# FDC regulation of self-reactive B cells

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $531,000

## Abstract

TITLE: FDC regulation of self-reactive B cells
Abstract:
Systemic lupus erythematosus (lupus) is a B cell disease characterized by secretion of pathogenic
autoantibody specific for nuclear antigens or "DAMPS". A hallmark of the disease is spontaneous formation of
germinal centers (GC) in spleen and lymph nodes and development of pathogenic long- lived memory B cells.
Follicular dendritic cells (FDC) which are stromal derived and important in maintaining the architecture of B cell
follicles are essential to formation and maintenance of GC as they are a major source of B cell antigen and
survival factors. We propose FDC play a critical role in the regulation of tolerance of autoreactive B cells and
their differentiation and secretion of pathogenic antibodies. Using a lupus-prone mouse model, we found that
FDC uptake of nuclear antigens via CD21 triggers endosomal TLR promoting B cell loss of tolerance and
differentiation. Thus, FDC are not only a critical source of self-antigen; but they are an important source of
signals that can “drive” self-reactive B cells to differentiate into autoantibody producing cells and memory B
cells. These findings suggest FDC may be a novel target for therapy in lupus patients. To test this possibility in
a pre-clinical model, lupus mice will be treated over a period of 1 month with a blocking antibody to the CD21
receptor expressed by FDC. Our hypothesis will take advantage of several novel murine models such as a
human-mouse CD21 chimeric lupus mouse where the FDC express murine CD21 and the B cells express
human CD21. Using this novel system, we will test the efficacy of anti-mouse CD21 therapy in the elimination
of retention of nuclear antigens by FDC and "turning-off" TLR signaling and cytokine secretion.
Three aims are proposed:
Aim 1. Test the hypothesis that the tolerance of self-reactive B cells is regulated by FDCs
Aim 2. Test the hypothesis that the maintenance of self-reactive memory B cells is FDC-dependent
Aim 3. Test the efficacy of blocking CD21 in lupus mouse models
Summary: The successful completion of this study will not only provide valuable reagents and novel tools to
push the field forward but it could lead to development of novel strategies and/or blocking therapies for
systemic autoimmunity such as lupus.

## Key facts

- **NIH application ID:** 10308457
- **Project number:** 5R01AI130307-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Michael Craig Carroll
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $531,000
- **Award type:** 5
- **Project period:** 2017-12-14 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308457

## Citation

> US National Institutes of Health, RePORTER application 10308457, FDC regulation of self-reactive B cells (5R01AI130307-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10308457. Licensed CC0.

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