# Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $496,333

## Abstract

ABSTRACT
The hallmark of systemic lupus erythematosus (SLE) is the production of antibodies to nuclear
antigens such as ribonucleoproteins and DNA, with the resulting immune complexes causing systemic
immune activation and tissue inflammation. High-affinity IgG antibodies to double-stranded DNA
(dsDNA) are particularly pathogenic and associate with the severity of tissue damage. The
mechanisms of tolerance to self-DNA and of its breakdown in SLE are poorly understood. We have
studied these mechanisms by focusing on DNASE1L3, a secreted DNase that is mutated in several
cases of early-onset familial SLE. We found that DNASE1L3-deficient mice develop a massive anti-
dsDNA antibody response, whereas the response to other antigens was absent or delayed. This
response and the ensuing immune activation and tissue damage required innate immune signaling
through the adaptor protein MyD88. DNASE1L3-deficient mice and human patients showed the
accumulation of genomic DNA within circulating apoptotic microparticles, and this DNA was
recognized by autoantibodies in a DNASE1L3-sensitive manner. Thus, DNASE1L3 maintains
tolerance to self-DNA by digesting potentially antigenic cell-extrinsic DNA in apoptotic microparticles.
The proposed work will apply the newly developed conceptual framework and experimental tools to
analyze the fundamental mechanisms of anti-DNA immune responses and their relevance to human
SLE. In Aim 1, we will use DNASE1L3-deficient mice as a model of primary anti-dsDNA reactivity to
characterize the nature and regulation of DNA-reactive B cells. In Aim 2, we will characterize innate
immune mechanisms of anti-DNA antibody response, particularly the identity of MyD88-dependent
sensing pathways. In Aim 3, we will translate our findings to human SLE patients, studying the
antibody response to DNASE1L3-sensitive chromatin on microparticles. Collectively, these studies
would provide insights into the origin and mechanisms of the pathogenic anti-DNA responses in SLE,
and facilitate targeted approaches towards their therapeutic blockade.

## Key facts

- **NIH application ID:** 9932890
- **Project number:** 5R01AR071703-03
- **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:** 2020
- **Award amount:** $496,333
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932890

## Citation

> US National Institutes of Health, RePORTER application 9932890, Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus (5R01AR071703-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9932890. Licensed CC0.

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