# Project 3: Regulation of atheroprotective IgM - producing B cells in murine and human atherosclerosis

> **NIH NIH P01** · LA JOLLA INSTITUTE FOR IMMUNOLOGY · 2022 · $43,069

## Abstract

Project 3 Summary
We and others have extensively studied B-1 cells in mice, clearly showing that these cells and
the IgM to oxidation-specific epitopes (OSE) on LDL (IgMOSE) that they produce are anti-
inflammatory and block atherosclerosis (AS) development. Yet, despite a wealth of evidence
that plasma levels of IgM to the OSE, malondialdehyde-modified LDL (IgMMDA-LDL) in humans
are associated with less CAD and fewer CV events, identification of the IgMMDA-LDL producing
human B cell has remained elusive. Our novel data from the previous cycle, utilizing the well
characterized CAVA cohort and high dimensional phenotyping of circulating B cells, are the first
to identify human B cell subtypes that produce IgMMDA-LDL, and demonstrate that they are indeed
associated with high plasma levels of IgMMDA-LDL and inversely correlated with CAD severity in
humans. One of these subtypes (B27+IgM+24hi cells) trafficked to the spleen and could be
stimulated by MDA antigen to produce higher levels of IgMMDA-LDL in vivo. Our findings revealed
the novel discovery that the sialogycoprotein, CD24, regulated expression of the chemokine
receptor CCR6 and splenic localization of these cells. CD24, a GPI-anchored
sialoglycoprotein that resides in lipid rafts and regulates signaling of the IgM BCR, has not
previously been implicated in murine or human AS. Utilizing our antibody and transcriptome
sequencing core (Core B), we discovered that B27+IgM+24hi cells express more CCR6 and IgM
specifically in subjects with low compared to high CAD and we identified signaling molecules
downstream of CCR6 and the IgM BCR associated with CAD severity. Accordingly, we
hypothesize that humans with severe CAD and rapid CAD progression have fewer
B27+IgM+24hi cells and that CD24 acts as a rheostat promoting key surface receptor function
and signaling pathways in B27+IgM+ cells leading to enhanced production of IgMOSE and
atheroprotection. We will utilize novel clinical cohorts (aim 1) and loss- and gain- of function
approaches in vitro and in vivo (aim 2) to define the mechanisms whereby CD24 regulates the
B27+IgM+ phenotype with particular emphasis on CCR6, the BCR, key signaling events and the
IgM repertoire in atherosclerosis.

## Key facts

- **NIH application ID:** 10334096
- **Project number:** 2P01HL136275-06
- **Recipient organization:** LA JOLLA INSTITUTE FOR IMMUNOLOGY
- **Principal Investigator:** Coleen A McNamara
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $43,069
- **Award type:** 2
- **Project period:** 2017-08-01 → 2022-06-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334096

## Citation

> US National Institutes of Health, RePORTER application 10334096, Project 3: Regulation of atheroprotective IgM - producing B cells in murine and human atherosclerosis (2P01HL136275-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10334096. Licensed CC0.

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