# Collaborative  Project

> **NIH NIH U19** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $113,708

## Abstract

ABSTRACT Collaborative Project; PI – Lyden, D.
Systemic autoimmune diseases are heterogeneous both clinically and molecularly. Among them, systemic
lupus erythematosus (SLE) is relatively frequent, affecting ~1:5000 people, with a higher prevalence in
women. Lupus phenotypes are heterogeneous, but robust biomarkers that predict SLE progression, organ
involvement and response to treatment are lacking. One of the fundamental criteria for SLE diagnosis is the
presence of anti-nuclear antibodies (ANA), which comprise nucleic acids as well as proteins. Lupus presents
as an interferonopathy, though IL1-b activation is also broadly observed. Given the central role of ANA in
activating and propagating chronic IFN responses, understanding the sources of immunogenic DNA and
mechanisms of IFN activation are critical. Despite their great clinical relevance major questions remain
including how anti-DNA responses are prevented in healthy individuals, whether differences in structure or
levels of DNA are responsible for immunogenicity in SLE and potentially other SAD, and how these
mechanisms could be exploited for therapeutic purposes. We have recently discovered that activated T cell-
derived exosomes (ATexo) carry large amounts of double stranded DNA complexed with histones (exoDNA),
and that ATexo are efficient activators of IFN responses in a DNA-dependent manner. Thus, we hypothesize
that, in SAD patients (SLE, scleroderma), due to anti-DNAse antibodies and DNASE1, DNASE1L3 mutations,
combined with chronic T and B, plasma cell activation and expansion, the amount of circulating exoDNA
exceeds DNA-degrading capacity and DNA-laden exosomes accumulate, chronically activating anti-DNA
responses and leading to chronic inflammation. We propose to isolate and characterize DNA and protein
cargo of T and B cells from healthy controls and SAD subjects, defining the function of activated T, B cell and
plasma cell exoDNA in activating anti-DNA responses in antigen presenting cells and identifying the enzymes
controlling circulating exoDNA levels. Testing this hypothesis will provide a systems-level understanding of
relationships between the clinical, molecular, and functional heterogeneity in SLE and other SADs. By profiling
the cargo of adaptive immune cell exosomes, and investigating, for the first time, the roles of activated immune
cell-derived exoDNA in driving SAD chronic inflammation, these studies will help dissect the pathogenic
mechanisms of the disease and designing novel, personalized treatments. Since exosomes reflect the
systemic status of a disease, and, unlike circulating immune cells, can reflect pathologies associated with
distant organs, often before these changes can be detected by other approaches, they are the ideal biomarker
candidate for heterogeneous, multifactorial, systemic diseases such as autoimmune diseases in general and
SLE in particular.

## Key facts

- **NIH application ID:** 10845042
- **Project number:** 2U19AI144301-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** DAVID CHARLES LYDEN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $113,708
- **Award type:** 2
- **Project period:** 2019-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845042

## Citation

> US National Institutes of Health, RePORTER application 10845042, Collaborative  Project (2U19AI144301-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10845042. Licensed CC0.

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