# The antigenic origin of anti-dsDNA antibodies in SLE

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $245,625

## Abstract

PROJECT SUMMARY/ABSTRACT
Anti-dsDNA antibodies are serological hallmarks of systemic lupus erythematosus (SLE), and key markers for
diagnosis and disease activity. The close association of anti-dsDNA antibodies with SLE has suggested that
understanding the origin of these antibodies would reveal key mechanisms in SLE pathogenesis. Nonetheless,
while anti-dsDNA antibodies are likely the best-characterized autoantibodies at the genetic and molecular level,
their antigenic origin and mechanisms of pathogenicity remain unclear. To date, the conclusion from previous
studies is that anti-dsDNA antibodies in SLE originate from non-reactive precursors, which undergone affinity
maturation against dsDNA as the primary antigen. Different to this paradigm, our preliminary studies suggest an
alternative hypothesis in which anti-dsDNA antibodies are cross-reactive antibodies that originate from germline
precursors targeting a protein self-antigen, and that cross-reactivity to dsDNA results from somatic
hypermutation. Because gaining reactivity to dsDNA has little or no effect on reactivity to the original protein
antigen, this process creates cross-reactive autoantibodies with the functional capacity to target the protein and
bind dsDNA with high affinity. As a model, this new paradigm offers a rational explanation for the high
heterogeneity of anti-dsDNA antibodies in terms of origin, physicochemical and pathogenic properties. To
address this novel hypothesis, we will define the extended antigen specificity of a large set of mutated and
germline reverted SLE-derived monoclonal anti-dsDNA antibodies using a human proteome microarray platform.
The goal is to uncover both the primary specificities that preceded the origin of anti-dsDNA antibodies, and the
protein targets that may determine their pathogenic effect in SLE. The final goal of this work is to gain new
insights into disease mechanisms, thus laying the foundation to explore novel therapies.

## Key facts

- **NIH application ID:** 10889736
- **Project number:** 1R21AI183329-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Felipe Andrade
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $245,625
- **Award type:** 1
- **Project period:** 2024-02-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889736

## Citation

> US National Institutes of Health, RePORTER application 10889736, The antigenic origin of anti-dsDNA antibodies in SLE (1R21AI183329-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10889736. Licensed CC0.

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