# Effector functions and cellular targets of pathogenic plasmacytoid cells in lupus.

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $396,250

## Abstract

Abstract
Systemic lupus erythematosus (SLE) is a heterogenous systemic autoimmune disorder of unknown
etiology. It has been more than a decade since it was first shown that a significant proportion of patients
diagnosed with SLE express an “interferon signature” in the peripheral blood mononuclear cells (PBMCs);
that is upregulated levels of interferon-alpha (IFNα)-induced gene transcripts. Many cells can produce IFNα,
but plasmacytoid dendritic cells (pDCs), in particular SiglecH+ pDCs, are particularly potent in part due to
their high expression of endosomal toll like receptors (TLR7, TLR8 and TLR9), and the presence of pre-
made IRF7; a key mediator of TLR7/9 induced signaling. Plasmacytoid DCs are found in elevated numbers
in SLE patients and some mouse models of lupus, and recent data from us and others showed that
depletion of SiglecH+ pDCs in mouse models of lupus ameliorates disease development. Despite these
exciting results suggesting SiglecH+ pDCs as a new target for therapeutics, it remains to be determined
how IFNα production is induced in SiglecH+ pDCs, what cells respond to SiglecH+ pDC-derived IFNα and
consequently what pathological effects are driven by such cells. Based on the overwhelming evidence
showing a correlation between pDCs, IFNα and SLE, we will test the hypothesis that SiglecH+ pDCs
produce IFNα in response to endogenous activation of TLR7 signaling, and that IFNα act upon T
cells, B cells and myeloid cells, all of which are responsible for specific measures driving lupus
pathogenesis.
In order to test our hypothesis, we propose a series of unique new approaches in which we take advantage
of, and combine, a number of genetically modified, already existing, mouse models. First of all, we will
identify critical target cells of pathogenic IFNα involved in, and necessary for, driving individual or
overlapping symptoms of lupus-like disease in vivo. For these studies we have created cell-type specific
IFNα-receptor deficient B6.Nba2 lupus-prone mice and will specifically identify the pathogenic effect of IFNα
stimulated CD4+ T cells, B cells and LysM+ myeloid cells. Secondly, we will create mixed bone marrow
chimera mice to test if TLR7 is directly acting in SiglecH+ pDCs instigating IFNα synthesis and driving lupus
pathogenesis. For these studies we will take advantage of our B6.Nba2.BDCA2-DTR transgenic mice, in
which SiglecH+ pDCs can be specifically ablated upon treatment with diphtheria toxin, and systemic TLR7-
deficient mice. The completion of our proposed studies will provide critical new information
regarding the relationship between SiglecH+ pDCs, IFNα, TLR7 and target cells of IFNα and lupus
pathogenesis. It is our expectation that such knowledge will result in new therapeutic targets with the
potential to help the millions of individuals suffering not just from SLE, but also from other autoimmune
disorders (dermatomyositis, vitiligo, and Aicardi-Goutières syndrome etc.) in which IFNα has been shown to
be pathog...

## Key facts

- **NIH application ID:** 9828588
- **Project number:** 5R01AI118774-04
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Trine Norgaard Jorgensen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2016-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828588

## Citation

> US National Institutes of Health, RePORTER application 9828588, Effector functions and cellular targets of pathogenic plasmacytoid cells in lupus. (5R01AI118774-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828588. Licensed CC0.

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