# B cell anergy, modified LDL uptake, and atherosclerosis

> **NIH NIH R01** · EASTERN VIRGINIA MEDICAL SCHOOL · 2020 · $483,862

## Abstract

Project Summary
Cardiovascular disease is the leading cause of death worldwide. It is a multifaceted chronic inflammatory
disease characterized by the accumulation of modified lipoproteins and immune cells in the aorta, vascular
dysfunction, and low-grade chronic inflammation. Despite the strides that have been made in the past decade,
there is still much that is unknown about the mechanisms behind disease progression. The uptake of modified
low density lipoproteins (mLDL) by macrophages has been well characterized as being a major mechanism in
the development of atherosclerosis. Our laboratory show that B cells can uptake mLDL and this uptake
induces some significant phenotypical changes in B cells and upregulation of LXR-dependent targets. While
mechanisms and role of mLDL uptake by Ms are well-characterized, the pathways of mLDL uptake in B cells
are unclear and nothing is yet known about the impact of mLDL uptake on B cell functions. Our preliminary
data suggest that acLDL uptake by B cells induces a unique gene profile, which supports inhibitory pathways
including GRAIL. GRAIL is a well-known regulator for T-cell tolerance and T cell activation. Our data
demonstrate that GRAIL is also expressed in B cells and play an important role in B cell activation and B cell
anergy. Importantly, B cell-specific deficiency results in increased atherosclerosis. In Aim 1 of this application,
we propose to test molecular mechanisms whereby GRAIL expression and mLDL uptake control B cell
activation in atherosclerosis. First, we will test mechanisms of mLDL uptake by B cells using SR-B1, MARCO,
CXCL16, and CD163 deficient mice or blocking Abs BCR-transgenic and FcRIIB- deficient mice. We will test
how mLDL uptake induces some inhibitory pathways in B cells with the focus on LXR-mTOR-Otub1-GRAIL
axis. Next, we will determine pathways by which GRAIL shapes B cell activation, investigate GRAIL-dependent
BCR signaling, B cell survival and IL-4-dependent signaling in B cells, and examine the role of B cell specific
GRAIL in atherosclerosis. In Aim 2, we will determine how atherosclerosis affects B cell anergy and test a role
of GRAIL and mLDL uptake in stability and functions of anergic B cells. We will compare phenotypes of anergic
B cells from young, aged Apoe-/- mice, and age-matched naturally occurring anergic BL/6 B cells. We will also
test how atherosclerosis affects stability of anergic B cells in adoptive transfer experiments using Ars/A1
transgenic mice, a model of B cell anergy. Next, we will investigate how GRAIL affects B cell anergy and
atherogenesis using Ars/A1 mice that would receive AAV–shRNA-Rnf128 under B cell specific promoter and
AAV-PSCK9. The implications from this work are significant since the results will provide the first evidence for
a role of mLDL uptake in B cell biology via GRAIL-dependent regulation of B cell anergy and B cell activation in
atherosclerosis.

## Key facts

- **NIH application ID:** 9886286
- **Project number:** 5R01HL139000-03
- **Recipient organization:** EASTERN VIRGINIA MEDICAL SCHOOL
- **Principal Investigator:** Elena V Galkina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,862
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886286

## Citation

> US National Institutes of Health, RePORTER application 9886286, B cell anergy, modified LDL uptake, and atherosclerosis (5R01HL139000-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9886286. Licensed CC0.

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