# Upstream drivers of type I interferons in lupus

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $796,681

## Abstract

Project Summary/Abstract
This is a multi-PI project in which the 3 PIs each have a set of unique, but complimentary, cutting-
edge technologies, patient resources, and computational tools that together enable us to fill a key
knowledge gap: what are the upstream pathways that drive the chronic production of type I
interferons (IFN-Is) in systemic lupus erythematosus (SLE)? Our work with focus on innate
immune cells (neutrophils and monocytes) and skin biopsies from SLE patients (compared to
healthy donors) obtained at the University of Washington and the University of Michigan,
respectively. These samples will be subjected to ultrasensitive protein detection and protein-
bound nucleic acid sequencing at Rockefeller University, as well as joint experiments in the first
two labs. We anticipate that the synthesis of data from these approaches will be transformative
for our understanding of SLE pathogenesis and the molecular mechanisms of lupus flares. Our
aims are:
AIM 1. To identify the NA(s) that triggers IFN-I production in SLE neutrophils and monocytes.
Because SLE is a systemic disease involving numerous cell types, including immune cells, we
focus this aim on neutrophils and monocytes. This choice is in part based on many recent papers
indicating that they play an important role in SLE and in part because our preliminary data show
that neutrophils are much altered in this disease, contain all the components for nucleic acid
sensing and IFN-I production, and are the lineage with the highest retrotransposon expression.
Monocytes likely play a (similar?) role in SLE. In this Aim, we will focus on identifying the nucleic
acid species that are associated with the nucleic acid sensors that drive IFN-I using ultrasensitive
detection methods.
AIM 2. To identify the pathogenic DNA species that triggers IFN-I production in lupus skin. The
skin is a key location of pathology in SLE patients. Ultraviolet (UV) light triggers flares of rashes
and systemic disease in SLE patients, yet the reasons for this are unknown. IFN-Is are chronically
upregulated in SLE epidermis, drive inflammatory responses in the skin, and are dysregulated
after UV light exposure such that more IFN-I is produced in SLE vs. healthy control skin. The
reasons for increased IFN-I production in SLE skin remain undefined yet are critical targets for
novel therapeutic development and flare prevention. In this Aim, the macromolecular aggregates
of nucleic acid sensors and the associated nucleic acids will be identified in keratinocytes before
and after UVB exposure and the source of the pathogenic nucleic acid(s) determined.

## Key facts

- **NIH application ID:** 10998342
- **Project number:** 1R01AI186337-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Joanne Michelle Kahlenberg
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $796,681
- **Award type:** 1
- **Project period:** 2024-05-28 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998342

## Citation

> US National Institutes of Health, RePORTER application 10998342, Upstream drivers of type I interferons in lupus (1R01AI186337-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10998342. Licensed CC0.

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