# Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $717,625

## Abstract

PROJECT SUMMARY/ABSTRACT
The hallmark of systemic lupus erythematosus (SLE) is the production of antibodies (Abs) to nuclear antigens
such as ribonucleoproteins and chromatin. High-affinity IgG Abs to double-stranded DNA (dsDNA) are
associated with more severe disease and the development of lupus nephritis (LN). DNASE1L3 is a unique
secreted DNase that is capable of digesting DNA packaged in chromatin, and null mutations in human
DNASE1L3 cause monogenic early-onset SLE with anti-DNA reactivity. Similar to humans, DNASE1L3-deficient
mice rapidly develop Abs to chromatin and dsDNA. Our analysis of this model revealed that the anti-DNA Ab
response arises from the short-lived extrafollicular plasmablasts supported by the extrafollicular helper T cell
(EF-TFH) subset. Confirming the relevance of DNASE1L3 to human patients with sporadic SLE, we demonstrated
that many SLE patients with LN have reduced DNASE1L3 activity, which is associated with the presence of
blocking Abs to DNASE1L3. These results suggest that by blocking D1L3, anti-D1L3 Abs facilitate autoreactivity
to chromatin and thereby contribute to SLE pathogenesis. In this cycle of the award, these advances will be
leveraged to dissect the mechanisms and clinical consequences of anti-DNA responses in SLE patients with
autoantibody-mediated D1L3 deficiency. The project will continue the team effort that includes experimental
immunology (Reizis), human SLE phenotyping and biobanking (Buyon), and immune repertoires analysis
(Ippolito). In Aim 1, we will further characterize the dynamics and clinical correlates of anti-DNASE1L3 Abs in
SLE patients, and analyze their role in the control of cell-free DNA. In Aim 2, we will clone anti-DNASE1L3 Abs
from SLE patients and analyze their reactivity spectrum and pathogenic potential in vivo. In Aim 3, we will use
single-cell TCR sequencing to characterize the autoreactive T cell clones in SLE patients with Ab-mediated
blockade of DNASE1L3, and in DNASE1L3-deficient mice. Collectively, these studies should provide insights
into the origin and mechanisms of the pathogenic anti-DNA responses in SLE, and facilitate more targeted
approaches towards their therapeutic blockade.

## Key facts

- **NIH application ID:** 10883203
- **Project number:** 2R01AR071703-06A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Jill P Buyon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $717,625
- **Award type:** 2
- **Project period:** 2018-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883203

## Citation

> US National Institutes of Health, RePORTER application 10883203, Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus (2R01AR071703-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10883203. Licensed CC0.

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