# Transcription factor A mitochondria in SLE pathogenesis

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2022 · $245,625

## Abstract

PROJECT SUMMARY/ABSTRACT
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by sterile inflammation and high
titer antibodies against self-antigens. Although the etiology of SLE is still unknown, cumulative evidence suggest
that interferons (IFNs) might play a critical role in disease pathogenesis, likely with type I IFN (IFN-I) as the
dominant mediator. While different mechanisms may dysregulate the production of IFN-I in SLE, studies for the
last 20 years have been focused on immune complexes (ICs) containing genomic DNA and RNA–protein (RNP)
complexes as critical players in TLR activation and the induction of IFN-I by plasmacytoid dendritic cells (pDCs).
Recent paradigm shifting data, however, suggest that the mitochondria is an important source of interferogenic
signals in SLE. In particular, upon activation with TLR7-agonist autoantibodies, SLE neutrophils release oxidized
(Ox) mitochondrial DNA (mtDNA) in complex with transcription factor A mitochondria (TFAM), which together
have an exceptional capacity to activate pDCs to produce IFN-I via TLR9 activation. Yet, mechanisms that
modulate the delivery of Ox-mtDNA/TFAM complexes into TLR9 endosomes in SLE are not fully understood.
Interestingly, our preliminary studies demonstrate for the first time that patients with SLE have autoantibodies to
TFAM. Based on this premise, we hypothesize that anti-TFAM antibodies may facilitate the internalization and
interferogenic response to Ox-mtDNA/TFAM complexes by pDCs, which may influence disease activity in SLE.
The major goal of this proposal is to gain further insights into the potential significance of these novel hypotheses
and preliminary findings in the context of SLE pathogenesis. In Aim 1, we will determine the prevalence and
clinical associations of antibodies to TFAM and their relationship to the IFN-signature in a prospective
observational cohort of patients with SLE, for which extensive clinical and serologic data is available, as well as
IFN-induced gene expression analysis. In Aim 2, we will generate anti-TFAM monoclonal antibodies from single
SLE anti-TFAM memory B cells to define their autoreactive origin [e.g. V(D)J usage, somatic hypermutations
and determinants of antigen recognition], as well as their capacity and mechanism to activate pDCs in complex
with Ox-mtDNA/TFAM. Together, these studies seek to enhance our understanding of self-immunogenic
pathways underlying sterile inflammation and IFN production 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:** 10467330
- **Project number:** 1R21AI169851-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Felipe Andrade
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $245,625
- **Award type:** 1
- **Project period:** 2022-02-22 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467330

## Citation

> US National Institutes of Health, RePORTER application 10467330, Transcription factor A mitochondria in SLE pathogenesis (1R21AI169851-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10467330. Licensed CC0.

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