# Cellular Sources of Self Antigen in SLE

> **NIH VA I01** · DURHAM VA MEDICAL CENTER · 2021 · —

## Abstract

Abstract
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the production of
antinuclear antibodies (ANAs) in association with severe multisystem inflammatory disease manifestations.
ANAs target a wide array of nuclear macromolecules and can mediate disease by the formation of immune
complexes that deposit in the tissue to promote inflammation and damage; these complexes can also stimulate
the production of cytokines including type 1 interferon to drive generalized immune system disturbances.
Among ANAs forming immune complexes, antibodies to DNA (anti-DNA) are the serological hallmark of SLE
and markers of diagnosis and prognosis. These antibodies bind to both single and double stranded DNA and
form immune complexes that deposit in the tissue, especially the kidney, to promote inflammation; in addition,
these immune complexes can stimulate the production of cytokines by plasmacytoid dendritic cells, triggering
internal sensors of DNA. While the properties of anti-DNA antibodies have been extensively studied, much
less is known about the origin of antigenic DNA, its access to the immune system and its unique molecular
properties. In general, the source of this DNA has been considered to be nuclear in origin and the product of
dead and dying cells. Our studies have provided a new perspective on this issue by demonstrating two
important features of extracellular DNA: 1) its existence in the form of microparticles and 2) the presence in
these particles of mitochondrial (mt) as well as nuclear DNA (nDNA). This presence of mtDNA is important
since mtDNA is intrinsically immunostimulatory because of structural features that differ from those of nDNA.
These involve CpG motifs in mtDNA, a consequence of the origin of mitochondria from bacteria, and oxidation
of guanosine residues. Furthermore, we have shown that mitochondria released from cells have properties
similar to those of microparticles, suggesting that mitochondria may serve as self-antigens in lupus,
contributing to immune activities attributed to microparticles and providing a nidus for immune complex
formation. Building on preliminary work, the proposed studies will focus on three main hypotheses: 1) DNA
autoantigen can be released from cells undergoing various death forms and exist in both a free and particle
form; 2) the metabolism of DNA during cell death influences the amount in the blood, its size and its
representation in particle or soluble form; and 3) anti-DNA antibodies can bind to various antigenic forms of
DNA, both free and particulate, with assay of antibodies to these forms providing more informative biomarkers.
We will pursue three specific aims. Specific Aim 1: To determine the extracellular release of cellular DNA
during different forms of in vitro cell death. We will induce different forms of cell death in cell lines in vitro and
determine the representation of mtDNA and nDNA in soluble and particulate forms; Specific Aim 2. To use in
vi...

## Key facts

- **NIH application ID:** 10265341
- **Project number:** 5I01BX003772-04
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** DAVID STEPHEN PISETSKY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265341

## Citation

> US National Institutes of Health, RePORTER application 10265341, Cellular Sources of Self Antigen in SLE (5I01BX003772-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10265341. Licensed CC0.

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