestingly, we observed that ezrin is hyperphosphorylated in Lyn-/- B cells, and that
conditional deletion of ezrin in B cells of Lyn-/- mice leads to a significant decrease in B cell activation,
differentiation, autoantibody production and immune complex deposition in the kidneys. Our data suggest that
ezrin is an important mediator of B cell hyperactivation in the absence of Lyn, and thus a potential molecular
target. We hypothesize that ezrin facilitates B cell pathogenesis in Lyn-/- mice by promoting molecular
and cellular processes that rely on membrane-cytoskeletal reorganization. Our specific aims are, (1) to
investigate the impact of ezrin deletion on immunopathology in vivo, (2) to determine the effect of ezrin deletion
on B cell differentiation in vivo, and (3) to examine the effect of ezrin deletion on BCR organization and B cell
activation in vitro. We will employ genetic, immunological, proteomic, molecular biology, and high-resolution
live-cell imaging techniques to accomplish our aims. We expect that the results of these studies will identify the
pathological features of SLE that are altered by loss of ezrin in Lyn-/- mice at different stages of disease
progression, ascertain if ezrin promotes autoimmunity in Lyn-/- mice by enhancing germinal center B cell
response, and reveal the spatial and molecular mechanisms employed by ezrin to facilitate hyperactive B cell
responses in the absence of Lyn. Significance & Impact: We anticipate that the innovative mouse models and
experimental analyses proposed here will establish ezrin-dependent membrane-cytoskeletal remodeling as a
novel mode of regulating B cell autoimmunity arising from the deficiency of Lyn. Mor...

## Key facts

- **NIH application ID:** 9899915
- **Project number:** 5R01AR067705-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Neetu Gupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $379,654
- **Award type:** 5
- **Project period:** 2016-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899915

## Citation

> US National Institutes of Health, RePORTER application 9899915, Regulation of B cell activation in lupus (5R01AR067705-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9899915. Licensed CC0.

---

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