# Mechanisms of altered T cell epigenetics in lupus

> **NIH NIH R56** · UNIVERSITY OF PENNSYLVANIA · 2022 · $406,250

## Abstract

PROJECT
SUMMARY
Lupus
lead
is an autoimmune disease in which environmental effects acting within a permissive genetic background
to immune dysregulation.Dysfunction of multiple cell types is associated with production of anti-nuclear
autoantibodies (ANA), generation of immune complexes, and tissue damage. Genome wide association
studies have identified >100 susceptibility loci that contribute to disease; however, the cellular mechanisms
through which these polymorphisms lead to cellular dysfunction are unknown. Accumulating evidence
suggests that genetic susceptibility to lupus is mediated via cell-specific epigenetic changes altering
transcriptional profiles. Inpreliminary experiments, we identified alupus-specific epigenetic and
transcriptional signature in naïve and effector CD4+ T cells. We find that: 1) the epigenetic
and
segregates
and
identified
susceptibility,
milieu
cells;
enriched
together,
immunologic
landscape of naive
activated CD4+ T cells i s significantly different in patients with lupus as compared with healthy donors and
by disease; 2) A significant number of OCRs of CD4+ T cells in lupus are present in naïve T cells
precede T cell activation; 3) The lupus-specific OCRs disproportionately align with susceptibility alleles
in GWAS analyses of lupus . Epigenetic hanges could be cell-intrinsic, secondary to genetic
and precede clinical presentation or cell-extrinsic and induced by the abnormal immunologic
of lupus Intrinsic pathways are suggested by the presence of a disease-specific pathway in naïve T
extrinsic effects of inflammation are suggested by analyses showing t hat the lupus-specific signature is
in NF-kB-dependent DNA-binding motifs downstream of signaling via TNF family members. Taken
our data lead us to hypothesize that genetic predisposition to l upus cooperates with the lupus
environment to alter the epigenome of hematopoietic cells prior to activation.
c
.
First, we will probe
the hypothesis that the open epigenetic landscape that characterizes lupus is cell intrinsic and precedes
disease. We will define the minimal hematopoietic lupus signature by characterizing the epigenome of resting
B cells and monocytes. We will perform a cross sectional analysis of patients and their healthy first degree
relatives to define the lupus-specific epigenetic modules that precede disease. Secondly, we will define the
effect of TNF family members on the epigenetic landscape by manipulating cytokines in in vitro assays. We
will then examine CD4 + T cells in patients treated with TNF blockade to directly define a TNF-dependent
epigenetic signature. Finally, we have utilized bioinformatic approaches to generate disease-specific
enrichment scores for multiple pathways, including TNF-dependent signaling and the Type I interferon
pathway. With this information, we will determine the relationship between clinical disease and epigenetic
changes at a level of detail that has not been previously possible. Our findings will lead to basic insig...

## Key facts

- **NIH application ID:** 10536870
- **Project number:** 1R56AI165769-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** TERRI M. LAUFER
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $406,250
- **Award type:** 1
- **Project period:** 2022-01-19 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536870

## Citation

> US National Institutes of Health, RePORTER application 10536870, Mechanisms of altered T cell epigenetics in lupus (1R56AI165769-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10536870. Licensed CC0.

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