# Unraveling the molecular mechanisms of impaired central tolerance in COPA syndrome

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $690,613

## Abstract

PROJECT SUMMARY:
 Our lab discovered COPA syndrome, a monogenic autoimmune disorder that involves inflammation of
the lungs, joints and kidneys. We established a mouse model of COPA syndrome by generating CopaE241K/+
knock-in mice that spontaneously developed clinical and immunologic features of patients, including interstitial
lung disease (ILD) and increased levels of activated, cytokine-secreting T cells. We performed bone marrow
chimera and thymic transplant experiments to reveal that expression of mutant COPA in the thymic stroma is
sufficient to cause a defect in negative selection of CD4+ T cells. Our work revealed that a key step in the initiation
of disease in COPA syndrome is a breakdown in central tolerance. The goal of this grant is to unravel the
mechanisms by which mutant COPA causes impaired thymic tolerance.
 COPA syndrome presents in childhood with inflammatory arthritis of the small and large joints and lung
disease that manifests as pulmonary capillaritis or ILD. Patients develop clinical features that are observed in
systemic lupus erythematosus (SLE) including high-titer anti-nuclear antibodies, autoantibodies to double
stranded DNA and immune complex glomerulonephritis. In addition, peripheral blood mononuclear cells from all
COPA syndrome subjects exhibit a markedly elevated type I interferon stimulated gene signature, a hallmark of
SLE. We recently demonstrated that activation of type I interferon (IFN) signaling in COPA syndrome is caused
by constitutive activation of the innate immune adapter molecule STING, which is missorted at the Golgi by
mutant COPA. Mutant COPA-mediated STING activation upregulates IFNs in immune cells of CopaE241K/+ mice,
and remarkably, also within the thymic epithelium. Taken together, this suggests STING has a functional role in
the thymus with the potential to alter thymocyte selection and/or development. We hypothesize mutant COPA
breaks central tolerance by causing activation of STING in thymic epithelial cells (TEC).
 We will use our mouse model to determine how activated STING in thymic epithelial cells alters T cell
maturation and selection. We will define the cellular and molecular mechanisms by which mutant COPA impairs
autophagic flux and determine whether proteins missorted by mutant COPA are involved in STING-induced
autophagy. Finally, we will test whether small molecule STING agonists and inhibitors can fine-tune STING
signaling in the thymus to alter thymocyte development and selection. Taken together, our work provides new
insight into how activated STING in the thymus shapes the T cell repertoire to cause autoimmunity and
immune dysregulation. These findings have important implications for settings in which systemic inflammation
causes activation of STING in the thymic stroma including cancer therapy and infections.

## Key facts

- **NIH application ID:** 10423686
- **Project number:** 1R01AI168299-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Anthony Shum
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $690,613
- **Award type:** 1
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10423686

## Citation

> US National Institutes of Health, RePORTER application 10423686, Unraveling the molecular mechanisms of impaired central tolerance in COPA syndrome (1R01AI168299-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10423686. Licensed CC0.

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