# Role of plasmacytoid dendritic cells in autoimmunity

> **NIH NIH R01** · HOSPITAL FOR SPECIAL SURGERY · 2020 · $440,000

## Abstract

Systemic Sclerosis (SSc) is a multisystem, fibrosing disorder in which vasculopathy, autoimmunity, and
inflammation lead to diverse life-altering and life-threatening clinical manifestations. Treatment is typically
focused on specific organ involvement and there is no standardized drug to treat the symptoms with
significant differences in the therapeutic approaches between experts. Furthermore, the development of
new drug is complicated by the heterogeneity of the disease but also by the absence of validated outcome
measures. Recent reports have demonstrated that the chronic activation of plasmacytoid dendritic cell
(pDCs) and subsequent secretion of both IFN-α and the chemokine CXCL4 is associated with the
pathogenesis of SSc. Our preliminary data show that pDCs have a key role in promoting skin fibrosis in a
mouse model of scleroderma. We also show that the pattern of TLR expression is altered in the pDCs of
SSc patients with high expression of TLR8, a receptor that is absent in pDCs from healthy donors or SLE
patients. Signaling though TLR8 induced both IFN and CXCL4. Using mice that we have engineered so
they bear human TLR8, we show that TLR8 promotes fibrosis as these mice have exacerbated disease.
We will test the hypothesis that pDCs is the critical cell type promoting SSc due to the aberrant expression
of TLR8 on pDCs that impacts the response to self-nucleic acids in patients. The project will use two
separate mouse models of scleroderma to define the role of pDCs, TLRs and key signaling molecules of
the TLR pathway such as PI3Kδ in the development of disease. We will also dissect the underlying defect
that leads to the production of CXCL4 in pDCs from SSc patients and will aim to better understand the
interplay between CXCL4 and the IFN response following TLR triggering in patients. To tackle these
questions, we are proposing to (1) determine what controls pDCs activation in SSc patients and how these
cells promote disease and (2) to characterize the nature of TLR8 stimulation of SSc pDCs and evaluate
how CXCL4 and IFN impact TLR8 response. We will also determine whether key signaling molecules
induced following TLR triggering are involved in disease progression. The data generated here will provide
key understanding of the role of pDCs in skin pathology and the factors that control pDCs activation in SSc
patients, thus identifying new ways to manipulate these cells in pathological conditions.

## Key facts

- **NIH application ID:** 9878756
- **Project number:** 5R01AI132447-03
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** Franck Barrat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,000
- **Award type:** 5
- **Project period:** 2018-03-09 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878756

## Citation

> US National Institutes of Health, RePORTER application 9878756, Role of plasmacytoid dendritic cells in autoimmunity (5R01AI132447-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878756. Licensed CC0.

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