# LINE1-ORF0 in SLE pathogenesis

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2024 · $204,688

## Abstract

PROJECT SUMMARY/ABSTRACT
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by sustained
interferon (IFN) signaling and high titer autoantibodies leading to immune-mediated tissue damage. An abnormal
accumulation of nucleic acids derived from retrotransposons, a class of transposable element, has been linked
to diseases characterized by sustained IFN-I production, such as SLE. In particular, retrotransposons of the non-
LTR LINE1 (L1) family have been shown to be activated in patients with SLE. More recently, it was found that
the RNA-binding protein (ORF1p) and the ORF2p endonuclease/reverse transcriptase encoded by L1s are SLE
autoantigens, supporting the notion that L1 elements may play a role in SLE pathogenesis. This proposal is
focused on the study of a recently discovered antisense open reading frame (ORF) found in the L1 5’UTR,
termed ORF0. ORF0 encodes for a small nuclear protein (ORF0p) of 71 amino acid residues, which increases
L1 mobility. ORF0 has several unique features, which may have critical implications on the potential mechanistic
role of L1s in SLE pathogenesis. First, the number of ORF0 loci capable of encoding full-length ORF0p (~781
loci) is ~8-10 times higher than ORF1 and ORF2 (~80–100 active copies). Thus, in the setting of L1 activation,
such as in SLE, it is expected that the antigenic load of ORF0p would be more robust than ORF1p and ORF2p.
Second, ORF0 has two prominent splice donor sites that act in concert with splice acceptors in downstream
genomic sequences, generating ORF0p-fusion proteins. This is, the N-terminus of the “host” protein would be
replaced by the ORF0p N-terminal sequence, producing hybrid proteins. Based on this premise, our central
hypothesis is that L1 activation in SLE leads to ORF0 dysregulation, which drives the production of anti-ORF0p
antibodies and an abnormal expression of hybrid ORF0p-fusion proteins, generating neoantigens targeted in
SLE. Indeed, our preliminary studies demonstrate that ORF0p is an autoantigen in SLE. The major goal of this
exploratory/developmental research grant is to investigate the clinical significance of anti-ORF0p antibodies in
SLE and to address the hypothesis that patients with SLE have an abnormal production of ORF0p-host fusion
proteins containing lupus autoantigens.

## Key facts

- **NIH application ID:** 10778627
- **Project number:** 5R21AI176766-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Felipe Andrade
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $204,688
- **Award type:** 5
- **Project period:** 2023-02-06 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10778627

## Citation

> US National Institutes of Health, RePORTER application 10778627, LINE1-ORF0 in SLE pathogenesis (5R21AI176766-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10778627. Licensed CC0.

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