# Contribution and interplay of CXCR4 and integrins in central B cell tolerance

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $568,467

## Abstract

PROJECT SUMMARY
The objective of this research is to understand the role and mechanism by which chemoattractant and integrin
signaling plays in the bone marrow selection of B cells and in shaping the peripheral primary B cell repertoire
and its degree of self-reactivity. The fact that 30% of the millions of B cells produced daily express a B cell
receptor with high-avidity for self-antigen suggests we may not be healthy and live a full life in the absence of
central B cell tolerance. Intriguingly, individuals affected by common autoimmune diseases display defects of
central B cell tolerance manifesting with much higher numbers of bone marrow autoreactive B cells entering
the peripheral tissue. However, these individuals also have defects in peripheral tolerance. A better
understanding of how newly generated high-avidity autoreactive B cells are controlled by or escape tolerance
can have profound implications for the development of therapies that may reduce the self-reactive burden of
the circulating B cell population in individuals predisposed to autoimmunity. We have recently documented that
the chemokine receptor CXCR4 is expressed at higher levels by autoreactive B cells undergoing central
tolerance than non-self-reactive B cells licensed to leave the bone marrow. Moreover, in vivo treatment of mice
with a CXCR4 antagonist, releases high-avidity autoreactive B cells from the bone marrow into the circulation
from where they relocate into the spleen. The mechanisms by which CXCR4 signaling retains self-reactive B
cells within the bone marrow is not clear. It is known that CXCR4 signaling can modulate the function of
integrins, molecules that regulate cell adhesion to tissues. Chemokine receptors and integrins can also be
regulated by PI3K signaling or can themselves promote the activity of PI3K, which is important for the positive
selection of immature B cells out of the bone marrow. The goal of this grant is to define the contribution of
CXCR4 and integrin receptors to central B cell tolerance and the impact of central B cell tolerance on
peripheral tolerance and autoimmune responses. Experiments in Aim 1 will establish whether CXCR4 signaling
controls the bone marrow retention of autoreactive B cells in human beings. Aim 2 will resolve the contribution
of integrins in bone marrow B cell selection and the crosstalk between CXCR4, integrins and PI3K.
Experiments in Aim 3 will test the hypothesis that the CXCR4-mediated central B cell tolerance process is
necessary to reduce the chances of systemic autoantibody and autoimmune responses. Overall, these studies
are significant because they generate a deeper mechanistic understanding of how B cell tolerance can be
breached during the development of autoreactive B cells to raise the autoreactive capacity of the primary
circulating B cell repertoire and the general risk for autoimmunity.

## Key facts

- **NIH application ID:** 10852681
- **Project number:** 1R01AI181854-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Roberta Pelanda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $568,467
- **Award type:** 1
- **Project period:** 2024-05-10 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10852681

## Citation

> US National Institutes of Health, RePORTER application 10852681, Contribution and interplay of CXCR4 and integrins in central B cell tolerance (1R01AI181854-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10852681. Licensed CC0.

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